45 results on '"Bruno Derudas"'
Search Results
2. Time-of-day-dependent variation of the human liver transcriptome and metabolome is disrupted in MASLD
- Author
-
Manuel Johanns, Joel T. Haas, Violetta Raverdy, Jimmy Vandel, Julie Chevalier-Dubois, Loic Guille, Bruno Derudas, Benjamin Legendre, Robert Caiazzo, Helene Verkindt, Viviane Gnemmi, Emmanuelle Leteurtre, Mehdi Derhourhi, Amélie Bonnefond, Philippe Froguel, Jérôme Eeckhoute, Guillaume Lassailly, Philippe Mathurin, François Pattou, Bart Staels, and Philippe Lefebvre
- Subjects
Liver homeostasis ,daytime rhythmicity ,gene expression ,metabolomic ,transcriptomic ,NAFLD ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to MASLD progression in rodent models. We therefore investigated whether the time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers. Methods: Liver biopsies, collected within an 8 h-window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, steatotic or MASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, steatotic and MASH livers. Results: Herein, we provide a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in MASLD. Transcriptomic analysis showed a robustness of core molecular clock components in steatotic and MASH livers. It also revealed stage-specific, time-of-day-dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intracellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFα and PPARγ signaling were predicted as important contributors to altered rhythmicity. Conclusion: MASLD progression to MASH perturbs time-of-day-dependent processes in human livers, while the differential expression of core molecular clock components is maintained. Impact and implications: This work characterizes the rhythmic patterns of the transcriptome and metabolome in the human liver. Using a cohort of well-phenotyped patients (n = 290) for whom the time-of-day at biopsy collection was known, we show that time-of-day variations observed in histologically normal livers are gradually perturbed in liver steatosis and metabolic dysfunction-associated steatohepatitis. Importantly, these observations, albeit obtained across a restricted time window, provide further support for preclinical studies demonstrating alterations of rhythmic patterns in diseased livers. On a practical note, this study indicates the importance of considering time-of-day as a critical biological variable which may significantly affect data interpretation in animal and human studies of liver diseases.
- Published
- 2024
- Full Text
- View/download PDF
3. Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis
- Author
-
Hélène Dehondt, Arianna Marino, Laura Butruille, Denis A. Mogilenko, Arielle C. Nzoussi Loubota, Oscar Chávez-Talavera, Emilie Dorchies, Emmanuelle Vallez, Joel Haas, Bruno Derudas, Antonino Bongiovanni, Meryem Tardivel, Folkert Kuipers, Philippe Lefebvre, Sophie Lestavel, Anne Tailleux, David Dombrowicz, Sandrine Caron, and Bart Staels
- Subjects
White adipose tissue ,Nuclear receptor FXR ,Inflammation ,Oxidative stress ,Glucose metabolism ,Internal medicine ,RC31-1245 - Abstract
Objective: Obesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. The bile acid (BA)-activated nuclear Farnesoid X Receptor (FXR) controls systemic glucose and lipid metabolism. Here, we studied the role of FXR in adipose tissue function. Methods: We first investigated the immune phenotype of epididymal WAT (eWAT) from high fat diet (HFD)-fed whole-body FXR-deficient (FXR−/−) mice by flow cytometry and gene expression analysis. We then generated adipocyte-specific FXR-deficient (Ad-FXR−/−) mice and analyzed systemic and eWAT metabolism and immune phenotype upon HFD feeding. Transcriptomic analysis was done on mature eWAT adipocytes from HFD-fed Ad-FXR−/− mice. Results: eWAT from HFD-fed whole-body FXR−/− and Ad-FXR−/− mice displayed decreased pro-inflammatory macrophage infiltration and inflammation. Ad-FXR−/− mice showed lower blood glucose concentrations, improved systemic glucose tolerance and WAT insulin sensitivity and oxidative stress. Transcriptomic analysis identified Gsta4, a modulator of oxidative stress in WAT, as the most upregulated gene in Ad-FXR−/− mouse adipocytes. Finally, chromatin immunoprecipitation analysis showed that FXR binds the Gsta4 gene promoter. Conclusions: These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.
- Published
- 2023
- Full Text
- View/download PDF
4. Fingolimod treatment modulates PPARγ and CD36 gene expression in women with multiple sclerosis
- Author
-
Véronique Ferret-Sena, Carlos Capela, Ana Macedo, António Vasco Salgado, Bruno Derudas, Bart Staels, and Armando Sena
- Subjects
fingolimod ,peroxisome proliferator-activated receptors (PPAR) ,cluster of differentiation 36 (CD36) ,lipoproteins ,multiple sclerosis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Fingolimod is an oral immunomodulatory drug used in the treatment of multiple sclerosis (MS) that may change lipid metabolism. Peroxisome proliferator-activated receptors (PPAR) are transcription factors that regulate lipoprotein metabolism and immune functions and have been implicated in the pathophysiology of MS. CD36 is a scavenger receptor whose transcription is PPAR regulated. The objective of this study was to evaluate whether fingolimod treatment modifies PPAR and CD36 gene expression as part of its action mechanisms. Serum lipoprotein profiles and PPAR and CD36 gene expression levels in peripheral leukocytes were analysed in 17 female MS patients before and at 6 and 12 months after fingolimod treatment initiation. Clinical data during the follow-up period of treatment were obtained. We found that fingolimod treatment increased HDL-Cholesterol and Apolipoprotein E levels and leukocyte PPARγ and CD36 gene expression. No correlations were found between lipid levels and variations in PPARγ and CD36 gene expression. PPARγ and CD36 variations were significantly correlated during therapy and in patients free of relapse and stable disease. Our results suggest that PPARγ and CD36-mediated processes may contribute to the mechanisms of action of fingolimod in MS. Further studies are required to explore the relation of the PPARγ/CD36 pathway to the clinical efficacy of the drug and its involvement in the pathogenesis of the disease.
- Published
- 2022
- Full Text
- View/download PDF
5. Hepatic transcriptomic signatures of statin treatment are associated with impaired glucose homeostasis in severely obese patients
- Author
-
Daniel Margerie, Philippe Lefebvre, Violeta Raverdy, Uwe Schwahn, Hartmut Ruetten, Philip Larsen, Alain Duhamel, Julien Labreuche, Dorothée Thuillier, Bruno Derudas, Céline Gheeraert, Hélène Dehondt, Quentin Dhalluin, Jérémy Alexandre, Robert Caiazzo, Pamela Nesslany, Helene Verkindt, François Pattou, and Bart Staels
- Subjects
Statin ,Human ,Liver ,Iatrogenic diabetes ,Gene expression ,Gene networks ,Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown. Methods An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index (BMI) 46.7 (8.7), treated with or without statins (ABOS cohort: a biological atlas of severe obesity). Data and sample collection took place in France between 2006 and 2016. Transcriptomic signatures of statin treatment in human liver obtained from genome-wide transcriptomic profiling of five different statin drugs using microarrays were correlated to clinico-biological phenotypes and also assigned to biological pathways and mechanisms. Patients from the non-statin-users group were matched to patients in the statin users group by propensity score analysis to minimize confounding effects from age, gender, parental familial history of diabetes, BMI, waist circumference, systolic and diastolic blood pressure and use of anti-hypertensive drugs as pre-specified covariates. Results We determined the hepatic, statin-related gene signature from genome-wide transcriptomic profiling in severely obese patients with varying degrees of glucose tolerance and cardio-metabolic comorbidities. One hundred and fifty seven patients on statin treatment in the matched cohort showed higher diabetes prevalence (OR = 2.67; 95%CI, 1.60–4.45; P = 0.0002) and impairment of glucose homeostasis. This phenotype was associated with molecular signatures of increased hepatic de novo lipogenesis (DNL) via activation of sterol regulatory element-binding protein 1 (SREBP1) and concomitant upregulation of the expression of key genes in both fatty acid and triglyceride metabolism. Conclusions A DNL gene activation profile in response to statins is associated with insulin resistance and the diabetic status of the patients. Identified molecular signatures thus suggest that statin treatment increases the risk for diabetes in humans at least in part via induction of DNL. Trial registration NCT01129297. Registered May 242,010 (retrospectively registered).
- Published
- 2019
- Full Text
- View/download PDF
6. Natalizumab Treatment Modulates Peroxisome Proliferator-Activated Receptors Expression in Women with Multiple Sclerosis
- Author
-
Véronique Ferret-Sena, Alexandra Maia e Silva, Armando Sena, Inês Cavaleiro, José Vale, Bruno Derudas, Giulia Chinetti-Gbaguidi, and Bart Staels
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPARα, PPARβ/δ, PPARγ, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPARβ/δ mRNA (p=0.009) in comparison to baseline, while mRNA expression of PPARγ and CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls (p=0.026 and p=0.028, resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients (p=0.002) and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy.
- Published
- 2016
- Full Text
- View/download PDF
7. Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis
- Author
-
Fanny Lalloyer, Denis A. Mogilenko, Ann Verrijken, Joel T. Haas, Antonin Lamazière, Mostafa Kouach, Amandine Descat, Sandrine Caron, Emmanuelle Vallez, Bruno Derudas, Céline Gheeraert, Eric Baugé, Gaëtan Despres, Eveline Dirinck, Anne Tailleux, David Dombrowicz, Luc Van Gaal, Jerôme Eeckhoute, Philippe Lefebvre, Jean-François Goossens, Sven Francque, and Bart Staels
- Subjects
Hepatology - Published
- 2023
8. Time-of-day-dependent variation of the hepatic transcriptome and metabolome is disrupted in non-alcoholic fatty liver disease patients
- Author
-
Manuel Johanns, Joel T. Haas, Violetta Raverdy, Jimmy Vandel, Julie Chevalier-Dubois, Loic Guille, Bruno Derudas, Benjamin Legendre, Robert Caiazzo, Helene Verkindt, Viviane Gnemmi, Emmanuelle Leteurtre, Mehdi Derhourhi, Amélie Bonnefond, Philippe Froguel, Jérôme Eeckhoute, Guillaume Lassailly, Philippe Mathurin, François Pattou, Bart Staels, and Philippe Lefebvre
- Abstract
Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and clock disruption increases susceptibility to non-alcoholic fatty liver disease (NAFLD) progression in rodent models. We therefore investigated whether time-of-day-dependent transcriptome and metabolome are significantly altered in human NAFL and NASH livers. Liver biopsies, collected within an 8 hour- window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, NAFL or NASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, NAFL and NASH livers. We provide here a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in NAFLD. Transcriptomic analysis showed a robustness of core molecular clock components in NAFL and NASH livers. It also revealed stage-specific, time-of-day- dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intra- cellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFa and PPARγ signaling are predicted as important contributors to altered rhythmicity. NAFLD progression to NASH perturbs time-of-day-dependent processes in human livers, while core molecular clock component differential expression is maintained.
- Published
- 2023
9. Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride-rich lipoprotein metabolism
- Author
-
Audrey Deprince, Nathalie Hennuyer, Sander Kooijman, Amanda C. M. Pronk, Eric Baugé, Viktor Lienard, An Verrijken, Eveline Dirinck, Luisa Vonghia, Eloïse Woitrain, Niels J. Kloosterhuis, Eléonore Marez, Pauline Jacquemain, Justina C. Wolters, Fanny Lalloyer, Delphine Eberlé, Sandrine Quemener, Emmanuelle Vallez, Anne Tailleux, Mostafa Kouach, Jean‐Francois Goossens, Violeta Raverdy, Bruno Derudas, Jan Albert Kuivenhoven, Mikaël Croyal, Bart van de Sluis, Sven Francque, François Pattou, Patrick C. N. Rensen, Bart Staels, Joel T. Haas, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
Hepatology ,Human medicine - Abstract
Background: NAFLD affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis. Approach and Results: To identify liver-regulated pathways linking intrahepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic encoding apolipoprotein F (APOF) expression showed the fourth-strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic very low density lipoprotein (VLDL)-TG secretion and hepatic lipoprotein remnant clearance, associated a similar to 25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo, and reduced hepatocyte VLDL uptake by similar to 15% in vitro. Transcriptomic analysis of APOF-overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1, among others. Conclusion: These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance.
- Published
- 2022
10. Characterization of one anastomosis gastric bypass and impact of biliary and common limbs on bile acid and postprandial glucose metabolism in a minipig model
- Author
-
Audrey Quenon, Gregory Baud, Jean François Goossens, Blandine Laferrère, Mathilde Gobert, Oscar Chávez-Talavera, Anne Tailleux, Violeta Raverdy, François Pattou, Bart Staels, Vincent Vangelder, Valery Gmyr, Bruno Derudas, Emmanuelle Vallez, Amandine Descat, Thomas Hubert, Lorea Zubiaga, Sophie Lestavel, Mostafa Kouach, Mehdi Daoudi, Robert Caiazzo, Camille Marciniak, Andre Klein, and Pascal Pigny
- Subjects
Blood Glucose ,medicine.medical_specialty ,Swine ,Physiology ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Gastric bypass ,Gastric Bypass ,030209 endocrinology & metabolism ,Anastomosis ,Carbohydrate metabolism ,Bile Acids and Salts ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Weight loss ,Physiology (medical) ,Internal medicine ,Weight Loss ,medicine ,Animals ,Biliary Tract ,Common Bile Duct ,Bile acid ,business.industry ,Anastomosis, Surgical ,Postprandial Period ,Obesity, Morbid ,body regions ,Biliary Tract Surgical Procedures ,Glucose ,Postprandial ,Endocrinology ,Models, Animal ,Swine, Miniature ,Female ,030211 gastroenterology & hepatology ,sense organs ,medicine.symptom ,business ,Research Article - Abstract
The alimentary limb has been proposed to be a key driver of the weight-loss-independent metabolic improvements that occur upon bariatric surgery. However, the one anastomosis gastric bypass (OAGB) procedure, consisting of one long biliary limb and a short common limb, induces similar beneficial metabolic effects compared to Roux-en-Y Gastric Bypass (RYGB) in humans, despite the lack of an alimentary limb. The aim of this study was to assess the role of the length of biliary and common limbs in the weight loss and metabolic effects that occur upon OAGB. OAGB and sham surgery, with or without modifications of the length of either the biliary limb or the common limb, were performed in Gottingen minipigs. Weight loss, metabolic changes, and the effects on plasma and intestinal bile acids (BAs) were assessed 15 days after surgery. OAGB significantly decreased body weight, improved glucose homeostasis, increased postprandial GLP-1 and fasting plasma BAs, and qualitatively changed the intestinal BA species composition. Resection of the biliary limb prevented the body weight loss effects of OAGB and attenuated the postprandial GLP-1 increase. Improvements in glucose homeostasis along with changes in plasma and intestinal BAs occurred after OAGB regardless of the biliary limb length. Resection of only the common limb reproduced the glucose homeostasis effects and the changes in intestinal BAs. Our results suggest that the changes in glucose metabolism and BAs after OAGB are mainly mediated by the length of the common limb, whereas the length of the biliary limb contributes to body weight loss. NEW & NOTEWORTHY Common limb mediates postprandial glucose metabolism change after gastric bypass whereas biliary limb contributes to weight loss.
- Published
- 2021
11. IFNγ-producing NK cells in adipose tissue are associated with hyperglycemia and insulin resistance in obese women: Adipose IFNγ-producing NK cells in obesity
- Author
-
Violeta Raverdy, François Pattou, Laurent L'Homme, Laurent Pineau, David Dombrowicz, R. Caiazzo, Denis A. Mogilenko, Bruno Derudas, Bart Staels, Jerome Noulette, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), and Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD)
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,Medicine (miscellaneous) ,Adipose tissue ,030209 endocrinology & metabolism ,Inflammation ,Biology ,Intra-Abdominal Fat ,03 medical and health sciences ,chemistry.chemical_compound ,Interferon-gamma ,Young Adult ,0302 clinical medicine ,Insulin resistance ,Immune system ,Internal medicine ,Adipocyte ,medicine ,Humans ,030212 general & internal medicine ,Cells, Cultured ,Nutrition and Dietetics ,Innate lymphoid cell ,Middle Aged ,medicine.disease ,3. Good health ,Obesity, Morbid ,Killer Cells, Natural ,Endocrinology ,chemistry ,Hyperglycemia ,Female ,medicine.symptom ,Insulin Resistance ,Cell activation ,CD8 - Abstract
International audience; Background/Objectives: Innate lymphoid cells (ILCs) play an important role in the maintenance of immune and metabolic homeostasis in adipose tissue (AT). The crosstalk between AT ILCs and adipocytes and other immune cells coordinates adipocyte differentiation, beiging, glucose metabolism and inflammation. Although the metabolic and homeostatic functions of mouse ILCs have been extensively investigated, little is known about human adipose ILCs and their roles in obesity and insulin resistance (IR). Subjects/Methods: Here we characterized T and NK cell populations in omental AT (OAT) from women (n=18) with morbid obesity and varying levels of IR and performed an integrated analysis of metabolic parameters and adipose tissue transcriptomics. Results: In OAT, we found a distinct population of CD56-NKp46 + EOMES + NK cells characterized by expression of cytotoxic molecules, pro-inflammatory cytokines, and markers of cell activation. AT IFNγ + NK cells, but not CD4, CD8 or γδ T cells, were positively associated with glucose levels, glycated hemoglobin (HbA1c) and IR. AT NK cells were linked to a pro-inflammatory gene expression profile in AT and developed an effector phenotype in response to IL-12 and IL-15. Moreover, integrated transcriptomic analysis revealed a potential implication of AT IFNγ + NK cells in controlling adipose tissue inflammation, remodeling, and lipid metabolism. Conclusions: Our results suggest that a distinct IFNγ−producing NK cell subset is involved in metabolic homeostasis in visceral AT in humans with obesity and may be a potential target for therapy of IR.
- Published
- 2021
12. A targeted multi-omics approach reveals paraoxonase-1 as a determinant of obesity-associated fatty liver disease
- Author
-
An Verrijken, Wim Vanden Berghe, Bart Cuypers, Luc Van Gaal, Asta Tvarijonaviciute, Bruno Derudas, Philippe Lefebvre, José J. Cerón, Evelien Van Dijck, Kris Laukens, Wim Van Hul, Sara Diels, and Sven Francque
- Subjects
Adult ,Male ,Candidate gene ,Adolescent ,Disease ,Biology ,Bioinformatics ,Methylation ,Epigenesis, Genetic ,Liver disease ,Young Adult ,Non-alcoholic Fatty Liver Disease ,NAFLD ,medicine ,Genetics ,Humans ,Genetic Predisposition to Disease ,Epigenetics ,Obesity ,PON1 ,Molecular Biology ,Genetics (clinical) ,Aged ,Computer. Automation ,medicine.diagnostic_test ,Aryldialkylphosphatase ,Research ,Integrative analysis ,Fatty liver ,DNA Methylation ,Middle Aged ,medicine.disease ,Human genetics ,Liver biopsy ,DNA methylation ,Female ,Omics ,Human medicine ,Developmental Biology - Abstract
Background The multifactorial nature of non-alcoholic fatty liver disease cannot be explained solely by genetic factors. Recent evidence revealed that DNA methylation changes take place at proximal promoters within susceptibility genes. This emphasizes the need for integrating multiple data types to provide a better understanding of the disease’s pathogenesis. One such candidate gene is paraoxonase-1 (PON1). Substantial interindividual differences in PON1 are apparent and could influence disease risk later in life. The aim of this study was therefore to determine the different regulatory aspects of PON1 variability and to examine them in relation to the predisposition to obesity-associated fatty liver disease. Results A targeted multi-omics approach was applied to investigate the interplay between PON1 genetic variants, promoter methylation, expression profile and enzymatic activity in an adult patient cohort with extensive metabolic and hepatic characterisation including liver biopsy. Alterations in PON1 status were shown to correlate with waist-to-hip ratio and relevant features of liver pathology. Particularly, the regulatory polymorphism rs705379:C > T was strongly associated with more severe liver disease. Multivariable data analysis furthermore indicated a significant association of combined genetic and epigenetic PON1 regulation. This identified relationship postulates a role for DNA methylation as a mediator between PON1 genetics and expression, which is believed to further influence liver disease progression via modifications in PON1 catalytic efficiency. Conclusions Our findings demonstrate that vertical data-integration of genetic and epigenetic regulatory mechanisms generated a more in-depth understanding of the molecular basis underlying the development of obesity-associated fatty liver disease. We gained novel insights into how NAFLD classification and outcome are orchestrated, which could not have been obtained by exclusively considering genetic variation.
- Published
- 2021
13. Transcriptional Network Analysis Implicates Altered Hepatic Immune Function in NASH development and resolution
- Author
-
Audrey Deprince, David Dombrowicz, Artemii Nikitin, Bart Staels, Ann Driessen, Sébastien Fleury, An Verrijken, Denis A. Mogilenko, Hélène Dehondt, Samuel Pic, Luisa Vonghia, Bruno Derudas, Sven Francque, Joel T. Haas, Philippe Lefebvre, Luc Van Gaal, Olivier Molendi-Coste, Céline Gheeraert, Lucie Ducrocq-Geoffroy, Eloise Woitrain, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Gastroenterology and Hepatology [Antwerp, Belgium], Antwerp University Hospital [Edegem] (UZA), Department of Endocrinology, Diabetology and Metabolism [Antwerp, Belgium], Department of Pathology [Antwerp, Belgium], ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Derudas, Marie-Hélène, and Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID
- Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology ,Transcription, Genetic ,Endocrinology, Diabetes and Metabolism ,Antigen presentation ,Inflammation ,Biology ,Diet, High-Fat ,digestive system ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Non-alcoholic Fatty Liver Disease ,Physiology (medical) ,Internal Medicine ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Gene Regulatory Networks ,030304 developmental biology ,[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,0303 health sciences ,Microarray analysis techniques ,Fatty liver ,nutritional and metabolic diseases ,Cell Biology ,Gene signature ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,medicine.disease ,digestive system diseases ,3. Good health ,Mice, Inbred C57BL ,Liver ,Cancer research ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,030211 gastroenterology & hepatology ,Human medicine ,Steatohepatitis ,medicine.symptom - Abstract
Luisa Vonghia and David Dombrowicz equally contributed to the work.; International audience; Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health problem. The presence of inflammatory infiltrates in the liver and hepatocyte damage distinguish NASH from simple steatosis. However, the underlying molecular mechanisms involved in the development of NASH remain to be fully understood. Here we perform transcriptional and immune profiling of patients with NASH before and after lifestyle intervention (LSI). Analysis of liver microarray data from a cohort of patients with histologically assessed non-alcoholic fatty liver disease (NAFLD) reveals a hepatic gene signature, which is associated with NASH and is sensitive to regression of NASH activity on LSI independently of body weight loss. Enrichment analysis reveals the presence of immune-associated genes linked to inflammatory responses, antigen presentation and cytotoxic cells in the NASH-linked gene signature. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDC) type 1 and 2, and cytotoxic CD8 T cells. Lobular inflammation and ballooning are associated with the accumulation of CD8 T cells in the liver. Progression from simple steatosis to NASH in a mouse model of diet-driven NASH results in a comparable immune-related hepatic expression signature and the accumulation of intrahepatic cDC and CD8 T cells. These results show that NASH, compared to normal liver or simple steatosis, is associated with a distinct hepatic immune-related gene signature, elevated hepatic CD8 T cells, and altered antigen-presenting and cytotoxic cells in blood. These findings expand our understanding of NASH and may identify potential targets for NASH therapy.
- Published
- 2019
14. Hepatic PPARα is critical in the metabolic adaptation to sepsis
- Author
-
Nathalie Hennuyer, Bruno Derudas, Fanny Lalloyer, Céline Gheeraert, Vanessa Legry, Emmanuelle Vallez, Emmanuel Bouchaert, Hélène Dehondt, Bart Staels, Yann Deleye, Dieter Mesotten, Steve Lancel, Greet Van den Berghe, Céline Cudejko, Hervé Guillou, Réjane Paumelle, Sébastien Fleury, Alexandra Montagner, Kristiaan Wouters, Anne Tailleux, Joel T. Haas, Lies Langouche, Jonathan Vanhoutte, Eric Baugé, Pierre Gourdy, David Dombrowicz, Sarra Smati, Walter Wahli, Arnaud Polizzi, Sarah Anissa Hannou, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Intensive care Medicine, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Maastricht University [Maastricht], Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Nanyang Technological University [Singapour], Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Derudas, Marie-Hélène, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Interne Geneeskunde, RS: CARIM - R3 - Vascular biology, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, and Lee Kong Chian School of Medicine (LKCMedicine)
- Subjects
0301 basic medicine ,BACTERIAL ,Peroxisome proliferator-activated receptor ,nuclear receptors ,PROTECTS ,sepsis ,Mice ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Nuclear receptors ,Ketogenesis ,GENE-EXPRESSION ,chemistry.chemical_classification ,Fatty Acids ,INTENSIVE INSULIN THERAPY ,Bacterial Infections ,Adaptation, Physiological ,3. Good health ,Liver ,SURVIVAL ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,030211 gastroenterology & hepatology ,lipids (amino acids, peptides, and proteins) ,hepatocytes ,medicine.symptom ,medicine.medical_specialty ,FATTY-ACID OXIDATION ,Inflammation ,Article ,Sepsis ,03 medical and health sciences ,Internal medicine ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Animals ,Humans ,Medicine [Science] ,PPAR alpha ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,TOLERANCE ,Hepatology ,business.industry ,Lipid metabolism ,Lipid signaling ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Glucose ,Metabolism ,chemistry ,PROLIFERATOR-ACTIVATED RECEPTORS ,inflammation ,Metabolic control analysis ,Hepatocytes ,Steatosis ,business ,metabolism - Abstract
Background & Aims: Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)alpha, which controls both lipid metabolism and inflammation. We aimed to elucidate the previously unknown role of hepatic PPAR alpha in the response to sepsis.Methods: Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific PPAR alpha-deficiency and their controls. The systemic and hepatic metabolic response was analyzed using biochemical, transcriptomic and functional assays. PPAR alpha expression was analyzed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters.Results: Both whole body and non-hematopoietic PPAR alpha-deficiency in mice decreased survival upon bacterial infection. Livers of septic PPAR alpha-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPAR alpha impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPAR alpha expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers.Conclusion: During sepsis, PPAR alpha-deficiency in hepatocytes is deleterious as it impairs the adaptive metabolic shift from glucose to FA utilization. Metabolic control by PPAR alpha in hepatocytes plays a key role in the host defense against infection.Lay summary: As the main cause of death in critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have mostly been overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPAR alpha in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
- Published
- 2019
15. Transducin-like enhancer of split-1 is expressed and functional in human macrophages
- Author
-
Manjula Vinod, Corinne Copin, Giulia Chinetti-Gbaguidi, Stéphan Haulon, Bart Staels, Sophie Susen, Bruno Derudas, Christophe Zawadzki, Jonathan Vanhoutte, Federica De Paoli, François Pattou, and Jérôme Eeckhoute
- Subjects
Male ,0301 basic medicine ,Mice, 129 Strain ,Adipose tissue macrophages ,Biophysics ,Macrophage polarization ,Bone Marrow Cells ,Inflammation ,Intra-Abdominal Fat ,Biology ,Biochemistry ,Body Mass Index ,Proinflammatory cytokine ,03 medical and health sciences ,Structural Biology ,Genetics ,medicine ,Animals ,Humans ,Obesity ,Enhancer ,Molecular Biology ,Cells, Cultured ,Interleukin 4 ,Macrophages ,Cell Biology ,Macrophage Activation ,Molecular biology ,Plaque, Atherosclerotic ,Recombinant Proteins ,Interleukin-10 ,Repressor Proteins ,Interleukin 1 Receptor Antagonist Protein ,Interleukin 10 ,030104 developmental biology ,Gene Expression Regulation ,Female ,RNA Interference ,Tumor necrosis factor alpha ,Interleukin-4 ,medicine.symptom ,Co-Repressor Proteins ,Biomarkers - Abstract
Macrophages display heterogeneous phenotypes, including the classical M1 proinflammatory and the alternative M2 anti-inflammatory polarization states. The transducin-like enhancer of split-1 (TLE1) is a transcriptional corepressor whose functions in macrophages have not been studied yet. We report that TLE1 is highly expressed in human alternative macrophages in vitro and in atherosclerotic plaques as well as in adipose tissue M1/M2 mixed macrophages. TLE1 silencing in alternative macrophages decreases the expression of the M2 markers IL-1Ra and IL-10, while it exacerbates TNFα and CCL3 induction by lipopolysaccharide. Hence, TLE1 is expressed in human macrophages where it has potential anti-inflammatory and alternative phenotype promoting properties.
- Published
- 2015
16. The RBM14/CoAA-interacting, long intergenic non-coding RNA Paral1 regulates adipogenesis and coactivates the nuclear receptor PPARγ
- Author
-
François F, Firmin, Frederik, Oger, Céline, Gheeraert, Julie, Dubois-Chevalier, Anne-Sophie, Vercoutter-Edouart, Fawaz, Alzaid, Claire, Mazuy, Hélène, Dehondt, Jeremy, Alexandre, Bruno, Derudas, Quentin, Dhalluin, Maheul, Ploton, Alexandre, Berthier, Eloise, Woitrain, Tony, Lefebvre, Nicolas, Venteclef, François, Pattou, Bart, Staels, Jérôme, Eeckhoute, Philippe, Lefebvre, Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Fédération de Recherche Biochimie Structurale et Fonctionnelle des Assemblages Biomoléculaires (FRABio - CNRS FR3688), Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Recherche translationelle sur le diabète (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut Européen de Génomique du Diabète - EGID, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Biochimie Structurale et Fonctionnelle des Assemblages Biomoléculaires - CNRS FR3688 (FRABio), Université de Lille-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Derudas, Marie-Hélène, and École Pratique des Hautes Études (EPHE)
- Subjects
Adult ,Transcription, Genetic ,[SDV]Life Sciences [q-bio] ,lcsh:Medicine ,Article ,Body Mass Index ,Mice ,Adipocytes ,Animals ,Humans ,Obesity ,lcsh:Science ,Cell Nucleus ,Inflammation ,Adipogenesis ,lcsh:R ,Intracellular Signaling Peptides and Proteins ,Mesenchymal Stem Cells ,3T3 Cells ,Middle Aged ,PPAR gamma ,[SDV] Life Sciences [q-bio] ,Disease Models, Animal ,Female ,RNA, Long Noncoding ,lcsh:Q ,Transcription Factors - Abstract
International audience; Adipocyte differentiation and function relies on a network of transcription factors, which is disrupted in obesity-associated low grade, chronic inflammation leading to adipose tissue dysfunction. In this context, there is a need for a thorough understanding of the transcriptional regulatory network involved in adipose tissue pathophysiology. Recent advances in the functional annotation of the genome has highlighted the role of non-coding RNAs in cellular differentiation processes in coordination with transcription factors. Using an unbiased genome-wide approach, we identified and characterized a novel long intergenic non-coding RNA (lincRNA) strongly induced during adipocyte differentiation. This lincRNA favors adipocyte differentiation and coactivates the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARγ) through interaction with the paraspeckle component and hnRNP-like RNA binding protein 14 (RBM14/NCoAA), and was therefore called PPARγ-activator RBM14-associated lncRNA (Paral1). Paral1 expression is restricted to adipocytes and decreased in humans with increasing body mass index. A decreased expression was also observed in diet-induced or genetic mouse models of obesity and this down-regulation was mimicked in vitro by TNF treatment. In conclusion, we have identified a novel component of the adipogenic transcriptional regulatory network defining the lincRNA Paral1 as an obesity-sensitive regulator of adipocyte differentiation and function.
- Published
- 2017
17. The tumour suppressor CDKN2A/p16(INK4a) regulates adipogenesis and bone marrow-dependent development of perivascular adipose tissue
- Author
-
Emmanuelle Vallez, Augustin Coisne, François Pattou, Casper G. Schalkwijk, Sarah Anissa Hannou, David Montaigne, Jonathan Vanhoutte, Réjane Paumelle, Bart Staels, Madjid Tagzirt, Emmanuel Bouchaert, Yann Deleye, Kristiaan Wouters, Christian Duhem, Xavier Marechal, Bruno Derudas, Interne Geneeskunde, RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, and MUMC+: DA KG Polikliniek (9)
- Subjects
0301 basic medicine ,medicine.medical_specialty ,FGF21 ,bone marrow ,POLARIZATION ,CDK4 ,Endocrinology, Diabetes and Metabolism ,Adipose tissue macrophages ,Adipose tissue ,White adipose tissue ,DISEASE ,adipogenesis ,03 medical and health sciences ,CDKN2A ,0302 clinical medicine ,Internal medicine ,Precursor cell ,perivascular adipose tissue ,Internal Medicine ,medicine ,LOCUS ,MACROPHAGES ,neoplasms ,2. Zero hunger ,business.industry ,PPAR-GAMMA ACTIVATION ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Adipogenesis ,030220 oncology & carcinogenesis ,CELLS ,Bone marrow ,Stem cell ,Cardiology and Cardiovascular Medicine ,business ,p16(INK4a) - Abstract
The genomic CDKN2A/B locus, encoding p16(INK4a) among others, is linked to an increased risk for cardiovascular disease and type 2 diabetes. Obesity is a risk factor for both cardiovascular disease and type 2 diabetes. p16(INK4a) is a cell cycle regulator and tumour suppressor. Whether it plays a role in adipose tissue formation is unknown. p16(INK4a) knock-down in 3T3/L1 preadipocytes or p16(INK4a) deficiency in mouse embryonic fibroblasts enhanced adipogenesis, suggesting a role for p16(INK4a) in adipose tissue formation. p16(INK4a)-deficient mice developed more epicardial adipose tissue in response to the adipogenic peroxisome proliferator activated receptor gamma agonist rosiglitazone. Additionally, adipose tissue around the aorta from p16(INK4a)-deficient mice displayed enhanced rosiglitazone-induced gene expression of adipogenic markers and stem cell antigen, a marker of bone marrow-derived precursor cells. Mice transplanted with p16(INK4a)-deficient bone marrow had more epicardial adipose tissue compared to controls when fed a high-fat diet. In humans, p16(INK4a) gene expression was enriched in epicardial adipose tissue compared to other adipose tissue depots. Moreover, epicardial adipose tissue from obese humans displayed increased expression of stem cell antigen compared to lean controls, supporting a bone marrow origin of epicardial adipose tissue. These results show that p16(INK4a) modulates epicardial adipose tissue development, providing a potential mechanistic link between the genetic association of the CDKN2A/B locus and cardiovascular disease risk.
- Published
- 2017
18. PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis
- Author
-
Réjane Paumelle, Bruno Derudas, Janne Prawitt, Luc Van Gaal, Wim Van Hul, Bart Staels, Peter Michielsen, Philippe Lefebvre, An Verrijken, Eric Van Marck, Sven Francque, Guy Hubens, Marja-Riitta Taskinen, Ilse Mertens, and Sandrine Caron
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Biopsy ,Peroxisome proliferator-activated receptor ,Biology ,Real-Time Polymerase Chain Reaction ,Young Adult ,Animal data ,Insulin resistance ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,medicine ,Humans ,PPAR alpha ,Prospective Studies ,Aged ,chemistry.chemical_classification ,Hepatology ,medicine.diagnostic_test ,Adiponectin ,Middle Aged ,medicine.disease ,Endocrinology ,Gene Expression Regulation ,Liver ,chemistry ,Liver biopsy ,RNA ,Female ,Human medicine ,Steatosis ,Steatohepatitis ,Metabolic syndrome ,Follow-Up Studies - Abstract
Background & Aims Peroxisome proliferator-activated receptors (PPARs) have been implicated in non-alcoholic steatohepatitis (NASH) pathogenesis, mainly based on animal data. Gene expression data in NASH patients are scarce. We studied liver PPARα, β/δ, and γ expression in a large cohort of obese patients assessed for presence of NAFLD at baseline and 1year follow-up. Methods Patients presented to the obesity clinic underwent a hepatic work-up. If NAFLD was suspected, liver biopsy was performed. Gene expression was studied by mRNA quantification. Patients were reassessed after 1year. Results 125 patients were consecutively included in the study, of which 85 patients had paired liver biopsy taken at 1year of follow-up. Liver PPARα expression negatively correlated with the presence of NASH ( p =0.001) and with severity of steatosis ( p =0.003), ballooning ( p =0.001), NASH activity score ( p =0.008) and fibrosis ( p =0.003). PPARα expression was positively correlated to adiponectin (R 2 =0.345, p =0.010) and inversely correlated to visceral fat (R 2 =−0.343, p 2 =−0.411, p 2 =−0.233, p =0.012). Liver PPARβ/δ and PPARγ expression did not correlate with any histological feature nor with glucose metabolism or serum lipids. At 1year, correlation of PPARα expression with liver histology was confirmed. In longitudinal analysis, an increase in expression of PPARα and its target genes was significantly associated with histological improvement ( p =0.008). Conclusion Human liver PPARα gene expression negatively correlates with NASH severity, visceral adiposity and insulin resistance and positively with adiponectin. Histological improvement is associated with an increase in expression of PPARα and its target genes. These data might suggest that PPARα is a potential therapeutic target in NASH.
- Published
- 2015
19. The tumour suppressor CDKN2A/p16
- Author
-
Kristiaan, Wouters, Yann, Deleye, Sarah A, Hannou, Jonathan, Vanhoutte, Xavier, Maréchal, Augustin, Coisne, Madjid, Tagzirt, Bruno, Derudas, Emmanuel, Bouchaert, Christian, Duhem, Emmanuelle, Vallez, Casper G, Schalkwijk, François, Pattou, David, Montaigne, Bart, Staels, and Réjane, Paumelle
- Subjects
Adult ,Male ,bone marrow ,Genotype ,Transfection ,adipogenesis ,Rosiglitazone ,Mice ,CDKN2A ,p16INK4a ,3T3-L1 Cells ,perivascular adipose tissue ,Adipocytes ,Animals ,Cyclin-Dependent Kinase Inhibitor p18 ,Humans ,Obesity ,neoplasms ,Cyclin-Dependent Kinase Inhibitor p16 ,Adiposity ,Aged ,Bone Marrow Transplantation ,Mice, Knockout ,Stem Cells ,Original Articles ,Middle Aged ,Mice, Inbred C57BL ,PPAR gamma ,Disease Models, Animal ,Phenotype ,Adipose Tissue ,Receptors, LDL ,Case-Control Studies ,Female ,RNA Interference ,Thiazolidinediones ,Signal Transduction - Abstract
The genomic CDKN2A/B locus, encoding p16INK4a among others, is linked to an increased risk for cardiovascular disease and type 2 diabetes. Obesity is a risk factor for both cardiovascular disease and type 2 diabetes. p16INK4a is a cell cycle regulator and tumour suppressor. Whether it plays a role in adipose tissue formation is unknown. p16INK4a knock-down in 3T3/L1 preadipocytes or p16INK4a deficiency in mouse embryonic fibroblasts enhanced adipogenesis, suggesting a role for p16INK4a in adipose tissue formation. p16INK4a-deficient mice developed more epicardial adipose tissue in response to the adipogenic peroxisome proliferator activated receptor gamma agonist rosiglitazone. Additionally, adipose tissue around the aorta from p16INK4a-deficient mice displayed enhanced rosiglitazone-induced gene expression of adipogenic markers and stem cell antigen, a marker of bone marrow-derived precursor cells. Mice transplanted with p16INK4a-deficient bone marrow had more epicardial adipose tissue compared to controls when fed a high-fat diet. In humans, p16INK4a gene expression was enriched in epicardial adipose tissue compared to other adipose tissue depots. Moreover, epicardial adipose tissue from obese humans displayed increased expression of stem cell antigen compared to lean controls, supporting a bone marrow origin of epicardial adipose tissue. These results show that p16INK4a modulates epicardial adipose tissue development, providing a potential mechanistic link between the genetic association of the CDKN2A/B locus and cardiovascular disease risk.
- Published
- 2017
20. The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions
- Author
-
Jason S. Carroll, Nathalie Hennuyer, Bruno Derudas, Eric Baugé, Parisa Mazrooei, Aurélien A. Sérandour, Julie Dubois-Chevalier, Jérôme Eeckhoute, Bart Staels, Guillemette Marot, Philippe Lefebvre, Mathieu Lupien, Céline Gheeraert, Vanessa Dubois, Penderia Guillaume, Hélène Dehondt, Réjane Paumelle, Claire Mazuy, Université de Lille, Droit et Santé, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Medical Biophysics (MBP), University of Toronto, University of Cambridge [UK] (CAM), MOdel for Data Analysis and Learning (MODAL), Laboratoire Paul Painlevé (LPP), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Carroll, Jason [0000-0003-3643-0080], Apollo - University of Cambridge Repository, Marot, Guillemette, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, CHU Lille, INSERM, Inserm, Université de Lille, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Department of Medical Biophysics [MBP], University of Cambridge [UK] [CAM], Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Paul Painlevé - UMR 8524 (LPP), and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-École polytechnique universitaire de Lille (Polytech Lille)
- Subjects
0301 basic medicine ,Transcription, Genetic ,Cytoplasmic and Nuclear/deficiency ,[SDV]Life Sciences [q-bio] ,Receptors, Cytoplasmic and Nuclear ,Mice ,0302 clinical medicine ,[STAT.ML]Statistics [stat]/Machine Learning [stat.ML] ,Receptors ,Transcriptional regulation ,Regulatory Elements, Transcriptional ,Genetics (clinical) ,Epigenomics ,Cis-regulatory module ,Regulation of gene expression ,Mice, Knockout ,PPAR alpha/deficiency ,[STAT.ME] Statistics [stat]/Methodology [stat.ME] ,[SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,Genome ,Genomics ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,[SDV] Life Sciences [q-bio] ,Liver ,Transcriptional ,Transcription ,[STAT.ME]Statistics [stat]/Methodology [stat.ME] ,Algorithms ,Liver/metabolism ,Knockout ,Computational biology ,PPAR alpha/genetics ,Biology ,03 medical and health sciences ,Genetic ,Genetics ,Animals ,PPAR alpha ,Enhancer ,Gene ,Gene Expression Profiling ,fungi ,Regulatory Elements ,[STAT.ML] Statistics [stat]/Machine Learning [stat.ML] ,Genomics/methods ,Gene expression profiling ,030104 developmental biology ,Gene Expression Regulation ,Cytoplasmic and Nuclear/genetics ,030217 neurology & neurosurgery - Abstract
Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs. Different combinations of TRMs add to a core TRM, broadly found across the whole landscape of CRMs, to discriminate promoters from enhancers. These combinations also specify distinct sets of CRM differentially organized along the genome and involved in regulation of either housekeeping/cellular maintenance genes or liver-specific functions. In addition to these TRMs which we define as obligatory, we show that facultative TRMs, such as one comprising core circadian TRs, are further recruited to selective subsets of CRMs to modulate their activities. TRMs transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRMs bring about independent transcriptional regulatory inputs defining different sets of CRMs with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TRs at CRMs.
- Published
- 2017
21. HDL does not influence the polarization of human monocytes toward an alternative phenotype
- Author
-
Geesje M. Dallinga-Thie, Mélanie Fanchon, Erik S.G. Stroes, Jan Albert Kuivenhoven, Bruno Derudas, Giulia Chinetti-Gbaguidi, G. Kees Hovingh, Loic Belloy, Bart Staels, Corinne Copin, Andrea E. Bochem, Sophie Colin, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), and Cardiovascular Centre (CVC)
- Subjects
Male ,Alternative polarization ,Gene Expression ,Monocytes ,DISEASE ,Phosphatidylcholine-Sterol O-Acyltransferase ,Orexin Receptors ,Macrophage ,MACROPHAGES ,Cells, Cultured ,Factor XIII ,CHOLESTEROL ,Cell Polarity ,PTX3 ,Middle Aged ,M2 Macrophage ,Cell biology ,DEFICIENCY ,Interleukin 10 ,Phenotype ,Antigens, Surface ,Female ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Mannose receptor ,Mannose Receptor ,ATP Binding Cassette Transporter 1 ,Adult ,EXPRESSION ,HDL ,Inflammation ,Receptors, Cell Surface ,Young Adult ,medicine ,Humans ,Lectins, C-Type ,business.industry ,Cholesterol, HDL ,ALPHA ,Mannose-Binding Lectins ,ATHEROSCLEROSIS ,Immunology ,CELLS ,business ,Human macrophages ,HIGH-DENSITY-LIPOPROTEIN ,Ex vivo ,Biomarkers ,Lipoprotein - Abstract
Background Macrophages are crucial cells in the pathogenesis of atherosclerosis. Macrophages are plastic cells which can switch from a classical pro-inflammatory M1 to an alternative anti-inflammatory M2 macrophage phenotype, depending on the environmental stimuli. Because high-density lipoprotein (HDL) cholesterol levels are inversely correlated to cardiovascular disease and since HDL displays anti-inflammatory properties, we investigated whether HDL can affect alternative macrophage differentiation of primary human monocytes in the presence of interleukin (IL)-4, a M2 macrophage polarization driver, in vitro and ex vivo . Methods and results M2 macrophages are highly responsive to HDL stimulation, since the expression of pentraxin 3 (PTX3), a well known HDL target gene, is induced by HDL more strongly in M2 macrophages than in control unpolarized resting macrophages (RM). As expected, the expression of M2 markers, such as Mannose Receptor (MR), CD200 Receptor (CD200R), Coagulation factor XIII A1 (F13A1), IL-1 receptor antagonist (IL-1RA) and IL10, was induced in IL-4 polarized M2 macrophages compared to RM. However, incubation with HDL added in vitro did not modulate the gene expression of M2 macrophage polarization markers. Moreover, monocytes isolated from subjects with genetically low HDL levels, carrying ABCA1 or LCAT mutations, differentiated ex vivo into M2 macrophages without any difference in the alternative macrophage marker expression profile. Conclusions These in vitro and ex vivo results indicate that, contrary to mouse macrophages, HDL does not influence macrophage M2 polarization of human monocyte-derived macrophages. Thus, the anti-inflammatory properties of HDL in humans are probably not related to the enhancement of the M2 macrophage phenotype.
- Published
- 2014
22. SULF2strongly prediposes to fasting and postprandial triglycerides in patients with obesity and type 2 diabetes mellitus
- Author
-
Giel Nijpels, Geesje M. Dallinga-Thie, Kevin Jon Williams, Bart Staels, Leen M 't Hart, Sven Francque, An Verrijken, H. Carlijne Hassing, Jacqueline M. Dekker, Erik S.G. Stroes, Luc Van Gaal, Hans L. Mooij, R. Preethi Surendran, Max Nieuwdorp, Bruno Derudas, and Sophie J. Bernelot Moens
- Subjects
medicine.medical_specialty ,Nutrition and Dietetics ,Triglyceride ,business.industry ,Endocrinology, Diabetes and Metabolism ,nutritional and metabolic diseases ,Medicine (miscellaneous) ,Type 2 Diabetes Mellitus ,medicine.disease ,Obesity ,chemistry.chemical_compound ,Endocrinology ,Postprandial ,chemistry ,Internal medicine ,Genotype ,Medicine ,SNP ,business ,Prospective cohort study ,Dyslipidemia - Abstract
Objective Hepatic overexpression of sulfatase-2 (SULF2), a heparan sulfate remodeling enzyme, strongly contributes to high triglyceride (TG) levels in obese, type 2 diabetic (T2DM) db/db mice. Nevertheless, data in humans are lacking. Here, the association of human hepatic SULF2 expression and SULF2 gene variants with TG metabolism in patients with obesity and/or T2DM was investigated. Methods Liver biopsies from 121 obese subjects were analyzed for relations between hepatic SULF2 mRNA levels and plasma TG. Associations between seven SULF2 tagSNPs and TG levels were assessed in 210 obese T2DM subjects with dyslipidemia. Replication of positive findings was performed in 1,316 independent obese T2DM patients. Postprandial TRL clearance was evaluated in 29 obese T2DM subjects stratified by SULF2 genotype. Results Liver SULF2 expression was significantly associated with fasting plasma TG (r = 0.271; P = 0.003) in obese subjects. The SULF2 rs2281279(A>G) SNP was reproducibly associated with lower fasting plasma TG levels in obese T2DM subjects (P < 0.05). Carriership of the minor G allele was associated with lower levels of postprandial plasma TG (P < 0.05) and retinyl esters levels (P < 0.001). Conclusions These findings implicate SULF2 as potential therapeutic target in the atherogenic dyslipidemia of obesity and T2DM.
- Published
- 2014
23. Human Alternative Macrophages Populate Calcified Areas of Atherosclerotic Lesions and Display Impaired RANKL-Induced Osteoclastic Bone Resorption Activity
- Author
-
Sophie Susen, Bart Staels, Ziad A. Massy, Loïc Louvet, Christophe Zawadzki, Manjula Vinod, Stéphan Haulon, Corinne Copin, Mickael Rosa, Jonathan Vanhoutte, Mehdi Daoudi, Mélanie Fanchon, Jérôme Eeckhoute, Giulia Chinetti-Gbaguidi, Bruno Derudas, and Loic Belloy
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Physiology ,Osteoclasts ,Laser Capture Microdissection ,Bone resorption ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,Osteoclast ,Cathepsin K ,medicine ,Humans ,Bone Resorption ,Vascular Calcification ,Cells, Cultured ,Cathepsin ,biology ,Activator (genetics) ,CD68 ,Macrophages ,RANK Ligand ,Plaque, Atherosclerotic ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,RANKL ,biology.protein ,Leukocytes, Mononuclear ,Cardiology and Cardiovascular Medicine - Abstract
Rationale: Vascular calcification is a process similar to bone formation leading to an inappropriate deposition of calcium phosphate minerals in advanced atherosclerotic plaques. Monocyte-derived macrophages, located in atherosclerotic lesions and presenting heterogeneous phenotypes, from classical proinflammatory M1 to alternative anti-inflammatory M2 macrophages, could potentially display osteoclast-like functions. Objective: To characterize the phenotype of macrophages located in areas surrounding the calcium deposits in human atherosclerotic plaques. Methods and Results: Macrophages near calcium deposits display an alternative phenotype being both CD68 and mannose receptor–positive, expressing carbonic anhydrase type II, but relatively low levels of cathepsin K. In vitro interleukin-4-polarization of human primary monocytes into macrophages results in lower expression and activity of cathepsin K compared with resting unpolarized macrophages. Moreover, interleukin-4 polarization lowers expression levels of the osteoclast transcriptional activator nuclear factor of activated T cells type c-1, associated with increased gene promoter levels of the transcriptional repression mark H3K27me3 (histone 3 lysine 27 trimethylation). Despite higher expression of the receptor activator of nuclear factor κB receptor, receptor activator of nuclear factor κB ligand/macrophage colony-stimulating factor induction of nuclear factor of activated T cells type c-1 and cathepsin K expression is defective in these macrophages because of reduced Erk/c-fos–mediated downstream signaling resulting in impaired bone resorption capacity. Conclusions: These results indicate that macrophages surrounding calcium deposits in human atherosclerotic plaques are phenotypically defective being unable to resorb calcification.
- Published
- 2016
24. The logic of transcriptional regulator recruitment architecture at
- Author
-
Julie, Dubois-Chevalier, Vanessa, Dubois, Hélène, Dehondt, Parisa, Mazrooei, Claire, Mazuy, Aurélien A, Sérandour, Céline, Gheeraert, Penderia, Guillaume, Eric, Baugé, Bruno, Derudas, Nathalie, Hennuyer, Réjane, Paumelle, Guillemette, Marot, Jason S, Carroll, Mathieu, Lupien, Bart, Staels, Philippe, Lefebvre, and Jérôme, Eeckhoute
- Subjects
Mice, Knockout ,Genome ,Transcription, Genetic ,Gene Expression Profiling ,Research ,fungi ,Receptors, Cytoplasmic and Nuclear ,Genomics ,Mice ,Gene Expression Regulation ,Liver ,Animals ,PPAR alpha ,Regulatory Elements, Transcriptional ,Algorithms - Abstract
Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs. Different combinations of TRMs add to a core TRM, broadly found across the whole landscape of CRMs, to discriminate promoters from enhancers. These combinations also specify distinct sets of CRM differentially organized along the genome and involved in regulation of either housekeeping/cellular maintenance genes or liver-specific functions. In addition to these TRMs which we define as obligatory, we show that facultative TRMs, such as one comprising core circadian TRs, are further recruited to selective subsets of CRMs to modulate their activities. TRMs transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRMs bring about independent transcriptional regulatory inputs defining different sets of CRMs with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TRs at CRMs.
- Published
- 2016
25. Author Correction: Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution
- Author
-
Luisa Vonghia, Eloise Woitrain, Olivier Molendi-Coste, Hélène Dehondt, Philippe Lefebvre, Denis A. Mogilenko, Ann Driessen, Samuel Pic, Sébastien Fleury, Bruno Derudas, Luc Van Gaal, David Dombrowicz, Bart Staels, Sven Francque, Céline Gheeraert, Lucie Ducrocq-Geoffroy, Artemii Nikitin, An Verrijken, Audrey Deprince, and Joel T. Haas
- Subjects
Computer science ,Physiology (medical) ,Endocrinology, Diabetes and Metabolism ,Resolution (electron density) ,Internal Medicine ,Cell Biology ,Computational biology ,Network analysis - Abstract
In the version of this article initially published, ANR grant ANR-16-RHUS-0006 to author Joel T. Haas was not included in the Acknowledgements. The error has been corrected in the HTML and PDF versions of the article.
- Published
- 2019
26. Natalizumab treatment modulates Peroxisome Proliferator-Activated Receptors expression in women with multiple sclerosis
- Author
-
Inês Cavaleiro, Alexandra Maia e Silva, Bart Staels, Bruno Derudas, Giulia Chinetti-Gbaguidi, Armando Sena, Véronique Ferret-Sena, and José Vale
- Subjects
0301 basic medicine ,medicine.medical_specialty ,HSAC NEU ,Multiple Sclerosis ,Article Subject ,CD36 ,Peroxisome Proliferator-Activated Receptors ,Peroxisome proliferator-activated receptor ,Peripheral blood mononuclear cell ,03 medical and health sciences ,0302 clinical medicine ,Natalizumab ,Internal medicine ,Drug Discovery ,Gene expression ,parasitic diseases ,medicine ,Pharmacology (medical) ,Women ,Osteopontin ,Receptor ,lcsh:QH301-705.5 ,chemistry.chemical_classification ,biology ,Multiple sclerosis ,medicine.disease ,Treatment ,030104 developmental biology ,Endocrinology ,lcsh:Biology (General) ,chemistry ,biology.protein ,030217 neurology & neurosurgery ,medicine.drug ,Research Article - Abstract
Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPARα, PPARβ/δ, PPARγ, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPARβ/δmRNA (p=0.009) in comparison to baseline, while mRNA expression of PPARγand CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls (p=0.026andp=0.028, resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients (p=0.002) and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy.
- Published
- 2016
27. Human adipose tissue macrophages display activation of cancer-related pathways.: ATM link obesity and cancer?
- Author
-
John Brozek, Robert Caiazzo, Alberto Mantovani, Gael Bories, Bruno Derudas, Marie Pigeyre, Giulia Chinetti-Gbaguidi, Bart Staels, Barbara Gross, Thérèse Hèrvée Mayi, Violeta Raverdi, Paola Allavena, François Pattou, Mehdi Daoudi, Kristiaan Wouters, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Genfit, Entreprise biopharmaceutique GENFIT Loos, Thérapie cellulaire du diabète, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Service de chirurgie générale et endocrinienne, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de Nutrition, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Immunology and Cell Biology, Mario Negri Institute, The research leading to these results has received funding from the 'Nouvelle Societé Française d'Athérosclérose / Sanofi-Aventis' (to Mayi T.H.), the 'Societé Française de Cardiologie / SanofiAventis', the COST Action BM0602 and the European Community's 7th Framework Programme (FP7/2007-2013) under grant agreement n° 201608. G. Chinetti-Gbaguidi is a recipient of a Contrat d'Interface from the CHRU de Lille. B. Staels is a member of the IUF., and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
obesity ,medicine.medical_specialty ,Chemokine ,Adipose tissue macrophages ,Adipose tissue ,chemokines ,Inflammation ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,Internal medicine ,Adipocytes ,medicine ,Humans ,cancer ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Molecular Biology ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Cancer ,Cell Biology ,medicine.disease ,Immunohistochemistry ,macrophages ,adipose tissue ,Gene Expression Regulation, Neoplastic ,Phenotype ,Metabolism ,Endocrinology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,Disease Progression ,Cancer research ,biology.protein ,medicine.symptom ,Azo Compounds - Abstract
International audience; Obesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function. Therefore, ATM were isolated and compared with monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed overexpression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signaling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumor-associated macrophages showed that ATM, but not MDM resemble tumor-associated macrophages. Indirect co-culture experiments demonstrated that factors secreted by preadipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM-secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype.
- Published
- 2012
- Full Text
- View/download PDF
28. Peroxisome Proliferator-Activated Receptor-α Activation Protects Brain Capillary Endothelial Cells from Oxygen-Glucose Deprivation-Induced Hyperpermeability in the Blood-Brain Barrier
- Author
-
Caroline Mysiorek, Régis Bordet, Lucie Dehouck, Laurence Fenart, Vincent Berezowski, Roméo Cecchelli, Maxime Culot, Bruno Derudas, and Bart Staels
- Subjects
chemistry.chemical_classification ,Agonist ,0303 health sciences ,Endothelium ,medicine.drug_class ,Peroxisome proliferator-activated receptor ,Biology ,Blood–brain barrier ,Neuroprotection ,Cell biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine.anatomical_structure ,nervous system ,Developmental Neuroscience ,Neurology ,chemistry ,Cell culture ,Immunology ,medicine ,Peroxisome proliferator-activated receptor alpha ,Receptor ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
That promising neuroprotectants failed to demonstrate benefit against stroke highlights the great difficulties to translate preclinical pharmacological effects in clinical outcomes. Part of this hurdle implies the complex response to injury of the neurovascular unit increasing the cerebrovascular permeability at the level of the blood-brain barrier (BBB). Previous studies reported neuroprotection in animal models upon activation of the nuclear receptor PPARα (peroxisome proliferator-activated receptor) α, but the cellular targets at the BBB level remain largely unexplored. Here, to study whether PPAR-α activation acts on BBB permeability, we adapted a mouse BBB cell model to ischaemic conditions at the stage of occlusion defined in vitro as oxygen-glucose deprivation (OGD). This model consists of a co-culture of brain capillary endothelial cells (ECs) on a filter insert placed upon a rat glial cell culture. The EC monolayer permeability increase induced by 4 h of OGD was significantly restricted after treatment with the PPAR-α agonist fenofibric acid (FA) 24 h before or at the onset of OGD. Treatments of separated ECs or glial cells showed that this protective effect was conferred by BBB ECs but not glial cells. Furthermore, co-cultures with ECs from PPAR-α-deficient mice revealed that FA had no effect on OGD-induced hyperpermeability. No transcriptional modulation of classical PPAR-α target genes such as SOD, ICAM-1, VCAM-1, ACO, CPT-1, PDK-4 or ET-1 was observed in wild type mouse ECs. In conclusion, these results suggest that part of the preventive PPAR-α-mediated protection may occur via BBB ECs by limiting hyperpermeability.
- Published
- 2009
- Full Text
- View/download PDF
29. The coronary artery disease-associated gene C6ORF105 is expressed in human macrophages under the transcriptional control of PPARγ
- Author
-
Christophe Zawadzki, Brigitte Jude, Corinne Copin, Bart Staels, Nikolaus Marx, Bruno Derudas, Stéphan Haulon, François Pattou, Giulia Chinetti-Gbaguidi, and Jonathan Vanhoutte
- Subjects
Transcriptional Activation ,medicine.medical_specialty ,Macrophage ,Biophysics ,Peroxisome proliferator-activated receptor ,Gene Expression ,Coronary Artery Disease ,Biology ,Biochemistry ,Structural Biology ,Internal medicine ,Gene expression ,Genetics ,medicine ,Transcriptional regulation ,Humans ,Obesity ,Receptor ,Molecular Biology ,Gene ,Transcription factor ,Cells, Cultured ,Regulation of gene expression ,chemistry.chemical_classification ,Macrophages ,Membrane Proteins ,Cell Biology ,Atherosclerosis ,Gene regulation ,PPAR gamma ,Endocrinology ,chemistry ,Diabetes Mellitus, Type 2 ,Female - Abstract
Coronary artery disease (CAD) is a major cause of morbidity and mortality. Mutations in C6ORF105, associated with decreased gene expression, positively correlate with the risk of CAD in Chinese populations. Moreover, the C6ORF105-encoded protein may play a role in coagulation. Here, we report that C6ORF105 gene expression is lower in circulating mononuclear cells from obese diabetic than lean subjects. Moreover, C6ORF105 is expressed in human macrophages and atherosclerotic lesions, where its expression positively correlates with expression of the transcription factor Peroxisome Proliferator-Activated Receptor (PPAR)γ. Activation of PPARγ increases, in a PPARγ-dependent manner, the expression of C6ORF105 in human macrophages and atherosclerotic lesions.
- Published
- 2014
30. The neuron-derived orphan receptor 1 (NOR1) is induced upon human alternative macrophage polarization and stimulates the expression of markers of the M2 phenotype
- Author
-
Stéphan Haulon, Corinne Copin, Julie Dubois-Chevalier, Bart Staels, Christophe Zawadzki, Jérôme Eeckhoute, Giulia Chinetti-Gbaguidi, Sophie Colin, F. De Paoli, Christian Duhem, Jonathan Vanhoutte, Philippe Lefebvre, Brigitte Jude, and Bruno Derudas
- Subjects
Macrophage colony-stimulating factor ,Carotid Artery Diseases ,Receptors, Steroid ,Time Factors ,Nerve growth factor IB ,Macrophage-activating factor ,Primary Cell Culture ,Macrophage polarization ,Biology ,Transfection ,Animals ,Humans ,Gene Silencing ,Cells, Cultured ,Orphan receptor ,Receptors, Thyroid Hormone ,Macrophages ,Cell Differentiation ,Macrophage Activation ,Molecular biology ,Plaque, Atherosclerotic ,Neuron-derived orphan receptor 1 ,Cell biology ,Interleukin-10 ,DNA-Binding Proteins ,Mice, Inbred C57BL ,Interleukin 10 ,Interleukin 1 Receptor Antagonist Protein ,Phenotype ,Matrix Metalloproteinase 9 ,RNA Interference ,Interleukin-4 ,Cardiology and Cardiovascular Medicine ,STAT6 Transcription Factor ,Mannose receptor ,Biomarkers ,Signal Transduction - Abstract
Background Atherosclerosis is an inflammatory disease in which macrophages play a crucial role. Macrophages are present in different phenotypes, with at the extremes of the spectrum the classical M1 pro-inflammatory and the alternative M2 anti-inflammatory macrophages. The neuron-derived orphan receptor 1 (NOR1), together with Nur77 and Nurr1, are members of the NR4A orphan nuclear receptor family, expressed in human atherosclerotic lesion macrophages. However, the role of NOR1 in human macrophages has not been studied yet. Objectives To determine the expression and the functions of NOR1 in human alternative macrophages. Methods and results In vitro IL-4 polarization of primary monocytes into alternative M2 macrophages enhances NOR1 expression in human but not in mouse macrophages. Moreover, NOR1 expression is most abundant in CD68+MR+ alternative macrophage-enriched areas of human atherosclerotic plaques in vivo . Silencing NOR1 in human alternative macrophages decreases the expression of several M2 markers such as the Mannose Receptor (MR), Interleukin-1 Receptor antagonist (IL-1Ra), CD200 Receptor (CD200R), coagulation factor XIII A1 polypeptide (F13A1), Interleukin 10 (IL-10) and the Peroxisome Proliferator-Activated Receptor (PPAR)γ. Bioinformatical analysis identified F13A1, IL-1Ra, IL-10 and the Matrix Metalloproteinase-9 (MMP9) as potential target genes of NOR1 in human alternative macrophages. Moreover, expression and enzymatic activity of MMP9 are induced by silencing and repressed by NOR1 overexpression in M2 macrophages. Conclusions These data identify NOR1 as a transcription factor induced during alternative differentiation of human macrophages and demonstrate that NOR1 modifies the alternative macrophage phenotype.
- Published
- 2014
31. LXR controls macrophage iron metabolism
- Author
-
Mehdi Daoudi, Gael Bories, Sophie Colin, Bruno Derudas, Bart Staels, Stéphan Haulon, Brigitte Jude, Corinne Copin, Mélanie Fanchon, Loic Belloy, Christophe Zawadzki, Jonathan Vanhoutte, Giulia Chinetti-Gbaguidi, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen du Diabète (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Droit et Santé, and Grants from the Région Nord-Pas de Calais/FEDER (CPER N. 1449), the Agence Nationale de la Recherche, France (AlMHA project), the Fondation de France, the Fondation pour la Recherche Médicale, the transatlantic Leducq HDL Network, the 'European Genomic Institute for Diabetes' (EGID, ANR-10-LABX-46)
- Subjects
Apolipoprotein E ,Physiology ,Ferroportin ,030204 cardiovascular system & hematology ,0302 clinical medicine ,Homeostasis ,Macrophage ,MESH: Antigens, Differentiation, Myelomonocytic ,MESH: Antigens, CD ,Cells, Cultured ,ATP Binding Cassette Transporter, Subfamily G, Member 1 ,Liver X Receptors ,MESH: Receptors, Cell Surface ,0303 health sciences ,MESH: Iron ,biology ,CD68 ,Orphan Nuclear Receptors ,MESH: Apolipoproteins E ,Plaque, Atherosclerotic ,Cell biology ,Phenotype ,Biochemistry ,MESH: Orphan Nuclear Receptors ,MESH: Homeostasis ,MESH: ATP-Binding Cassette Transporters ,Cardiology and Cardiovascular Medicine ,Mannose Receptor ,Mannose receptor ,ATP Binding Cassette Transporter 1 ,MESH: Cells, Cultured ,Iron ,MESH: Biological Transport ,Antigens, Differentiation, Myelomonocytic ,Receptors, Cell Surface ,In Vitro Techniques ,MESH: Phenotype ,Article ,03 medical and health sciences ,Apolipoproteins E ,Antigens, CD ,Hepcidin ,MESH: Mannose-Binding Lectins ,Humans ,Lectins, C-Type ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: ATP Binding Cassette Transporter 1 ,MESH: Plaque, Atherosclerotic ,Liver X receptor ,030304 developmental biology ,MESH: Humans ,Macrophages ,MESH: Macrophages ,Biological Transport ,Mannose-Binding Lectins ,Nuclear receptor ,biology.protein ,ATP-Binding Cassette Transporters ,MESH: Lectins, C-Type - Abstract
Rationale: In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. Objective: The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs). Methods and Results: Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68 + MR + ) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68 + MR + macrophages accumulate oxidized lipids, which activate LXRα and LXRβ, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. Conclusions: These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation.
- Published
- 2013
32. Peroxisome Proliferator-activated Receptor α Activators Improve Insulin Sensitivity and Reduce Adiposity
- Author
-
Rolf K. Berge, Eric Raspé, Bruno Derudas, Lise Madsen, Bart Staels, Michèle Guerre-Millo, Jean Marc Herbert, Timothy M. Willson, Philippe Gervois, Deborah A. Winegar, Philippe Poulain, and Jean Charles Fruchart
- Subjects
Male ,medicine.medical_specialty ,Peroxisome proliferator-activated receptor gamma ,medicine.medical_treatment ,Receptors, Cytoplasmic and Nuclear ,Adipose tissue ,Peroxisome proliferator-activated receptor ,Biology ,Biochemistry ,Mice ,Insulin resistance ,Fenofibrate ,Internal medicine ,medicine ,Hyperinsulinemia ,Animals ,Clofibrate ,Obesity ,Molecular Biology ,Hypolipidemic Agents ,chemistry.chemical_classification ,Phenylurea Compounds ,Insulin ,Cell Biology ,medicine.disease ,Rats ,Rats, Zucker ,Mice, Inbred C57BL ,Butyrates ,Endocrinology ,Adipose Tissue ,chemistry ,Ciprofibrate ,Insulin Resistance ,Transcription Factors ,medicine.drug - Abstract
Fibrates and glitazones are two classes of drugs currently used in the treatment of dyslipidemia and insulin resistance (IR), respectively. Whereas glitazones are insulin sensitizers acting via activation of the peroxisome proliferator-activated receptor (PPAR) gamma subtype, fibrates exert their lipid-lowering activity via PPARalpha. To determine whether PPARalpha activators also improve insulin sensitivity, we measured the capacity of three PPARalpha-selective agonists, fenofibrate, ciprofibrate, and the new compound GW9578, in two rodent models of high fat diet-induced (C57BL/6 mice) or genetic (obese Zucker rats) IR. At doses yielding serum concentrations shown to activate selectively PPARalpha, these compounds markedly lowered hyperinsulinemia and, when present, hyperglycemia in both animal models. This effect relied on the improvement of insulin action on glucose utilization, as indicated by a lower insulin peak in response to intraperitoneal glucose in ciprofibrate-treated IR obese Zucker rats. In addition, fenofibrate treatment prevented high fat diet-induced increase of body weight and adipose tissue mass without influencing caloric intake. The specificity for PPARalpha activation in vivo was demonstrated by marked alterations in the expression of PPARalpha target genes, whereas PPARgamma target gene mRNA levels did not change in treated animals. These results indicate that compounds with a selective PPARalpha activation profile reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR.
- Published
- 2000
33. Fibrates Suppress Fibrinogen Gene Expression in Rodents Via Activation of the Peroxisome Proliferator-Activated Receptor-
- Author
-
Maaike Kockx, Bruno Derudas, Teake Kooistra, Jeffrey M. Peters, Hans M.G. Princen, Philippe Gervois, Frank J. Gonzalez, Philippe Poulain, and Bart Staels
- Subjects
chemistry.chemical_classification ,medicine.medical_specialty ,Clofibrate ,Fenofibrate ,Triglyceride ,medicine.drug_class ,Immunology ,Peroxisome proliferator-activated receptor ,Cell Biology ,Hematology ,Biology ,Fibrinogen ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,Gene expression ,medicine ,Thiazolidinedione ,Receptor ,medicine.drug - Abstract
Plasma fibrinogen levels have been identified as an important risk factor for cardiovascular diseases. Among the few compounds known to lower circulating fibrinogen levels in humans are certain fibrates. We have studied the regulation of fibrinogen gene expression by fibrates in rodents. Treatment of adult male rats with fenofibrate (0.5% [wt/wt] in the diet) for 7 days decreased hepatic A-, Bβ-, and γ-chain mRNA levels to 52% ± 7%, 46% ± 8%, and 81% ± 19% of control values, respectively. In parallel, plasma fibrinogen concentrations were decreased to 63% ± 7% of controls. The suppression of fibrinogen expression was dose-dependent and was already evident after 1 day at the highest dose of fenofibrate tested (0.5% [wt/wt]). Nuclear run-on experiments showed that the decrease in fibrinogen expression after fenofibrate occurred at the transcriptional level, as exemplified for the gene for the A-chain. Other fibrates tested showed similar effects on fibrinogen expression and transcription. The effect of fibrates is specific for peroxisome proliferator-activated receptor- (PPAR) because a high-affinity ligand for PPARγ, the thiazolidinedione BRL 49653, lowered triglyceride levels, but was unable to suppress fibrinogen expression. Direct evidence for the involvement of PPAR in the suppression of fibrinogen by fibrates was obtained using PPAR-null (−/−) mice. Compared with (+/+) mice, plasma fibrinogen levels in (−/−) mice were significantly higher (3.20 ± 0.48 v 2.67 ± 0.42 g/L). Also, hepatic fibrinogen A-chain mRNA levels were 25% ± 11% higher in the (−/−) mice. On treatment with 0.2% (wt/wt) fenofibrate, a significant decrease in plasma fibrinogen to 77% ± 10% of control levels and in hepatic fibrinogen A-chain mRNA levels to 65% ± 12% of control levels was seen in (+/+) mice, but not in (−/−) mice. These studies show that PPAR regulates basal levels of plasma fibrinogen and establish that fibrate-suppressed expression of fibrinogen in rodents is mediated through PPAR.
- Published
- 1999
34. SULF2 strongly prediposes to fasting and postprandial triglycerides in patients with obesity and type 2 diabetes mellitus
- Author
-
H Carlijne, Hassing, R Preethi, Surendran, Bruno, Derudas, An, Verrijken, Sven M, Francque, Hans L, Mooij, Sophie J, Bernelot Moens, Leen M 't, Hart, Giel, Nijpels, Jacqueline M, Dekker, Kevin Jon, Williams, Erik S G, Stroes, Luc F, Van Gaal, Bart, Staels, Max, Nieuwdorp, and Geesje M, Dallinga-Thie
- Subjects
Male ,Fasting ,Middle Aged ,Postprandial Period ,Polymorphism, Single Nucleotide ,Article ,Postmenopause ,Diabetes Mellitus, Type 2 ,Liver ,Humans ,Female ,Obesity ,Prospective Studies ,Sulfatases ,Sulfotransferases ,Alleles ,Triglycerides ,Aged ,Dyslipidemias - Abstract
Hepatic overexpression of sulfatase-2 (SULF2), a heparan sulfate remodeling enzyme, strongly contributes to high triglyceride (TG) levels in obese, type 2 diabetic (T2DM) db/db mice. Nevertheless, data in humans are lacking. Here, the association of human hepatic SULF2 expression and SULF2 gene variants with TG metabolism in patients with obesity and/or T2DM was investigated.Liver biopsies from 121 obese subjects were analyzed for relations between hepatic SULF2 mRNA levels and plasma TG. Associations between seven SULF2 tagSNPs and TG levels were assessed in 210 obese T2DM subjects with dyslipidemia. Replication of positive findings was performed in 1,316 independent obese T2DM patients. Postprandial TRL clearance was evaluated in 29 obese T2DM subjects stratified by SULF2 genotype.Liver SULF2 expression was significantly associated with fasting plasma TG (r = 0.271; P = 0.003) in obese subjects. The SULF2 rs2281279(AG) SNP was reproducibly associated with lower fasting plasma TG levels in obese T2DM subjects (P0.05). Carriership of the minor G allele was associated with lower levels of postprandial plasma TG (P0.05) and retinyl esters levels (P0.001).These findings implicate SULF2 as potential therapeutic target in the atherogenic dyslipidemia of obesity and T2DM.
- Published
- 2013
35. Peroxisome proliferator-activated receptor-γ activation induces 11β-hydroxysteroid dehydrogenase type 1 activity in human alternative macrophages
- Author
-
Christian Duhem, Corinne Copin, Bernardette Neve, Bruno Derudas, Jérôme Eeckhoute, Bernard Noël, Mohamed Amine Bouhlel, Bart Staels, Jonathan R. Seckl, Giulia Chinetti-Gbaguidi, Philippe Lefebvre, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Endocrinology Unit, University of Edinburgh-Queen's Medical Researche Institute, University of Edinburgh, This work was supported by grants from the Nouvelle Société Française d'Athérosclérose/Sanofi-Aventis (to M.A.Bouhlel), the Région Nord-Pas de Calais/FEDER (ChoMetAlt project), the Fondation Coeur et Artères and theAgence Nationale de la Recherche (AlMHA project). G. Chinetti-Gbaguidi is a recipient of aContrat d'Interface from the CHRU de Lille., Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Derudas, Marie-Hélène
- Subjects
MESH: Inflammation ,Time Factors ,PPARgamma ,Hydrocortisone ,MESH: Receptors, Glucocorticoid ,Peroxisome proliferator-activated receptor ,MESH: Thiazolidinediones ,0302 clinical medicine ,Glucocorticoid receptor ,11β-hydroxysteroid dehydrogenase type 1 ,Genes, Reporter ,11-beta-Hydroxysteroid Dehydrogenase Type 1 ,Receptor ,Cells, Cultured ,chemistry.chemical_classification ,0303 health sciences ,biology ,MESH: Hydrocortisone ,Cell biology ,GR ,Enzyme Induction ,human alternative macrophages ,MESH: 11-beta-Hydroxysteroid Dehydrogenase Type 1 ,RNA Interference ,Cardiology and Cardiovascular Medicine ,Glucocorticoid ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,MESH: Cells, Cultured ,medicine.medical_specialty ,MESH: Enzyme Induction ,MESH: RNA Interference ,Macrophage polarization ,Transfection ,11beta-HSDI ,Article ,Proinflammatory cytokine ,Rosiglitazone ,03 medical and health sciences ,Receptors, Glucocorticoid ,Internal medicine ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,MESH: Humans ,Macrophages ,MESH: Transfection ,MESH: Time Factors ,MESH: Genes, Reporter ,MESH: Macrophages ,MESH: Interleukin-4 ,Cortisone ,PPAR gamma ,Endocrinology ,Nuclear receptor ,chemistry ,MESH: PPAR gamma ,inflammation ,biology.protein ,Thiazolidinediones ,Interleukin-4 ,MESH: Cortisone ,030217 neurology & neurosurgery - Abstract
Objective— 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the intracellular reduction of inactive cortisone to active cortisol, the natural ligand activating the glucocorticoid receptor (GR). Peroxisome proliferator– activated receptor-γ (PPARγ) is a nuclear receptor controlling inflammation, lipid metabolism, and the macrophage polarization state. In this study, we investigated the impact of macrophage polarization on the expression and activity of 11β-HSD1 and the role of PPARγ therein. Methods and Results— 11β-HSD1 gene expression is higher in proinflammatory M1 and anti-inflammatory M2 macrophages than in resting macrophages, whereas its activity is highest in M2 macrophages. Interestingly, PPARγ activation induces 11β-HSD1 enzyme activity in M2 macrophages but not in resting macrophages or M1 macrophages. Consequently, human M2 macrophages displayed enhanced responsiveness to the 11β-HSD1 substrate cortisone, an effect amplified by PPARγ induction of 11β-HSD1 activity, as illustrated by an increased expression of GR target genes. Conclusion— Our data identify a positive cross-talk between PPARγ and GR in human M2 macrophages via the induction of 11β-HSD1 expression and activity.
- Published
- 2012
36. Impaired alternative macrophage differentiation of peripheral blood mononuclear cells from obese subjects.: Macrophage alternative differentiation and obesity
- Author
-
Giulia Chinetti-Gbaguidi, Bart Staels, Gael Bories, Corinne Copin, François Pattou, Robert Caiazzo, Marie Pigeyre, Violeta Raverdy, Bruno Derudas, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Thérapie cellulaire du diabète, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Service de chirurgie générale et endocrinienne, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de Nutrition, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), The research leading to these results has received funding from the COST Action BM0602 and the European Community's 7th Framework Programme (FP7/2007-2013) under grant agreement n° 201608. G. Chinetti-Gbaguidi is a recipient of a Contrat d'Interface from the CHRU de Lille., European Project: 201608,EC:FP7:HEALTH,FP7-HEALTH-2007-A,TOBI(2008), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Adult ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Adipose tissue macrophages ,Adipose tissue ,Inflammation ,030204 cardiovascular system & hematology ,Peripheral blood mononuclear cell ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,Medicine ,Glucose homeostasis ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Obesity ,030304 developmental biology ,0303 health sciences ,polarization ,business.industry ,Monocyte ,Gene Expression Profiling ,Macrophages ,Cell Differentiation ,Middle Aged ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,Phenotype ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Immunology ,gene expression ,Leukocytes, Mononuclear ,Female ,Metabolic syndrome ,medicine.symptom ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,business - Abstract
International audience; Visceral obesity is a chronic, low-grade inflammatory disease that predisposes people to the metabolic syndrome, type 2 diabetes and its cardiovascular complications. Adipose tissue is not a passive storehouse for fat, but an endocrine organ synthesizing and releasing a variety of bioactive molecules, some of which are produced by infiltrated immune-inflammatory cells including macrophages. Two different subpopulations of macrophages have been identified in adipose tissue: pro-inflammatory 'classical' M1 and anti-inflammatory 'alternative' M2 macrophages, and their ratio is suggested to influence the metabolic complications of obesity. These macrophages derive primarily from peripheral blood mononuclear cells (PBMCs). We hypothesised that obesity and the metabolic syndrome modulate PBMC functions. Therefore, alteration of the monocyte response, and more specifically their ability to differentiate toward alternative anti-inflammatory macrophages, was assessed in PBMCs isolated from lean and obese subjects with or without alterations in glucose homeostasis. Our results indicate that PBMCs from obese subjects have an altered expression of M2 markers and that their monocytes are less susceptible to differentiate toward an alternative phenotype. Thus PBMCs in obesity are programmed, which may contribute to the inflammatory dysregulation and increased susceptibility to inflammatory diseases in these patients.
- Published
- 2011
37. Downregulation of the tumour suppressor p16INK4A contributes to the polarisation of human macrophages toward an adipose tissue macrophage (ATM)-like phenotype
- Author
-
Céline Cudejko, Réjane Paumelle, Lucía Fuentes, Sarah Anissa Hannou, Thérèse Hèrvée Mayi, François Pattou, Giulia Chinetti-Gbaguidi, Elena Rigamonti, Kristiaan Wouters, Bart Staels, Bruno Derudas, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de chirurgie générale et endocrinienne, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Therapie Cellulaire du Diabete, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, This work was supported by the EU FP6 grant (EIF 040851 to L. Fuentes), EU FP7 grants (PIEFGA- 2009-23522 to K. Wouters and grant no. 201608 to T. H. Mayi), an EFSD/GlaxoSmithKline Research Grant 2009 (K. Wouters and B. Staels), the Spanish Government MEC (Ministerio de Educación y Ciencia to L. Fuentes) and the Fondation pour la Recherche Médicale (DCV20070409276 to B. Staels), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Derudas, Marie-Hélène
- Subjects
Male ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,MESH: NF-kappa B ,MESH: Down-Regulation ,law.invention ,0302 clinical medicine ,law ,MESH: RNA, Small Interfering ,MESH: Obesity ,MESH: Gene Silencing ,RNA, Small Interfering ,0303 health sciences ,Adipose tissue macrophages ,NF-kappa B ,Cell Polarity ,Type 2 diabetes ,MESH: Toll-Like Receptor 4 ,Phenotype ,Plaque, Atherosclerotic ,Adipose Tissue ,030220 oncology & carcinogenesis ,MESH: Cyclin-Dependent Kinase Inhibitor p16 ,Female ,medicine.symptom ,MESH: Cell Polarity ,MESH: Adipose Tissue ,MESH: Diabetes Mellitus, Type 2 ,Down-Regulation ,Inflammation ,Biology ,Senescence ,Article ,03 medical and health sciences ,CDKN2A ,Downregulation and upregulation ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Internal Medicine ,medicine ,Humans ,Gene silencing ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Gene Silencing ,Obesity ,MESH: Plaque, Atherosclerotic ,neoplasms ,Cyclin-Dependent Kinase Inhibitor p16 ,030304 developmental biology ,MESH: Humans ,Macrophages ,MESH: Macrophages ,Macrophage polarisation ,NFKB1 ,MESH: Male ,Toll-Like Receptor 4 ,Diabetes Mellitus, Type 2 ,Immunology ,Cancer research ,Suppressor ,MESH: Female - Abstract
Human adipose tissue macrophages (ATMs) display an alternatively activated (M2) phenotype, but are still able to produce excessive inflammatory mediators. However, the processes driving this particular ATM phenotype are not understood. Genome-wide association studies associated the CDKN2A locus, encoding the tumour suppressor p16(INK4A), with the development of type 2 diabetes. In the present study, p16(INK4A) levels in human ATMs and the role of p16(INK4A) in acquiring the ATM phenotype were assessed.Gene expression of p16 ( INK4A ) in ATMs was analysed and compared with that in monocyte-derived macrophages (MDMs) from obese patients or with macrophages from human atherosclerotic plaques (AMs). Additionally, p16(INK4A) levels were studied during macrophage differentiation and polarisation of monocytes isolated from healthy donors. The role of p16(INK4A) in MDMs from healthy donors was investigated by small interfering (si)RNA-mediated silencing or adenovirus-mediated overproduction of p16(INK4A).Compared with MDMs and AMs, ATMs from obese patients expressed lower levels of p16 ( INK4A ). In vitro, IL-4-induced M2 polarisation resulted in lower p16(INK4A) protein levels after differentiation of monocytes from healthy donors in macrophages. Silencing of p16(INK4A) in MDMs mediated by siRNA increased the expression of M2 marker genes and enhanced the response to lipopolysaccharide (LPS), to give a phenotype resembling that of ATM. By contrast, adenovirus-mediated overproduction of p16(INK4A) in MDMs diminished M2 marker gene expression and the response to LPS. Western blot analysis revealed that p16(INK4A) overproduction inhibits LPS- and palmitate-induced Toll-like receptor 4 (TLR4)-nuclear factor of κ light polypeptide gene enhancer in B cells (NF-κB) signalling.These results show that p16(INK4A) inhibits the acquisition of the ATM phenotype. The age-related increase in p16(INK4A) level may thus influence normal ATM function and contribute to type 2 diabetes risk.
- Published
- 2011
38. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways.: Atherosclerotic plaque alternative macrophages
- Author
-
Corinne Copin, Bruno Derudas, Giulia Chinetti-Gbaguidi, Jonathan Vanhoutte, Brigitte Jude, Bart Staels, Gael Bories, Christophe Zawadzki, Stephane Haulon, Anne Tailleux, Yasmine Sebti, Mohamed Amine Bouhlel, Thérèse Hèrvée Mayi, Morgane Baron, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hémostase et pathologie cardiovasculaire, and EA2693-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé
- Subjects
Apolipoprotein E ,MESH: Cell Differentiation ,Physiology ,nuclear receptors ,030204 cardiovascular system & hematology ,Article ,03 medical and health sciences ,0302 clinical medicine ,MESH: Cholesterol ,Phagocytosis ,Lipid droplet ,Humans ,Genetic Predisposition to Disease ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: Plaque, Atherosclerotic ,Liver X receptor ,MESH: Phagocytosis ,Cells, Cultured ,030304 developmental biology ,Liver X Receptors ,0303 health sciences ,MESH: Humans ,biology ,CD68 ,MESH: Genetic Predisposition to Disease ,Interleukin ,cholesterol ,MESH: Macrophages ,Cell Differentiation ,Orphan Nuclear Receptors ,Atherosclerosis ,Plaque, Atherosclerotic ,Cell biology ,macrophages ,PPAR gamma ,MESH: Leukocytes, Mononuclear ,Biochemistry ,MESH: Orphan Nuclear Receptors ,MESH: PPAR gamma ,Monocyte differentiation ,ABCA1 ,biology.protein ,Leukocytes, Mononuclear ,Cardiology and Cardiovascular Medicine ,Mannose receptor ,MESH: Cells, Cultured - Abstract
Rationale: A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an “alternative” M2 phenotype. Objective: We previously reported the presence of CD68 + mannose receptor (MR) + M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68 + MR + macrophages is still unknown. Methods and Results: Histological analysis revealed that CD68 + MR + macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68 + MR − macrophages. Interleukin (IL)-4–polarized CD68 + MR + macrophages display a reduced capacity to handle and efflux cellular cholesterol because of low expression levels of the nuclear receptor liver x receptor (LXR)α and its target genes, ABCA1 and apolipoprotein E, attributable to the high 15-lipoxygenase activity in CD68 + MR + macrophages. By contrast, CD68 + MR + macrophages highly express opsonins and receptors involved in phagocytosis, resulting in high phagocytic activity. In M2 macrophages, peroxisome proliferator-activated receptor (PPAR)γ activation enhances the phagocytic but not the cholesterol trafficking pathways. Conclusions: These data identify a distinct macrophage subpopulation with a low susceptibility to become foam cells but high phagocytic activity resulting from different regulatory activities of the PPARγ-LXRα pathways.
- Published
- 2011
39. The nuclear receptor FXR is expressed in pancreatic beta-cells and protects human islets from lipotoxicity
- Author
-
François Pattou, Iuliana Popescu, Julie Kerr-Conte, Anthony Lucas, Sandrine Caron, Emmanuel Bouchaert, Audrey Helleboid-Chapman, Bart Staels, Julie Dumont, Bruno Derudas, Brigitte Vandewalle, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Thérapie cellulaire du diabète, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, and Derudas, Marie-Hélène
- Subjects
Male ,Palmitic Acid ,Receptors, Cytoplasmic and Nuclear ,Biochemistry ,Mice ,0302 clinical medicine ,Structural Biology ,Insulin-Secreting Cells ,Glucose homeostasis ,Receptor ,Cells, Cultured ,islets ,0303 health sciences ,Bile acid ,lipotoxicity ,Lipotoxicity ,FXR ,Small heterodimer partner ,type 2 diabetes ,Islet ,medicine.medical_specialty ,endocrine system ,medicine.drug_class ,Blotting, Western ,Biophysics ,030209 endocrinology & metabolism ,In Vitro Techniques ,Biology ,Islets of Langerhans ,03 medical and health sciences ,Farnesoid X receptor ,Internal medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Genetics ,medicine ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Obesity ,Liver X receptor ,Molecular Biology ,030304 developmental biology ,Isoxazoles ,Cell Biology ,Mice, Mutant Strains ,Rats ,Mice, Inbred C57BL ,Endocrinology ,Nuclear receptor - Abstract
International audience; Farnesoid X receptor (FXR) is highly expressed in liver and intestine where it controls bile acid (BA), lipid and glucose homeostasis. Here we show that FXR is expressed and functional, as assessed by target gene expression analysis, in human islets and beta-cell lines. FXR is predominantly cytosolic-localized in the islets of lean mice, but nuclear in obese mice. Compared to FXR+/+ mice, FXR-/- mice display a normal architecture and beta-cell mass but the expression of certain islet-specific genes is altered. Moreover, glucose-stimulated insulin secretion (GSIS) is impaired in the islets of FXR-/- mice. Finally, FXR activation protects human islets from lipotoxicity and ameliorates their secretory index.
- Published
- 2010
40. SUMOylation of human peroxisome proliferator-activated receptor alpha inhibits its trans-activity through the recruitment of the nuclear corepressor NCoR
- Author
-
Corine Glineur, Ines Pineda-Torra, Benoit Pourcet, Bart Staels, Bruno Derudas, Derudas, Marie-Hélène, Récepteurs nucléaires, lipoprotéines et athérosclérose, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Medicine Division, and University College of London [London] (UCL)
- Subjects
MESH: Protein Transport ,SUMO-1 Protein ,SUMO protein ,MESH: Co-Repressor Proteins ,Peroxisome proliferator-activated receptor ,Biology ,Biochemistry ,environment and public health ,Cell Line ,Ubiquitin ,MESH: Nuclear Receptor Co-Repressor 1 ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Humans ,Nuclear Receptor Co-Repressor 1 ,PPAR alpha ,MESH: Lysine ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: PPAR alpha ,Molecular Biology ,Nuclear receptor co-repressor 1 ,chemistry.chemical_classification ,Binding Sites ,MESH: Humans ,MESH: Kinetics ,Lysine ,MESH: SUMO-1 Protein ,Cell Biology ,MESH: Gene Expression Regulation ,MESH: Cell Line ,Nuclear receptor coactivator 1 ,Kinetics ,Protein Transport ,Nuclear receptor ,chemistry ,Gene Expression Regulation ,MESH: Binding Sites ,Protein Synthesis and Degradation ,Cancer research ,biology.protein ,Signal transduction ,Corepressor ,Co-Repressor Proteins - Abstract
International audience; The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is a key regulator of genes implicated in lipid homeostasis and inflammation. PPARalpha trans-activity is enhanced by recruitment of coactivators such as SRC1 and CBP/p300 and is inhibited by binding of corepressors such as NCoR and SMRT. In addition to ligand binding, PPARalpha activity is regulated by post-translational modifications such as phosphorylation and ubiquitination. In this report, we demonstrate that hPPARalpha is SUMOylated by SUMO-1 on lysine 185 in the hinge region. The E2-conjugating enzyme Ubc9 and the SUMO E3- ligase PIASy are implicated in this process. In addition, ligand treatment decreases the SUMOylation rate of hPPARalpha. Finally, our results demonstrate that SUMO-1 modification of hPPARalpha down-regulates its trans-activity through the specific recruitment of corepressor NCoR but not SMRT leading to the differential expression of a subset of PPARalpha target genes. In conclusion, hPPARalpha SUMOylation on lysine 185 down-regulates its trans-activity through the selective recruitment of NCoR.
- Published
- 2010
41. Unlike PPARgamma, PPARalpha or PPARbeta/delta activation does not promote human monocyte differentiation toward alternative macrophages
- Author
-
Mohamed Amine, Bouhlel, John, Brozek, Bruno, Derudas, Christophe, Zawadzki, Brigitte, Jude, Bart, Staels, and Giulia, Chinetti-Gbaguidi
- Subjects
PPAR gamma ,Macrophages ,Humans ,Cell Differentiation ,PPAR alpha ,PPAR delta ,Macrophage Activation ,Atherosclerosis ,PPAR-beta ,Cells, Cultured ,Monocytes - Abstract
Macrophages adapt their response to micro-environmental signals. While Th1 cytokines promote pro-inflammatory M1 macrophages, Th2 cytokines promote an "alternative" anti-inflammatory M2 macrophage phenotype. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors expressed in macrophages where they control the inflammatory response. It has been shown that PPARgamma promotes the differentiation of monocytes into anti-inflammatory M2 macrophages in humans and mice, while a role for PPARbeta/delta in this process has been reported only in mice and no data are available for PPARalpha. Here, we show that in contrast to PPARgamma, expression of PPARalpha and PPARbeta/delta overall does not correlate with the expression of M2 markers in human atherosclerotic lesions, whereas a positive correlation with genes of lipid metabolism exists. Moreover, unlike PPARgamma, PPARalpha or PPARbeta/delta activation does not influence human monocyte differentiation into M2 macrophages in vitro. Thus, PPARalpha and PPARbeta/delta do not appear to modulate the alternative differentiation of human macrophages.
- Published
- 2009
42. Regulation of bile acid synthesis by the nuclear receptor Rev-erbalpha
- Author
-
Jelske N. van der Veen, Christian Duhem, Vincent W. Bloks, Thierry Touvier, Eric Baugé, Benoit Pourcet, Bart Staels, Folkert Kuipers, Fjodor H. van der Sluijs, Hélène Duez, Henk Wolters, Coralie Fontaine, Björn Vennström, Bruno Derudas, Rick Havinga, and Center for Liver, Digestive and Metabolic Diseases (CLDM)
- Subjects
medicine.medical_specialty ,Time Factors ,medicine.drug_class ,Receptors, Cytoplasmic and Nuclear ,Biology ,Cholesterol 7 alpha-hydroxylase ,MICE LACKING ,TRIGLYCERIDE LEVELS ,Transfection ,Gene Expression Regulation, Enzymologic ,Bile Acids and Salts ,Feces ,Mice ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Bile ,Humans ,RNA, Messenger ,skin and connective tissue diseases ,Cholesterol 7-alpha-Hydroxylase ,Promoter Regions, Genetic ,Orphan receptor ,Mice, Knockout ,Hepatology ,Bile acid ,CIRCADIAN TRANSCRIPTION ,LIPID HOMEOSTASIS ,HYDROXYLASE GENE ,ORPHAN RECEPTOR ,Gastroenterology ,G protein-coupled bile acid receptor ,Cell biology ,Circadian Rhythm ,body regions ,DNA-Binding Proteins ,Endocrinology ,Basic-Leucine Zipper Transcription Factors ,Nuclear receptor ,Liver ,Nuclear Receptor Subfamily 1, Group D, Member 1 ,Small heterodimer partner ,Farnesoid X receptor ,CYP8B1 ,MESSENGER-RNA ,FARNESOID-X-RECEPTOR ,NEGATIVE FEEDBACK-REGULATION - Abstract
Background & Aims: Conversion into bile acids represents an important route to remove excess cholesterol from the body. Rev-erb alpha is a nuclear receptor that participates as one of the clock genes in the control of circadian rhythmicity and plays a regulatory role in lipid metabolism and adipogenesis. Here, we investigate a potential role for Rev-erb alpha in the control of bile acid metabolism via the regulation of the neutral bile acid synthesis pathway. Methods: Bile acid synthesis and CYP7A1 gene expression were studied in vitro and in vivo in mice deficient for or over expressing Rev-erb alpha. Results: Rev-erb alpha-deficient mice display a lower synthesis rate and an impaired excretion of bile acids into the bile and feces. Expression of CYP7A1, the rate-limiting enzyme of the neutral pathway, is decreased in livers of Rev-erb alpha-deficient mice, whereas adenovirus-mediated hepatic Rev-erb alpha overexpression induces its expression. Moreover, bile acid feeding resulted in a more pronounced suppression of hepatic CYP7A1 expression in Rev-erb alpha-deficient mice. Hepatic expression of E4BP4 and the orphan nuclear receptor small heterodimer partner (SHP), both negative regulators of CYP7A1 expression, is increased in Rev-erb alpha-deficient mice. Promoter analysis and chromatin immunoprecipitation experiments demonstrated that SHP and E4BP4 are direct Rev-erb alpha target genes. Finally, the circadian rhythms of liver CYP7A1, SHP, and E4BP4 messenger RNA levels were perturbed in Rev-erb alpha-deficient mice. Conclusions: These data identify a role for Rev-erb alpha in the regulatory loop of bile acid synthesis, likely acting by regulating both hepatic SHP and E4BP4 expression.
- Published
- 2007
43. O8 Rôle du gène suppresseur de tumeur CDKN2A/p16INK4a dans le développement du tissu adipeux périvasculaire
- Author
-
Sarah Anissa Hannou, Xavier Marechal, David Montaigne, Emmanuelle Vallez, Jonathan Vanhoutte, Kristiaan Wouters, Bruno Derudas, Bart Staels, and Réjane Paumelle
- Subjects
Endocrinology ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,General Medicine - Abstract
Introduction Des analyses d'association de genes montrent que le locus CDKN2A/B qui code notamment la proteine p16INK4a, pourrait etre associe au developpement des maladies coronariennes, de l'atherosclerose et du diabete de type 2. Ces pathologies sont associees a l'expansion et a l'inflammation de differents depots de tissu adipeux (TA), notamment le tissu adipeux perivasculaire (PVAT). p16INK4a est un regulateur du cycle cellulaire cependant sa fonction dans l'adipogenese reste encore inconnue. Materiels et methodes Dans cette etude, nous avons etudie le role de p16INK4a dans l'adipogenese in vitro en utilisant des preadipocytes 3T3L1 transfectes par un siRNA-CDKN2A ou des fibroblastes embryonnaires (MEF) isoles des souris p16+/+ et p16−/−, et in vivo, chez l'homme, en etudiant l'expression de p16INK4a dans le PVAT, et chez la souris, en etudiant le developpement des depots de TA induit par un traitement Rosiglitazone. Le role de p16INK4a dans le developpement du PVAT a partir de la moelle osseuse a ete etudie chez des souris chimeres p16−/−LDLRKO et p16+/+LDLRKO soumises a un regime western. Resultats La diminution de l'expression de p16INK4a dans les pre-adipocytes 3T3L1 augmente l'adipogenese, mesuree par une augmentation de l'expression de PPARgamma, adiponectine, perilipine et CEBPalpha et une accumulation de lipides, sans affecter l'expansion clonale. Des resultats similaires ont ete obtenus dans les MEF p16−/−. Chez l'homme, p16INK4a est fortement exprime dans le PVAT cardiaque compare aux autres depots de TA. Chez la souris, bien que la deficience de p16INK4a n'influence pas le developpement des differents depots de TA, le traitement des souris p16−/− par la Rosiglitazone augmente specifiquement le developpement du PVAT, associe a une augmentation de l'expression de marqueurs de cellules precurseurs des adipocytes de la moelle. La deficience de p16INK4a dans la moelle osseuse de souris chimeres p16−/− LDLRKO augmente le developpement du PVAT induit par un regime western. Conclusion L'ensemble de ces donnees demontre un nouveau role de p16INK4a dans l'adipogenese et le developpement du PVAT.
- Published
- 2014
44. Isolation and characterization of two sub-species of Lp(a), one containing apo E and one free of apo E
- Author
-
Bruno Derudas, Pascal Pont, Sophie Delattre-Lestavel, Jean-Marie Bard, H J Parra, Véronique Clavey, and Jean-Charles Fruchart
- Subjects
Apolipoprotein E ,Very low-density lipoprotein ,Apolipoprotein B ,Lipoproteins ,Biophysics ,Receptors, Cell Surface ,Apoprotein(a) ,Biochemistry ,Chromatography, Affinity ,chemistry.chemical_compound ,Endocrinology ,Apolipoproteins E ,Affinity chromatography ,Humans ,Particle Size ,Receptor ,Receptors, Lipoprotein ,biology ,Chemistry ,Cholesterol ,Immunosorbents ,Lipids ,Apolipoproteins ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Lipoprotein ,HeLa Cells ,Lipoprotein(a) - Abstract
Lipoprotein Lp(a) was isolated by immunoaffinity chromatography using anti apolipoprotein B and anti apolipoprotein (a) immunosorbents. Besides apolipoproteins (a) and B, this fraction was shown to contain apolipoproteins C and E. Therefore, it was decided to further purify this crude Lp(a) into particles containing apolipoprotein E and particles free of apo E, using chromatography with an anti apolipoprotein E immuosorbent. Lp(a), free of apolipoprotein E was cholesterol ester rich and triacylglycerol poor and was found mainly in the LDL size range. In contrast, Lp(a) containing apolipoprotein E was triacylglycerol rich and was distributed mainly in the VLDL nd IDL size range. Binding of these two fractions, one containing apo E and one free of it, to the apo B/E receptor of HeLa cells was studied. Both fractions bound to the receptor but the one containing apo E had a better affinity than the one free of apo E. Further studies are needed to identity the clinical importance of these two different entities.
- Published
- 1992
45. PPARγ Activation Primes Human Monocytes into Alternative M2 Macrophages with Anti-inflammatory Properties
- Author
-
John Brozek, Stéphan Haulon, Rebecca Dièvart, Nikolaus Marx, Bruno Derudas, Gérard Torpier, M. Amine Bouhlel, Christophe Zawadzki, Brigitte Jude, Elena Rigamonti, Bart Staels, and Giulia Chinetti-Gbaguidi
- Subjects
Agonist ,Carotid Artery Diseases ,medicine.drug_class ,Physiology ,HUMDISEASE ,Inflammation ,Biology ,Peripheral blood mononuclear cell ,Monocytes ,Benzophenones ,Paracrine Communication ,medicine ,Macrophage ,Humans ,Molecular Biology ,Cells, Cultured ,Blood Cells ,Macrophages ,Stem Cells ,Cell Differentiation ,Cell Biology ,M2 Macrophage ,Phenotype ,PPAR gamma ,Nuclear receptor ,Monocyte differentiation ,Immunology ,Tyrosine ,medicine.symptom ,Biomarkers ,Foam Cells - Abstract
Th1 cytokines promote monocyte differentiation into proatherogenic M1 macrophages, while Th2 cytokines lead to an "alternative" anti-inflammatory M2 macrophage phenotype. Here we show that in human atherosclerotic lesions, the expression of M2 markers and PPARgamma, a nuclear receptor controlling macrophage inflammation, correlate positively. Moreover, PPARgamma activation primes primary human monocytes into M2 differentiation, resulting in a more pronounced anti-inflammatory activity in M1 macrophages. However, PPARgamma activation does not influence M2 marker expression in resting or M1 macrophages, nor does PPARgamma agonist treatment influence the expression of M2 markers in atherosclerotic lesions, indicating that only native monocytes can be primed by PPARgamma activation to an enhanced M2 phenotype. Furthermore, PPARgamma activation significantly increases expression of the M2 marker MR in circulating peripheral blood mononuclear cells. These data demonstrate that PPARgamma activation skews human monocytes toward an anti-inflammatory M2 phenotype.
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.