227 results on '"Hofker MH"'
Search Results
2. Hematopoietic Npc1 mutation shifts gut microbiota composition in Ldlr -/- mice on a high-fat, high-cholesterol diet.
- Author
-
Houben T, Penders J, Oligschlaeger Y, Dos Reis IAM, Bonder MJ, Koonen DP, Fu J, Hofker MH, and Shiri-Sverdlov R
- Subjects
- Animals, Bone Marrow Transplantation, Cholesterol, Dietary, Diet, High-Fat, Female, Granuloma metabolism, Hepatocytes metabolism, Inflammation, Kupffer Cells, Lipid Metabolism, Liver metabolism, Lysosomes metabolism, Male, Mice, Mice, Knockout, Mutation, Niemann-Pick C1 Protein, Phenotype, Polymorphism, Single Nucleotide, RNA, Ribosomal, 16S metabolism, Receptors, LDL genetics, Gastrointestinal Microbiome, Hematopoietic Stem Cells cytology, Intracellular Signaling Peptides and Proteins genetics, Metabolic Syndrome microbiology
- Abstract
While the link between diet-induced changes in gut microbiota and lipid metabolism in metabolic syndrome (MetS) has been established, the contribution of host genetics is rather unexplored. As several findings suggested a role for the lysosomal lipid transporter Niemann-Pick type C1 (NPC1) in macrophages during MetS, we here explored whether a hematopoietic Npc1 mutation, induced via bone marrow transplantation, influences gut microbiota composition in low-density lipoprotein receptor knockout (Ldlr
-/- ) mice fed a high-fat, high-cholesterol (HFC) diet for 12 weeks. Ldlr-/- mice fed a HFC diet mimic a human plasma lipoprotein profile and show features of MetS, providing a model to explore the role of host genetics on gut microbiota under MetS conditions. Fecal samples were used to profile the microbial composition by 16 s ribosomal RNA gene sequencing. The hematopoietic Npc1 mutation shifted the gut microbiota composition and increased microbial richness and diversity. Variations in plasma lipid levels correlated with microbial diversity and richness as well as with several bacterial genera. This study suggests that host genetic influences on lipid metabolism affect the gut microbiome under MetS conditions. Future research investigating the role of host genetics on gut microbiota might therefore lead to identification of diagnostic and therapeutic targets for MetS.- Published
- 2019
- Full Text
- View/download PDF
3. Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk.
- Author
-
Kurilshikov A, van den Munckhof ICL, Chen L, Bonder MJ, Schraa K, Rutten JHW, Riksen NP, de Graaf J, Oosting M, Sanna S, Joosten LAB, van der Graaf M, Brand T, Koonen DPY, van Faassen M, Slagboom PE, Xavier RJ, Kuipers F, Hofker MH, Wijmenga C, Netea MG, Zhernakova A, and Fu J
- Subjects
- Adult, Aged, Cardiovascular Diseases genetics, Cohort Studies, Female, Humans, Male, Middle Aged, Netherlands epidemiology, Obesity genetics, Phenotype, Prospective Studies, Risk Factors, Cardiovascular Diseases epidemiology, Cardiovascular Diseases metabolism, Gastrointestinal Microbiome physiology, Metabolome physiology, Obesity epidemiology, Obesity metabolism
- Abstract
Rationale: Altered gut microbial composition has been linked to cardiovascular diseases (CVDs), but its functional links to host metabolism and immunity in relation to CVD development remain unclear., Objectives: To systematically assess functional links between the microbiome and the plasma metabolome, cardiometabolic phenotypes, and CVD risk and to identify diet-microbe-metabolism-immune interactions in well-documented cohorts., Methods and Results: We assessed metagenomics-based microbial associations between 231 plasma metabolites and microbial species and pathways in the population-based LLD (Lifelines DEEP) cohort (n=978) and a clinical obesity cohort (n=297). After correcting for age, sex, and body mass index, the gut microbiome could explain ≤11.1% and 16.4% of the variation in plasma metabolites in the population-based and obesity cohorts, respectively. Obese-specific microbial associations were found for lipid compositions in the VLDL, IDL, and LDL lipoprotein subclasses. Bacterial L-methionine biosynthesis and a Ruminococcus species were associated to cardiovascular phenotypes in obese individuals, namely atherosclerosis and liver fat content, respectively. Integration of microbiome-diet-inflammation analysis in relation to metabolic risk score of CVD in the population cohort revealed 48 microbial pathways associated to CVD risk that were largely independent of diet and inflammation. Our data also showed that plasma levels rather than fecal levels of short-chain fatty acids were relevant to inflammation and CVD risk., Conclusions: This study presents the largest metagenome-based association study on plasma metabolism and microbiome relevance to diet, inflammation, CVD risk, and cardiometabolic phenotypes in both population-based and clinical obesity cohorts. Our findings identified novel bacterial species and pathways that associated to specific lipoprotein subclasses and revealed functional links between the gut microbiome and host health that provide a basis for developing microbiome-targeted therapy for disease prevention and treatment.
- Published
- 2019
- Full Text
- View/download PDF
4. A Proinflammatory Gut Microbiota Increases Systemic Inflammation and Accelerates Atherosclerosis.
- Author
-
Brandsma E, Kloosterhuis NJ, Koster M, Dekker DC, Gijbels MJJ, van der Velden S, Ríos-Morales M, van Faassen MJR, Loreti MG, de Bruin A, Fu J, Kuipers F, Bakker BM, Westerterp M, de Winther MPJ, Hofker MH, van de Sluis B, and Koonen DPY
- Subjects
- Animals, Aorta pathology, Aortic Diseases genetics, Aortic Diseases metabolism, Aortic Diseases pathology, Atherosclerosis genetics, Atherosclerosis metabolism, Atherosclerosis pathology, Caspase 1 genetics, Caspase 1 metabolism, Disease Models, Animal, Disease Progression, Dysbiosis, Fatty Acids metabolism, Female, Host-Pathogen Interactions, Inflammation genetics, Inflammation metabolism, Inflammation pathology, Mice, Knockout, Plaque, Atherosclerotic, Receptors, LDL genetics, Receptors, LDL metabolism, Time Factors, Aorta metabolism, Aortic Diseases microbiology, Atherosclerosis microbiology, Bacteria metabolism, Cytokines metabolism, Fecal Microbiota Transplantation, Gastrointestinal Microbiome, Inflammation microbiology, Inflammation Mediators metabolism
- Abstract
Rationale: Several studies have suggested a role for the gut microbiota in inflammation and atherogenesis. A causal relation relationship between gut microbiota, inflammation, and atherosclerosis has not been explored previously., Objective: Here, we investigated whether a proinflammatory microbiota from Caspase1
-/- ( Casp1-/- ) mice accelerates atherogenesis in Ldlr-/- mice., Method and Results: We treated female Ldlr-/- mice with antibiotics and subsequently transplanted them with fecal microbiota from Casp1-/- mice based on a cohousing approach. Autologous transplantation of fecal microbiota of Ldlr-/- mice served as control. Mice were cohoused for 8 or 13 weeks and fed chow or high-fat cholesterol-rich diet. Fecal samples were collected, and factors related to inflammation, metabolism, intestinal health, and atherosclerotic phenotypes were measured. Unweighted Unifrac distances of 16S rDNA (ribosomal DNA) sequences confirmed the introduction of the Casp1-/- and Ldlr-/- microbiota into Ldlr-/- mice (referred to as Ldlr-/- ( Casp1-/- ) or Ldlr-/- ( Ldlr-/- ) mice). Analysis of atherosclerotic lesion size in the aortic root demonstrated a significant 29% increase in plaque size in 13-week high-fat cholesterol-fed Ldlr-/- ( Casp1-/- ) mice compared with Ldlr-/- ( Ldlr-/- ) mice. We found increased numbers of circulating monocytes and neutrophils and elevated proinflammatory cytokine levels in plasma in high-fat cholesterol-fed Ldlr-/- ( Casp1-/- ) compared with Ldlr-/- ( Ldlr-/- ) mice. Neutrophil accumulation in the aortic root of Ldlr-/- ( Casp1-/- ) mice was enhanced compared with Ldlr-/- ( Ldlr-/- ) mice. 16S-rDNA-encoding sequence analysis in feces identified a significant reduction in the short-chain fatty acid-producing taxonomies Akkermansia, Christensenellaceae, Clostridium, and Odoribacter in Ldlr-/- ( Casp1-/- ) mice. Consistent with these findings, cumulative concentrations of the anti-inflammatory short-chain fatty acids propionate, acetate and butyrate in the cecum were significantly reduced in 13-week high-fat cholesterol-fed Ldlr-/- ( Casp1-/- ) compared with Ldlr-/- ( Ldlr-/- ) mice., Conclusions: Introduction of the proinflammatory Casp1-/- microbiota into Ldlr-/- mice enhances systemic inflammation and accelerates atherogenesis.- Published
- 2019
- Full Text
- View/download PDF
5. Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome.
- Author
-
Vich Vila A, Imhann F, Collij V, Jankipersadsing SA, Gurry T, Mujagic Z, Kurilshikov A, Bonder MJ, Jiang X, Tigchelaar EF, Dekens J, Peters V, Voskuil MD, Visschedijk MC, van Dullemen HM, Keszthelyi D, Swertz MA, Franke L, Alberts R, Festen EAM, Dijkstra G, Masclee AAM, Hofker MH, Xavier RJ, Alm EJ, Fu J, Wijmenga C, Jonkers DMAE, Zhernakova A, and Weersma RK
- Subjects
- Bacteria growth & development, Bacteria pathogenicity, Biodiversity, Case-Control Studies, Drug Resistance, Microbial, Feces microbiology, Humans, Metagenome, Models, Biological, Phenotype, Principal Component Analysis, ROC Curve, Species Specificity, Virulence, Gastrointestinal Microbiome genetics, Inflammatory Bowel Diseases microbiology, Irritable Bowel Syndrome microbiology
- Abstract
Changes in the gut microbiota have been associated with two of the most common gastrointestinal diseases, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Here, we performed a case-control analysis using shotgun metagenomic sequencing of stool samples from 1792 individuals with IBD and IBS compared with control individuals in the general population. Despite substantial overlap between the gut microbiome of patients with IBD and IBS compared with control individuals, we were able to use gut microbiota composition differences to distinguish patients with IBD from those with IBS. By combining species-level profiles and strain-level profiles with bacterial growth rates, metabolic functions, antibiotic resistance, and virulence factor analyses, we identified key bacterial species that may be involved in two common gastrointestinal diseases., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
- Full Text
- View/download PDF
6. Author Correction: Individual variations in cardiovascular-disease-related protein levels are driven by genetics and gut microbiome.
- Author
-
Zhernakova DV, Le TH, Kurilshikov A, Atanasovska B, Bonder MJ, Sanna S, Claringbould A, Võsa U, Deelen P, Franke L, de Boer RA, Kuipers F, Netea MG, Hofker MH, Wijmenga C, Zhernakova A, and Fu J
- Abstract
In the version of this paper originally published, there was a typographical error. In the Discussion, the sentence "In line with this, Ep-CAM-deficient mice exhibited increased intestinal permeability and decreased ion transport
60 , which may contribute to CVD susceptibility risk59 " originally read iron instead of ion transport. This error has been corrected in the HTML, PDF and print versions of the article.- Published
- 2018
- Full Text
- View/download PDF
7. Individual variations in cardiovascular-disease-related protein levels are driven by genetics and gut microbiome.
- Author
-
Zhernakova DV, Le TH, Kurilshikov A, Atanasovska B, Bonder MJ, Sanna S, Claringbould A, Võsa U, Deelen P, Franke L, de Boer RA, Kuipers F, Netea MG, Hofker MH, Wijmenga C, Zhernakova A, and Fu J
- Subjects
- Adult, Biological Variation, Individual, Blood Proteins metabolism, Brain physiology, Cohort Studies, Female, Genome-Wide Association Study, Host Microbial Interactions genetics, Humans, Intestines innervation, Intestines microbiology, Lipid Metabolism genetics, Male, Metagenome genetics, Middle Aged, Netherlands, Oxidation-Reduction, Quantitative Trait Loci genetics, Blood Proteins genetics, Cardiovascular Diseases blood, Cardiovascular Diseases genetics, Cardiovascular Diseases microbiology, Gastrointestinal Microbiome physiology
- Abstract
Despite a growing body of evidence, the role of the gut microbiome in cardiovascular diseases is still unclear. Here, we present a systems-genome-wide and metagenome-wide association study on plasma concentrations of 92 cardiovascular-disease-related proteins in the population cohort LifeLines-DEEP. We identified genetic components for 73 proteins and microbial associations for 41 proteins, of which 31 were associated to both. The genetic and microbial factors identified mostly exert additive effects and collectively explain up to 76.6% of inter-individual variation (17.5% on average). Genetics contribute most to concentrations of immune-related proteins, while the gut microbiome contributes most to proteins involved in metabolism and intestinal health. We found several host-microbe interactions that impact proteins involved in epithelial function, lipid metabolism, and central nervous system function. This study provides important evidence for a joint genetic and microbial effect in cardiovascular disease and provides directions for future applications in personalized medicine.
- Published
- 2018
- Full Text
- View/download PDF
8. Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice.
- Author
-
Bijnen M, Josefs T, Cuijpers I, Maalsen CJ, van de Gaar J, Vroomen M, Wijnands E, Rensen SS, Greve JWM, Hofker MH, Biessen EAL, Stehouwer CDA, Schalkwijk CG, and Wouters K
- Subjects
- Adipose Tissue metabolism, Animals, CD11 Antigens metabolism, Cytokines metabolism, Liver metabolism, Liver pathology, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Non-alcoholic Fatty Liver Disease etiology, Non-alcoholic Fatty Liver Disease metabolism, Obesity metabolism, Obesity pathology, Adipose Tissue pathology, Macrophages physiology, Neutrophil Infiltration physiology, Non-alcoholic Fatty Liver Disease pathology, Obesity complications
- Abstract
Objective: Obesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c
+ proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development., Design: vAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr-/- acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH., Results: Transplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c+ and CD11c- macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c+ ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes., Conclusion: ATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)- Published
- 2018
- Full Text
- View/download PDF
9. The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking.
- Author
-
Fedoseienko A, Wijers M, Wolters JC, Dekker D, Smit M, Huijkman N, Kloosterhuis N, Klug H, Schepers A, Willems van Dijk K, Levels JHM, Billadeau DD, Hofker MH, van Deursen J, Westerterp M, Burstein E, Kuivenhoven JA, and van de Sluis B
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Atherosclerosis metabolism, Carrier Proteins genetics, Carrier Proteins metabolism, Cell Line, Cholesterol analysis, Chromatography, High Pressure Liquid, Cytoskeletal Proteins genetics, Gene Deletion, Gene Expression, HEK293 Cells, Hep G2 Cells, Humans, Liver chemistry, Liver metabolism, Low Density Lipoprotein Receptor-Related Protein-1, Male, Mice, Mice, Knockout, Protein Transport, Triglycerides analysis, Tumor Suppressor Proteins metabolism, Adaptor Proteins, Signal Transducing metabolism, Atherosclerosis prevention & control, Cholesterol, LDL blood, Cytoskeletal Proteins metabolism, Endosomes metabolism, Receptors, LDL metabolism
- Abstract
Rationale: COMMD (copper metabolism MURR1 domain)-containing proteins are a part of the CCC (COMMD-CCDC22 [coiled-coil domain containing 22]-CCDC93 [coiled-coil domain containing 93]) complex facilitating endosomal trafficking of cell surface receptors. Hepatic COMMD1 inactivation decreases CCDC22 and CCDC93 protein levels, impairs the recycling of the LDLR (low-density lipoprotein receptor), and increases plasma low-density lipoprotein cholesterol levels in mice. However, whether any of the other COMMD members function similarly as COMMD1 and whether perturbation in the CCC complex promotes atherogenesis remain unclear., Objective: The main aim of this study is to unravel the contribution of evolutionarily conserved COMMD proteins to plasma lipoprotein levels and atherogenesis., Methods and Results: Using liver-specific Commd1 , Commd6 , or Commd9 knockout mice, we investigated the relation between the COMMD proteins in the regulation of plasma cholesterol levels. Combining biochemical and quantitative targeted proteomic approaches, we found that hepatic COMMD1, COMMD6, or COMMD9 deficiency resulted in massive reduction in the protein levels of all 10 COMMDs. This decrease in COMMD protein levels coincided with destabilizing of the core (CCDC22, CCDC93, and chromosome 16 open reading frame 62 [C16orf62]) of the CCC complex, reduced cell surface levels of LDLR and LRP1 (LDLR-related protein 1), followed by increased plasma low-density lipoprotein cholesterol levels. To assess the direct contribution of the CCC core in the regulation of plasma cholesterol levels, Ccdc22 was deleted in mouse livers via CRISPR/Cas9-mediated somatic gene editing. CCDC22 deficiency also destabilized the complete CCC complex and resulted in elevated plasma low-density lipoprotein cholesterol levels. Finally, we found that hepatic disruption of the CCC complex exacerbates dyslipidemia and atherosclerosis in ApoE3*Leiden mice., Conclusions: Collectively, these findings demonstrate a strong interrelationship between COMMD proteins and the core of the CCC complex in endosomal LDLR trafficking. Hepatic disruption of either of these CCC components causes hypercholesterolemia and exacerbates atherosclerosis. Our results indicate that not only COMMD1 but all other COMMDs and CCC components may be potential targets for modulating plasma lipid levels in humans., (© 2018 American Heart Association, Inc.)
- Published
- 2018
- Full Text
- View/download PDF
10. Blood-derived macrophages prone to accumulate lysosomal lipids trigger oxLDL-dependent murine hepatic inflammation.
- Author
-
Houben T, Oligschlaeger Y, Bitorina AV, Hendrikx T, Walenbergh SMA, Lenders MH, Gijbels MJJ, Verheyen F, Lütjohann D, Hofker MH, Binder CJ, and Shiri-Sverdlov R
- Subjects
- Animals, Autoantibodies biosynthesis, Autoantibodies immunology, Autoantibodies therapeutic use, Cholesterol metabolism, Disease Models, Animal, Humans, Immunoglobulin M biosynthesis, Immunoglobulin M immunology, Inflammation blood, Inflammation complications, Inflammation therapy, Kupffer Cells metabolism, Lipids blood, Lipoproteins, LDL antagonists & inhibitors, Lipoproteins, LDL immunology, Liver metabolism, Liver pathology, Lysosomes metabolism, Macrophages pathology, Mice, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease pathology, Non-alcoholic Fatty Liver Disease therapy, Inflammation metabolism, Lipoproteins, LDL metabolism, Macrophages metabolism, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
Despite the consistent rise of non-alcoholic steatohepatitis (NASH) worldwide, the mechanisms that govern the inflammatory aspect of this disease remain unknown. Previous research showed an association between hepatic inflammation and lysosomal lipid accumulation in blood-derived hepatic macrophages. Additionally, in vitro findings indicated that lipids, specifically derived from the oxidized low-density lipoprotein (oxLDL) particle, are resistant to removal from lysosomes. On this basis, we investigated whether lysosomal lipid accumulation in blood-derived hepatic macrophages is causally linked to hepatic inflammation and assessed to what extent increasing anti-oxLDL IgM autoantibodies can affect this mechanism. By creating a proof-of-concept mouse model, we demonstrate a causal role for lysosomal lipids in blood-derived hepatic macrophages in mediating hepatic inflammation and initiation of fibrosis. Furthermore, our findings show that increasing anti-oxLDL IgM autoantibody levels reduces inflammation. Hence, therapies aimed at improving lipid-induced lysosomal dysfunction and blocking oxLDL-formation deserve further investigation in the context of NASH.
- Published
- 2017
- Full Text
- View/download PDF
11. NF-κB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFα-or diet-induced inflammation.
- Author
-
Riedlinger T, Dommerholt MB, Wijshake T, Kruit JK, Huijkman N, Dekker D, Koster M, Kloosterhuis N, Koonen DPY, de Bruin A, Baker D, Hofker MH, van Deursen J, Jonker JW, Schmitz ML, and van de Sluis B
- Subjects
- Aging metabolism, Aging pathology, Amino Acid Substitution genetics, Animals, Gene Expression Regulation, Gene Knock-In Techniques, Humans, Inflammation genetics, Inflammation pathology, Insulin metabolism, Liver metabolism, Liver pathology, Mice, Obesity metabolism, Obesity pathology, Phosphorylation, Serine metabolism, Transcription Factor RelA metabolism, Tumor Necrosis Factor-alpha metabolism, Weight Gain genetics, Aging genetics, Inflammation metabolism, Obesity genetics, Transcription Factor RelA genetics
- Abstract
The NF-κB family of transcription factors is essential for an effective immune response, but also controls cell metabolism, proliferation and apoptosis. Its broad relevance and the high connectivity to diverse signaling pathways require a tight control of NF-κB activity. To investigate the control of NF-κB activity by phosphorylation of the NF-κB p65 subunit, we generated a knock-in mouse model in which serine 467 (the mouse homolog of human p65 serine 468) was replaced with a non-phosphorylatable alanine (S467A). This substitution caused reduced p65 protein synthesis and diminished TNFα-induced expression of a selected group of NF-κB-dependent genes. Intriguingly, high-fat fed S467A mice displayed increased locomotor activity and energy expenditure, which coincided with a reduced body weight gain. Although glucose metabolism or insulin sensitivity was not improved, diet-induced liver inflammation was diminished in S467A mice. Altogether, this study demonstrates that phosphorylation of p65 serine 467 augment NF-κB activity and exacerbates various deleterious effects of overnutrition in mice., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
12. A liver-specific long noncoding RNA with a role in cell viability is elevated in human nonalcoholic steatohepatitis.
- Author
-
Atanasovska B, Rensen SS, van der Sijde MR, Marsman G, Kumar V, Jonkers I, Withoff S, Shiri-Sverdlov R, Greve JWM, Faber KN, Moshage H, Wijmenga C, van de Sluis B, Hofker MH, and Fu J
- Subjects
- Apoptosis genetics, Biopsy, Needle, Cells, Cultured metabolism, Cells, Cultured pathology, Disease Progression, Female, Hepatocytes pathology, Humans, Immunohistochemistry, Male, Microarray Analysis, Risk Assessment, Sampling Studies, Cell Survival genetics, Gene Expression Regulation, Hepatocytes metabolism, Non-alcoholic Fatty Liver Disease pathology, RNA, Long Noncoding genetics
- Abstract
Hepatocyte apoptosis in nonalcoholic steatohepatitis (NASH) can lead to fibrosis and cirrhosis, which permanently damage the liver. Understanding the regulation of hepatocyte apoptosis is therefore important to identify therapeutic targets that may prevent the progression of NASH to fibrosis. Recently, increasing evidence has shown that long noncoding (lnc) RNAs are involved in various biological processes and that their dysregulation underlies a number of complex human diseases. By performing gene expression profiling of 4,383 lncRNAs in 82 liver samples from individuals with NASH (n = 48), simple steatosis but no NASH (n = 11), and healthy controls (n = 23), we discovered a liver-specific lncRNA (RP11-484N16.1) on chromosome 18 that showed significantly elevated expression in the liver tissue of NASH patients. This lncRNA, which we named lnc18q22.2 based on its chromosomal location, correlated with NASH grade (r = 0.51, P = 8.11 × 10
-7 ), lobular inflammation (r = 0.49, P = 2.35 × 10-6 ), and nonalcoholic fatty liver disease activity score (r = 0.48, P = 4.69 × 10-6 ). The association of lnc18q22.2 to liver steatosis and steatohepatitis was replicated in 44 independent liver biopsies (r = 0.47, P = 0.0013). We provided a genetic structure of lnc18q22.2 showing an extended exon 2 in liver. Knockdown of lnc18q22.2 in four different hepatocyte cell lines resulted in severe phenotypes ranging from reduced cell growth to lethality. This observation was consistent with pathway analyses of genes coexpressed with lnc18q22.2 in human liver or affected by lnc18q22.2 knockdown., Conclusion: We identified an lncRNA that can play an important regulatory role in liver function and provide new insights into the regulation of hepatocyte viability in NASH. (Hepatology 2017;66:794-808)., (© 2017 by the American Association for the Study of Liver Diseases.)- Published
- 2017
- Full Text
- View/download PDF
13. Cathepsin D regulates lipid metabolism in murine steatohepatitis.
- Author
-
Houben T, Oligschlaeger Y, Hendrikx T, Bitorina AV, Walenbergh SMA, van Gorp PJ, Gijbels MJJ, Friedrichs S, Plat J, Schaap FG, Lütjohann D, Hofker MH, and Shiri-Sverdlov R
- Subjects
- Animals, Disease Models, Animal, Female, Inflammation complications, Inflammation enzymology, Mice, Inbred C57BL, Non-alcoholic Fatty Liver Disease complications, Cathepsin D metabolism, Lipid Metabolism, Non-alcoholic Fatty Liver Disease enzymology
- Abstract
Due to the obesity epidemic, non-alcoholic steatohepatitis (NASH) is a prevalent liver disease, characterized by fat accumulation and inflammation of the liver. However, due to a lack of mechanistic insight, diagnostic and therapeutic options for NASH are poor. Recent evidence has indicated cathepsin D (CTSD), a lysosomal enzyme, as a marker for NASH. Here, we investigated the function of CTSD in NASH by using an in vivo and in vitro model. In addition to diminished hepatic inflammation, inhibition of CTSD activity dramatically improved lipid metabolism, as demonstrated by decreased plasma and liver levels of both cholesterol and triglycerides. Mechanistically, CTSD inhibition resulted in an increased conversion of cholesterol into bile acids and an elevated excretion of bile acids via the feces, indicating that CTSD influences lipid metabolism. Consistent with these findings, treating Wt BMDMs with PepA in vitro showed a similar decrease in inflammation and an analogous effect on cholesterol metabolism., Conclusion: CTSD is a key player in the development of hepatic inflammation and dyslipidemia. Therefore, aiming at the inhibition of the activity of CTSD may lead to novel treatments to combat NASH.
- Published
- 2017
- Full Text
- View/download PDF
14. Oxidized LDL at the crossroads of immunity in non-alcoholic steatohepatitis.
- Author
-
Houben T, Brandsma E, Walenbergh SMA, Hofker MH, and Shiri-Sverdlov R
- Subjects
- Humans, Inflammation immunology, Inflammation metabolism, Lipid Metabolism immunology, Lipid Metabolism physiology, Liver immunology, Liver metabolism, Lipoproteins, LDL immunology, Lipoproteins, LDL metabolism, Non-alcoholic Fatty Liver Disease immunology, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
Non-alcoholic steatohepatitis (NASH) is viewed as the hepatic manifestation of the metabolic syndrome and is a condition hallmarked by lipid accumulation in the liver (steatosis) along with inflammation (hepatitis). Currently, the etiology and mechanisms leading to obesity-induced hepatic inflammation are not clear and, as a consequence, strategies to diagnose or treat NASH in an accurate manner do not exist. In the current review, we put forward the concept of oxidized lipids as a significant risk factor for NASH. We will focus on the contribution of the different types of oxidized lipids as part of the oxidized low-density lipoprotein (oxLDL) to the hepatic inflammatory response. Furthermore, we will elaborate on the underlying mechanisms linking oxLDL to inflammatory responses in the liver and on how these cascades can be used as therapeutic targets to combat NASH. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
15. Plasma cathepsin D correlates with histological classifications of fatty liver disease in adults and responds to intervention.
- Author
-
Walenbergh SM, Houben T, Rensen SS, Bieghs V, Hendrikx T, van Gorp PJ, Oligschlaeger Y, Jeurissen ML, Gijbels MJ, Buurman WA, Vreugdenhil AC, Greve JW, Plat J, Hofker MH, Kalhan S, Pihlajamäki J, Lindsey P, Koek GH, and Shiri-Sverdlov R
- Subjects
- Adult, Alanine Transaminase blood, Biomarkers blood, Biopsy, Cohort Studies, Female, Humans, Inflammation, Liver pathology, Liver surgery, Male, Middle Aged, Non-alcoholic Fatty Liver Disease pathology, Non-alcoholic Fatty Liver Disease surgery, Severity of Illness Index, Cathepsin D blood, Liver metabolism, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease diagnosis
- Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by liver lipid accumulation and inflammation. The mechanisms that trigger hepatic inflammation are poorly understood and subsequently, no specific non-invasive markers exist. We previously demonstrated a reduction in the plasma lysosomal enzyme, cathepsin D (CatD), in children with NASH compared to children without NASH. Recent studies have raised the concept that non-alcoholic fatty liver disease (NAFLD) in adults is distinct from children due to a different histological pattern in the liver. Yet, the link between plasma CatD to adult NASH was not examined. In the current manuscript, we investigated whether plasma CatD in adults correlates with NASH development and regression. Biopsies were histologically evaluated for inflammation and NAFLD in three complementary cohorts of adults (total n = 248). CatD and alanine aminotransferase (ALT) were measured in plasma. Opposite to our previous observations with childhood NASH, we observed increased levels of plasma CatD in patients with NASH compared to adults without hepatic inflammation. Furthermore, after surgical intervention, we found a reduction of plasma CatD compared to baseline. Our observations highlight a distinct pathophysiology between NASH in children and adults. The observation that plasma CatD correlated with NASH development and regression is promising for NASH diagnosis.
- Published
- 2016
- Full Text
- View/download PDF
16. The effect of host genetics on the gut microbiome.
- Author
-
Bonder MJ, Kurilshikov A, Tigchelaar EF, Mujagic Z, Imhann F, Vila AV, Deelen P, Vatanen T, Schirmer M, Smeekens SP, Zhernakova DV, Jankipersadsing SA, Jaeger M, Oosting M, Cenit MC, Masclee AA, Swertz MA, Li Y, Kumar V, Joosten L, Harmsen H, Weersma RK, Franke L, Hofker MH, Xavier RJ, Jonkers D, Netea MG, Wijmenga C, Fu J, and Zhernakova A
- Subjects
- Adolescent, Adult, Aged, Animals, Cohort Studies, Female, Genome-Wide Association Study, Humans, Immunity genetics, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Gastrointestinal Microbiome, Genome, Human
- Abstract
The gut microbiome is affected by multiple factors, including genetics. In this study, we assessed the influence of host genetics on microbial species, pathways and gene ontology categories, on the basis of metagenomic sequencing in 1,514 subjects. In a genome-wide analysis, we identified associations of 9 loci with microbial taxonomies and 33 loci with microbial pathways and gene ontology terms at P < 5 × 10
-8 . Additionally, in a targeted analysis of regions involved in complex diseases, innate and adaptive immunity, or food preferences, 32 loci were identified at the suggestive level of P < 5 × 10-6 . Most of our reported associations are new, including genome-wide significance for the C-type lectin molecules CLEC4F-CD207 at 2p13.3 and CLEC4A-FAM90A1 at 12p13. We also identified association of a functional LCT SNP with the Bifidobacterium genus (P = 3.45 × 10-8 ) and provide evidence of a gene-diet interaction in the regulation of Bifidobacterium abundance. Our results demonstrate the importance of understanding host-microbe interactions to gain better insight into human health.- Published
- 2016
- Full Text
- View/download PDF
17. Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer.
- Author
-
Fedoseienko A, Wieringa HW, Wisman GB, Duiker E, Reyners AK, Hofker MH, van der Zee AG, van de Sluis B, and van Vugt MA
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Apoptosis drug effects, Cell Line, Tumor, Cisplatin therapeutic use, Cohort Studies, Female, G2 Phase Cell Cycle Checkpoints drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, M Phase Cell Cycle Checkpoints drug effects, Neoplasm Grading, Neoplasm Staging, Ovarian Neoplasms genetics, Adaptor Proteins, Signal Transducing metabolism, Cell Nucleus drug effects, Cell Nucleus metabolism, Cisplatin pharmacology, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology
- Abstract
Copper metabolism MURR1 domain 1 (COMMD1) protein is a multifunctional protein, and its expression has been correlated with patients' survival in different types of cancer. In vitro studies revealed that COMMD1 plays a role in sensitizing cancer cell lines to cisplatin, however, the mechanism and its role in platinum sensitivity in cancer has yet to be established. We evaluated the role of COMMD1 in cisplatin sensitivity in A2780 ovarian cancer cells and the relation between COMMD1 expression and response to platinum-based therapy in advanced stage high-grade serous ovarian cancer (HGSOC) patients. We found that elevation of nuclear COMMD1 expression sensitized A2780 ovarian cancer cells to cisplatin-mediated cytotoxicity. This was accompanied by a more effective G2/M checkpoint, and decreased protein expression of the DNA repair gene BRCA1, and the apoptosis inhibitor BCL2. Furthermore, COMMD1 expression was immunohistochemically analyzed in two tissue micro-arrays (TMAs), representing a historical cohort and a randomized clinical trial-based cohort of advanced stage HGSOC tumor specimens. Expression of COMMD1 was observed in all ovarian cancer samples, however, specifically nuclear expression of COMMD1 was only observed in a subset of ovarian cancers. In our historical cohort, nuclear COMMD1 expression was associated with an improved response to chemotherapy (OR = 0.167; P = 0.038), although this association could not be confirmed in the second cohort, likely due to sample size. Taken together, these results suggest that nuclear expression of COMMD1 sensitize ovarian cancer to cisplatin, possibly by modulating the G2/M checkpoint and through controlling expression of genes involved in DNA repair and apoptosis., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
- Full Text
- View/download PDF
18. Low levels of IgM antibodies recognizing oxidation-specific epitopes are associated with human non-alcoholic fatty liver disease.
- Author
-
Hendrikx T, Watzenböck ML, Walenbergh SM, Amir S, Gruber S, Kozma MO, Grabsch HI, Koek GH, Pierik MJ, Staufer K, Trauner M, Kalhan SC, Jonkers D, Hofker MH, Binder CJ, and Shiri-Sverdlov R
- Subjects
- Adult, Aged, Biomarkers blood, Case-Control Studies, Female, Humans, Lipid Metabolism immunology, Male, Middle Aged, Non-alcoholic Fatty Liver Disease blood, Epitopes, Immunoglobulin G blood, Immunoglobulin M blood, Non-alcoholic Fatty Liver Disease immunology, Oxidation-Reduction
- Abstract
Background: Lipid oxidation of membrane phospholipids is accompanied by the formation of oxidation-specific epitopes (OSE). These epitopes are recognized by specific antibodies and represent danger-associated molecular patterns that are generated during chronic inflammatory processes. In a murine model for hepatic inflammation during non-alcoholic fatty liver disease (NAFLD), increased antibody levels targeting OSE were found to be protective. Here, our aim was to determine an association between OSE-specific antibody titers and NAFLD in humans., Methods: IgM and IgG levels with specificity for various OSE were assessed in the plasma of patients with NAFLD (n = 71) and healthy controls (n = 68). Antibody titers were comprehensively analyzed in patients with NAFLD after classification by histological evaluation of liver biopsies. Statistical analysis was performed to determine significant correlations and odds ratios. To study the specificity for NAFLD, plasma antibody titers were measured in patients with hepatitis C (n = 40) and inflammatory bowel disease (n = 62)., Results: IgM titers against OSE were lower in patients with NAFLD compared to controls. Further biopsy-based classification of patients with NAFLD did not show any difference in IgM levels. Plasma IgM titers towards the P1 mimotope demonstrated an inverse correlation with markers for obesity, systemic inflammation, and liver damage. In contrast, hepatitis C and increased disease activity during inflammatory bowel disease was not associated with reduced IgM titers., Conclusions: Our data highlight the importance of immune recognition of OSE by IgM antibodies in the pathophysiology of NAFLD.
- Published
- 2016
- Full Text
- View/download PDF
19. Novel Biomarkers to Improve the Prediction of Cardiovascular Event Risk in Type 2 Diabetes Mellitus.
- Author
-
van der Leeuw J, Beulens JW, van Dieren S, Schalkwijk CG, Glatz JF, Hofker MH, Verschuren WM, Boer JM, van der Graaf Y, Visseren FL, Peelen LM, and van der Schouw YT
- Subjects
- Adult, Diabetes Mellitus, Type 2 blood, Diabetic Angiopathies blood, Female, Humans, Male, Matrix Metalloproteinase 3 metabolism, Middle Aged, Natriuretic Peptide, Brain metabolism, Netherlands, Osteopontin metabolism, Peptide Fragments metabolism, Prospective Studies, Risk Assessment methods, Biomarkers metabolism, Diabetes Mellitus, Type 2 prevention & control, Diabetic Angiopathies prevention & control
- Abstract
Background: We evaluated the ability of 23 novel biomarkers representing several pathophysiological pathways to improve the prediction of cardiovascular event (CVE) risk in patients with type 2 diabetes mellitus beyond traditional risk factors., Methods and Results: We used data from 1002 patients with type 2 diabetes mellitus from the Second Manifestations of ARTertial disease (SMART) study and 288 patients from the European Prospective Investigation into Cancer and Nutrition-NL (EPIC-NL). The associations of 23 biomarkers (adiponectin, C-reactive protein, epidermal-type fatty acid binding protein, heart-type fatty acid binding protein, basic fibroblast growth factor, soluble FMS-like tyrosine kinase-1, soluble intercellular adhesion molecule-1 and -3, matrix metalloproteinase [MMP]-1, MMP-3, MMP-9, N-terminal prohormone of B-type natriuretic peptide, osteopontin, osteonectin, osteocalcin, placental growth factor, serum amyloid A, E-selectin, P-selectin, tissue inhibitor of MMP-1, thrombomodulin, soluble vascular cell adhesion molecule-1, and vascular endothelial growth factor) with CVE risk were evaluated by using Cox proportional hazards analysis adjusting for traditional risk factors. The incremental predictive performance was assessed with use of the c-statistic and net reclassification index (NRI; continuous and based on 10-year risk strata 0-10%, 10-20%, 20-30%, >30%). A multimarker model was constructed comprising those biomarkers that improved predictive performance in both cohorts. N-terminal prohormone of B-type natriuretic peptide, osteopontin, and MMP-3 were the only biomarkers significantly associated with an increased risk of CVE and improved predictive performance in both cohorts. In SMART, the combination of these biomarkers increased the c-statistic with 0.03 (95% CI 0.01-0.05), and the continuous NRI was 0.37 (95% CI 0.21-0.52). In EPIC-NL, the multimarker model increased the c-statistic with 0.03 (95% CI 0.00-0.03), and the continuous NRI was 0.44 (95% CI 0.23-0.66). Based on risk strata, the NRI was 0.12 (95% CI 0.03-0.21) in SMART and 0.07 (95% CI -0.04-0.17) in EPIC-NL., Conclusions: Of the 23 evaluated biomarkers from different pathophysiological pathways, N-terminal prohormone of B-type natriuretic peptide, osteopontin, MMP-3, and their combination improved CVE risk prediction in 2 separate cohorts of patients with type 2 diabetes mellitus beyond traditional risk factors. However, the number of patients reclassified to a different risk stratum was limited., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)
- Published
- 2016
- Full Text
- View/download PDF
20. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity.
- Author
-
Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, Mujagic Z, Vila AV, Falony G, Vieira-Silva S, Wang J, Imhann F, Brandsma E, Jankipersadsing SA, Joossens M, Cenit MC, Deelen P, Swertz MA, Weersma RK, Feskens EJ, Netea MG, Gevers D, Jonkers D, Franke L, Aulchenko YS, Huttenhower C, Raes J, Hofker MH, Xavier RJ, Wijmenga C, and Fu J
- Subjects
- Bacteria genetics, Bacteria isolation & purification, Chromogranin A analysis, Chromogranin A metabolism, Diet, Enteroendocrine Cells metabolism, Feces chemistry, Feces microbiology, Genetic Markers, High-Throughput Nucleotide Sequencing, Humans, Metagenomics, Netherlands, Phylogeny, RNA, Ribosomal, 16S genetics, Bacteria classification, Gastrointestinal Microbiome genetics, Gastrointestinal Tract microbiology
- Abstract
Deep sequencing of the gut microbiomes of 1135 participants from a Dutch population-based cohort shows relations between the microbiome and 126 exogenous and intrinsic host factors, including 31 intrinsic factors, 12 diseases, 19 drug groups, 4 smoking categories, and 60 dietary factors. These factors collectively explain 18.7% of the variation seen in the interindividual distance of microbial composition. We could associate 110 factors to 125 species and observed that fecal chromogranin A (CgA), a protein secreted by enteroendocrine cells, was exclusively associated with 61 microbial species whose abundance collectively accounted for 53% of microbial composition. Low CgA concentrations were seen in individuals with a more diverse microbiome. These results are an important step toward a better understanding of environment-diet-microbe-host interactions., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2016, American Association for the Advancement of Science.)
- Published
- 2016
- Full Text
- View/download PDF
21. CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL.
- Author
-
Bartuzi P, Billadeau DD, Favier R, Rong S, Dekker D, Fedoseienko A, Fieten H, Wijers M, Levels JH, Huijkman N, Kloosterhuis N, van der Molen H, Brufau G, Groen AK, Elliott AM, Kuivenhoven JA, Plecko B, Grangl G, McGaughran J, Horton JD, Burstein E, Hofker MH, and van de Sluis B
- Subjects
- Adolescent, Adult, Animals, Animals, Genetically Modified, Child, Child, Preschool, Chromatography, Liquid, Dogs, Female, Fluorescent Antibody Technique, HEK293 Cells, Humans, Immunoprecipitation, Male, Mice, Mice, Knockout, Middle Aged, Mutation, Protein Transport genetics, Transcriptome, Young Adult, Adaptor Proteins, Signal Transducing genetics, Cholesterol, LDL metabolism, Endosomes metabolism, Hypercholesterolemia genetics, Liver metabolism, Microfilament Proteins genetics, Proteins genetics, Receptors, LDL metabolism, Triglycerides metabolism
- Abstract
The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that patients with X-linked intellectual disability caused by mutations in CCDC22 are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific Commd1 knockout mice have elevated plasma LDL cholesterol levels. Furthermore, Commd1 depletion results in mislocalization of LDLR, accompanied by decreased LDL uptake. Increased total plasma cholesterol levels are also seen in hepatic COMMD9-deficient mice. Inactivation of the CCC-associated WASH complex causes LDLR mislocalization, increased lysosomal degradation of LDLR and impaired LDL uptake. Furthermore, a mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking.
- Published
- 2016
- Full Text
- View/download PDF
22. Effects of Anthocyanin and Flavanol Compounds on Lipid Metabolism and Adipose Tissue Associated Systemic Inflammation in Diet-Induced Obesity.
- Author
-
van der Heijden RA, Morrison MC, Sheedfar F, Mulder P, Schreurs M, Hommelberg PP, Hofker MH, Schalkwijk C, Kleemann R, Tietge UJ, Koonen DP, and Heeringa P
- Subjects
- Animals, Diet, Fat-Restricted, Diet, High-Fat adverse effects, Inflammation immunology, Inflammation metabolism, Male, Mice, Mice, Inbred C57BL, Obesity metabolism, Plant Extracts therapeutic use, Tumor Necrosis Factor-alpha metabolism, Vaccinium myrtillus chemistry, Adipose Tissue drug effects, Anthocyanins therapeutic use, Flavanones therapeutic use, Inflammation drug therapy, Lipid Metabolism drug effects, Obesity immunology
- Abstract
Background. Naturally occurring substances from the flavanol and anthocyanin family of polyphenols have been proposed to exert beneficial effects in the course of obesity. We hypothesized that their effects on attenuating obesity-induced dyslipidemia as well as the associated inflammatory sequelae especially have health-promoting potential. Methods. Male C57BL/6J mice (n = 52) received a control low-fat diet (LFD; 10 kcal% fat) for 6 weeks followed by 24 weeks of either LFD (n = 13) or high-fat diet (HFD; 45 kcal% fat; n = 13) or HFD supplemented with 0.1% w/w of the flavanol compound epicatechin (HFD+E; n = 13) or an anthocyanin-rich bilberry extract (HFD+B; n = 13). Energy substrate utilization was determined by indirect calorimetry in a subset of mice following the dietary switch and at the end of the experiment. Blood samples were collected at baseline and at 3 days and 4, 12, and 20 weeks after dietary switch and analyzed for systemic lipids and proinflammatory cytokines. Adipose tissue (AT) histopathology and inflammatory gene expression as well as hepatic lipid content were analyzed after sacrifice. Results. The switch from a LFD to a HFD lowered the respiratory exchange ratio and increased plasma cholesterol and hepatic lipid content. These changes were not attenuated by HFD+E or HFD+B. Furthermore, the polyphenol compounds could not prevent HFD-induced systemic rise of TNF-α levels. Interestingly, a significant reduction in Tnf gene expression in HFD+B mice was observed in the AT. Furthermore, HFD+B, but not HFD+E, significantly prevented the early upregulation of circulating neutrophil chemoattractant mKC. However, no differences in AT histopathology were observed between the HFD types. Conclusion. Supplementation of HFD with an anthocyanin-rich bilberry extract but not with the flavanol epicatechin may exert beneficial effects on the systemic early inflammatory response associated with diet-induced obesity. These systemic effects were transient and not observed after prolongation of HFD-feeding (24 weeks). On the tissue level, long-term treatment with bilberry attenuated TNF-α expression in adipose tissue.
- Published
- 2016
- Full Text
- View/download PDF
23. Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells.
- Author
-
Wang Y, van der Tuin S, Tjeerdema N, van Dam AD, Rensen SS, Hendrikx T, Berbée JF, Atanasovska B, Fu J, Hoekstra M, Bekkering S, Riksen NP, Buurman WA, Greve JW, Hofker MH, Shiri-Sverdlov R, Meijer OC, Smit JW, Havekes LM, van Dijk KW, and Rensen PC
- Subjects
- Adult, Aged, Animals, Female, Humans, Male, Mice, Mice, Transgenic, Middle Aged, Cholesterol Ester Transfer Proteins metabolism, Kupffer Cells metabolism
- Abstract
Unlabelled: The role of Kupffer cells (KCs) in the pathophysiology of the liver has been firmly established. Nevertheless, KCs have been underexplored as a target for diagnosis and treatment of liver diseases owing to the lack of noninvasive diagnostic tests. We addressed the hypothesis that cholesteryl ester transfer protein (CETP) is mainly derived from KCs and may predict KC content. Microarray analysis of liver and adipose tissue biopsies, obtained from 93 obese subjects who underwent elective bariatric surgery, showed that expression of CETP is markedly higher in liver than adipose tissue. Hepatic expression of CETP correlated strongly with that of KC markers, and CETP messenger RNA and protein colocalized specifically with KCs in human liver sections. Hepatic KC content as well as hepatic CETP expression correlated strongly with plasma CETP concentration. Mechanistic and intervention studies on the role of KCs in determining the plasma CETP concentration were performed in a transgenic (Tg) mouse model expressing human CETP. Selective elimination of KCs from the liver in CETP Tg mice virtually abolished hepatic CETP expression and largely reduced plasma CETP concentration, consequently improving the lipoprotein profile. Conversely, augmentation of KCs after Bacille-Calemette-Guérin vaccination largely increased hepatic CETP expression and plasma CETP. Also, lipid-lowering drugs fenofibrate and niacin reduced liver KC content, accompanied by reduced plasma CETP concentration., Conclusions: Plasma CETP is predominantly derived from KCs, and plasma CETP level predicts hepatic KC content in humans., (© 2015 by the American Association for the Study of Liver Diseases.)
- Published
- 2015
- Full Text
- View/download PDF
24. GWAS as a Driver of Gene Discovery in Cardiometabolic Diseases.
- Author
-
Atanasovska B, Kumar V, Fu J, Wijmenga C, and Hofker MH
- Subjects
- Genome-Wide Association Study, Humans, Cardiovascular Diseases genetics, Genetic Variation, Metabolic Diseases genetics
- Abstract
Cardiometabolic diseases represent a common complex disorder with a strong genetic component. Currently, genome-wide association studies (GWAS) have yielded some 755 single-nucleotide polymorphisms (SNPs) encompassing 366 independent loci that may help to decipher the molecular basis of cardiometabolic diseases. Going from a disease SNP to the underlying disease mechanisms is a huge challenge because the associated SNPs rarely disrupt protein function. Many disease SNPs are located in noncoding regions, and therefore attention is now focused on linking genetic SNP variation to effects on gene expression levels. By integrating genetic information with large-scale gene expression data, and with data from epigenetic roadmaps revealing gene regulatory regions, we expect to be able to identify candidate disease genes and the regulatory potential of disease SNPs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
25. The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids.
- Author
-
Fu J, Bonder MJ, Cenit MC, Tigchelaar EF, Maatman A, Dekens JA, Brandsma E, Marczynska J, Imhann F, Weersma RK, Franke L, Poon TW, Xavier RJ, Gevers D, Hofker MH, Wijmenga C, and Zhernakova A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Algorithms, Bacteria classification, Bacteria genetics, Cardiovascular Diseases blood, Cardiovascular Diseases genetics, Cardiovascular Diseases microbiology, Cholesterol blood, Cholesterol, HDL blood, Cholesterol, LDL blood, Cohort Studies, Female, Gastrointestinal Microbiome genetics, Host-Pathogen Interactions, Humans, Male, Middle Aged, RNA, Ribosomal, 16S genetics, Risk Assessment methods, Risk Assessment statistics & numerical data, Risk Factors, Triglycerides blood, Young Adult, Body Mass Index, Gastrointestinal Microbiome physiology, Lipids blood, Polymorphism, Single Nucleotide
- Abstract
Rationale: Evidence suggests that the gut microbiome is involved in the development of cardiovascular disease, with the host-microbe interaction regulating immune and metabolic pathways. However, there was no firm evidence for associations between microbiota and metabolic risk factors for cardiovascular disease from large-scale studies in humans. In particular, there was no strong evidence for association between cardiovascular disease and aberrant blood lipid levels., Objectives: To identify intestinal bacteria taxa, whose proportions correlate with body mass index and lipid levels, and to determine whether lipid variance can be explained by microbiota relative to age, sex, and host genetics., Methods and Results: We studied 893 subjects from the Life-Lines-DEEP population cohort. After correcting for age and sex, we identified 34 bacterial taxa associated with body mass index and blood lipids; most are novel associations. Cross-validation analysis revealed that microbiota explain 4.5% of the variance in body mass index, 6% in triglycerides, and 4% in high-density lipoproteins, independent of age, sex, and genetic risk factors. A novel risk model, including the gut microbiome explained ≤ 25.9% of high-density lipoprotein variance, significantly outperforming the risk model without microbiome. Strikingly, the microbiome had little effect on low-density lipoproteins or total cholesterol., Conclusions: Our studies suggest that the gut microbiome may play an important role in the variation in body mass index and blood lipid levels, independent of age, sex, and host genetics. Our findings support the potential of therapies altering the gut microbiome to control body mass, triglycerides, and high-density lipoproteins., (© 2015 The Authors.)
- Published
- 2015
- Full Text
- View/download PDF
26. Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr(-/-) mice.
- Author
-
Hendrikx T, Jeurissen ML, van Gorp PJ, Gijbels MJ, Walenbergh SM, Houben T, van Gorp R, Pöttgens CC, Stienstra R, Netea MG, Hofker MH, Donners MM, and Shiri-Sverdlov R
- Subjects
- Animals, Antigens, Ly blood, Antigens, Ly metabolism, Aorta, Thoracic immunology, Aorta, Thoracic pathology, Apoptosis, Atherosclerosis etiology, Atherosclerosis immunology, Atherosclerosis pathology, Bone Marrow Cells immunology, Bone Marrow Cells metabolism, Bone Marrow Cells pathology, Caspase 1 genetics, Caspases genetics, Caspases, Initiator, Cholesterol, Dietary adverse effects, Cytokines blood, Cytokines genetics, Cytokines metabolism, Diet, High-Fat adverse effects, Disease Progression, Female, Leukocytes immunology, Leukocytes pathology, Mice, Inbred C57BL, Mice, Knockout, Monocytes immunology, Monocytes pathology, Necrosis, Receptors, LDL genetics, Aorta, Thoracic metabolism, Atherosclerosis metabolism, Caspase 1 metabolism, Caspases metabolism, Leukocytes metabolism, Monocytes metabolism, Receptors, LDL metabolism
- Abstract
Recent investigations have suggested that inflammasome activation plays an important role during atherosclerosis. Upon activation, the inflammasome induces processing and release of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) via activation of caspase-1/11. Previously, it was shown that complete caspase-1 deficiency is protective against atherosclerosis development. However, while macrophages are the main inflammatory cells involved in atherosclerosis, the exact role of macrophage-specific caspase-1/11 activation during development of cardiovascular disease has never been investigated. We hypothesized that hematopoietic caspase-1/11 deficiency leads to reduced atherosclerosis development. To investigate the specific contribution of hematopoietic caspase-1/11 activation to atherosclerosis development, Ldlr(-/-) mice received a transplant (tp) of wild-type (WT) or caspase-1/11(-/-) bone marrow, to create WT-tp mice and caspase-1/11(-/-) -tp mice, and fed a high-fat, high-cholesterol diet for 12 weeks. Our results showed an increase in anti-inflammatory blood leukocytes in caspase-1/11(-/-) -tp mice compared with WT-tp mice, as indicated by a decreased level of Ly6C(high) monocytes and an increased level of Ly6C(low) monocytes. In line with our hypothesis, hematopoietic deletion of caspase-1/11 resulted in a strong reduction in atherosclerotic plaque size. Furthermore, necrotic core content was dramatically decreased in caspase-1/11(-/-) -tp mice. Our data indicate that hematopoietic caspase-1/11 activation is involved in vascular inflammation and atherosclerosis, and plays an important role in cardiovascular disease progression., (© 2015 FEBS.)
- Published
- 2015
- Full Text
- View/download PDF
27. High-fat diet induced obesity primes inflammation in adipose tissue prior to liver in C57BL/6j mice.
- Author
-
van der Heijden RA, Sheedfar F, Morrison MC, Hommelberg PP, Kor D, Kloosterhuis NJ, Gruben N, Youssef SA, de Bruin A, Hofker MH, Kleemann R, Koonen DP, and Heeringa P
- Subjects
- Adipose Tissue metabolism, Animals, Inflammation metabolism, Inflammation pathology, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Obesity etiology, Obesity metabolism, Up-Regulation, Adipose Tissue pathology, Diet, High-Fat, Insulin Resistance physiology, Liver pathology, Obesity pathology
- Abstract
Metabolic inflammation in adipose tissue and the liver is frequently observed as a result of diet-induced obesity in human and rodent studies. Although the adipose tissue and the liver are both prone to become chronically inflamed with prolonged obesity, their individual contribution to the development of metabolic inflammation remains speculative. Thus, we aimed to elucidate the sequence of inflammatory events in adipose and hepatic tissues to determine their contribution to the development of metabolic inflammation and insulin resistance (IR) in diet-induced obesity. To confirm our hypothesis that adipose tissue (AT) inflammation is initiated prior to hepatic inflammation, C57BL/6J male mice were fed a low-fat diet (LFD; 10% kcal fat) or high-fat diet (HFD; 45% kcal fat) for either 24, 40 or 52 weeks. Lipid accumulation and inflammation was measured in AT and liver. Glucose tolerance was assessed and plasma levels of glucose, insulin, leptin and adiponectin were measured at various time points throughout the study. With HFD, C57BL/6j mice developed a progressive obese phenotype, accompanied by IR at 24 and 40 weeks of HFD, but IR was attenuated after 52 weeks of HFD. AT inflammation was present after 24 weeks of HFD, as indicated by the increased presence of crown-like structures and up-regulation of pro-inflammatory genes Tnf, Il1β, Mcp1 and F4/80. As hepatic inflammation was not detected until 40 weeks of HFD, we show that AT inflammation is established prior to the development of hepatic inflammation. Thus, AT inflammation is likely to have a greater contribution to the development of IR compared to hepatic inflammation.
- Published
- 2015
- Full Text
- View/download PDF
28. The immunity-diet-microbiota axis in the development of metabolic syndrome.
- Author
-
Brandsma E, Houben T, Fu J, Shiri-Sverdlov R, and Hofker MH
- Subjects
- Animals, Antimicrobial Cationic Peptides physiology, Diet, Humans, Metabolic Syndrome microbiology, Receptors, Pattern Recognition physiology, Immunity, Innate, Metabolic Syndrome immunology, Microbiota immunology
- Abstract
Purpose of Review: Recent evidence demonstrates that the gut-microbiota can be considered as one of the major factors causing metabolic and cardiovascular diseases., Recent Findings: Pattern recognition receptors as well as antimicrobial peptides are a key factor in controlling the intestinal microbiota composition. Deficiencies in these genes lead to changes in the composition of the gut-microbiota, causing leakage of endotoxins into the circulation, and the development of low-grade chronic inflammation and insulin resistance. Dietary composition can also affect the microbiota: a diet rich in saturated fats allows the expansion of pathobionts that damage the intestinal epithelial cell layer and compromise its barrier function. In contrast, a diet high in fiber supports the microbiota to produce short-chain fatty acids, thereby promoting energy expenditure and protecting against inflammation and insulin resistance., Summary: The interactions between the microbiota, innate immunity, and diet play an important role in controlling metabolic homeostasis. A properly functioning innate immune system, combined with a low-fat and high-fiber diet, is important in preventing dysbiosis and reducing the susceptibility to developing the metabolic syndrome and its associated cardiovascular diseases.
- Published
- 2015
- Full Text
- View/download PDF
29. Plasma cathepsin D levels: a novel tool to predict pediatric hepatic inflammation.
- Author
-
Walenbergh SM, Houben T, Hendrikx T, Jeurissen ML, van Gorp PJ, Vreugdenhil AC, Adriaanse MP, Buurman WA, Hofker MH, Mosca A, Lindsey PJ, Alisi A, Liccardo D, Panera N, Koek GH, Nobili V, and Shiri-Sverdlov R
- Subjects
- Alanine Transaminase blood, Analysis of Variance, Area Under Curve, Biomarkers blood, Biopsy, Child, Child, Preschool, Disease Progression, Female, Humans, Keratin-18 blood, Male, Predictive Value of Tests, Prognosis, ROC Curve, Severity of Illness Index, Cathepsin D blood, Inflammation blood, Inflammation diagnosis, Inflammation physiopathology, Liver pathology, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease diagnosis, Non-alcoholic Fatty Liver Disease physiopathology
- Abstract
Objectives: Nonalcoholic steatohepatitis (NASH) is the most severe form of a hepatic condition known as nonalcoholic fatty liver disease (NAFLD). NASH is histologically characterized by hepatic fat accumulation, inflammation, and ballooning, and eventually coupled with fibrosis that, in turn, may progress to end-stage liver disease even in young individuals. Hence, there is a critical need for specific noninvasive markers to predict hepatic inflammation at an early age. We investigated whether plasma levels of cathepsin D (CatD), a lysosomal protease, correlated with the severity of liver inflammation in pediatric NAFLD., Methods: Liver biopsies from children (n=96) with NAFLD were histologically evaluated according to the criteria of Kleiner (NAFLD activity score) and the Brunt's criteria. At the time of liver biopsy, blood was taken and levels of CatD, alanine aminotransferase (ALT), and cytokeratin-18 (CK-18) were measured in plasma., Results: Plasma CatD levels were significantly lower in subjects with liver inflammation compared with steatotic subjects. Furthermore, we found that CatD levels were gradually reduced and corresponded with increasing severity of liver inflammation, steatosis, hepatocellular ballooning, and NAFLD activity score. CatD levels correlated with pediatric NAFLD disease progression better than ALT and CK-18. In particular, CatD showed a high diagnostic accuracy (area under receiver operating characteristic curve (ROC-AUC): 0.94) for the differentiation between steatosis and hepatic inflammation, and reached almost the maximum accuracy (ROC-AUC: 0.998) upon the addition of CK-18., Conclusions: Plasma CatD holds a high diagnostic value to distinguish pediatric patients with hepatic inflammation from children with steatosis.
- Published
- 2015
- Full Text
- View/download PDF
30. Mendelian randomization of blood lipids for coronary heart disease.
- Author
-
Holmes MV, Asselbergs FW, Palmer TM, Drenos F, Lanktree MB, Nelson CP, Dale CE, Padmanabhan S, Finan C, Swerdlow DI, Tragante V, van Iperen EP, Sivapalaratnam S, Shah S, Elbers CC, Shah T, Engmann J, Giambartolomei C, White J, Zabaneh D, Sofat R, McLachlan S, Doevendans PA, Balmforth AJ, Hall AS, North KE, Almoguera B, Hoogeveen RC, Cushman M, Fornage M, Patel SR, Redline S, Siscovick DS, Tsai MY, Karczewski KJ, Hofker MH, Verschuren WM, Bots ML, van der Schouw YT, Melander O, Dominiczak AF, Morris R, Ben-Shlomo Y, Price J, Kumari M, Baumert J, Peters A, Thorand B, Koenig W, Gaunt TR, Humphries SE, Clarke R, Watkins H, Farrall M, Wilson JG, Rich SS, de Bakker PI, Lange LA, Davey Smith G, Reiner AP, Talmud PJ, Kivimäki M, Lawlor DA, Dudbridge F, Samani NJ, Keating BJ, Hingorani AD, and Casas JP
- Subjects
- Case-Control Studies, Female, Gene Frequency, Genotype, Genotyping Techniques, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Risk Assessment, Cholesterol, HDL genetics, Coronary Artery Disease genetics, Polymorphism, Single Nucleotide genetics, Triglycerides genetics
- Abstract
Aims: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization., Methods and Results: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75)., Conclusion: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2015
- Full Text
- View/download PDF
31. Determining the association between adipokine expression in multiple tissues and phenotypic features of non-alcoholic fatty liver disease in obesity.
- Author
-
Wolfs MG, Gruben N, Rensen SS, Verdam FJ, Greve JW, Driessen A, Wijmenga C, Buurman WA, Franke L, Scheja L, Koonen DP, Shiri-Sverdlov R, van Haeften TW, Hofker MH, and Fu J
- Abstract
Objectives: Non-alcoholic fatty liver disease (NAFLD) is an obesity-associated disease, and in obesity adipokines are believed to be involved in the development of NAFLD. However, it is still not clear whether adipokines in the liver and/or adipose tissues can be related to the development of specific characteristics of NAFLD, such as steatosis and inflammation. We aimed to address this question by simultaneously examining the adipokine expression in three tissue types in obese individuals., Methods: We enrolled 93 severely obese individuals with NAFLD, varying from simple steatosis to severe non-alcoholic steatohepatitis. Their expression of 48 adipokines in the liver, visceral and subcutaneous adipose tissue (SAT) was correlated to their phenotypic features of NAFLD. We further determined whether the correlations were tissue specific and/or independent of covariates, including age, sex, obesity, insulin resistance and type 2 diabetes (T2D)., Results: The expression of adipokines showed a liver- and adipose tissue-specific pattern. We identified that the expression of leptin, angiopoietin 2 (ANGPT2) and chemerin in visceral adipose tissue (VAT) was associated with different NAFLD features, including steatosis, ballooning, portal and lobular inflammation. In addition, the expression of tumor necrosis factor (TNF), plasminogen activator inhibitor type 1 (PAI-1), insulin-like growth factor 1 (somatomedin C) (IGF1) and chemokine (C-X-C motif) ligand 10 (CXCL10) in the liver tissue and the expression of interleukin 1 receptor antagonist (IL1RN) in both the liver and SAT were associated with NAFLD features. The correlations between ANGPT2 and CXCL10, and NAFLD features were dependent on insulin resistance and T2D, but for the other genes the correlation with at least one NAFLD feature remained significant after correcting for the covariates., Conclusions: Our results suggest that in obese individuals, VAT-derived leptin and chemerin, and hepatic expression of TNF, IGF1, IL1RN and PAI-1 are involved in the development of NAFLD features. Further, functional studies are warranted to establish a causal relationship.
- Published
- 2015
- Full Text
- View/download PDF
32. Hematopoietic overexpression of Cyp27a1 reduces hepatic inflammation independently of 27-hydroxycholesterol levels in Ldlr(-/-) mice.
- Author
-
Hendrikx T, Jeurissen ML, Bieghs V, Walenbergh SM, van Gorp PJ, Verheyen F, Houben T, Guichot YD, Gijbels MJ, Leitersdorf E, Hofker MH, Lütjohann D, and Shiri-Sverdlov R
- Subjects
- Animals, Bone Marrow Transplantation, Cholestanetriol 26-Monooxygenase biosynthesis, Disease Models, Animal, Kupffer Cells metabolism, Kupffer Cells pathology, Lipoproteins, LDL metabolism, Male, Mice, Mice, Inbred C57BL, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Cholestanetriol 26-Monooxygenase genetics, DNA genetics, Gene Expression Regulation, Hydroxycholesterols metabolism, Non-alcoholic Fatty Liver Disease genetics
- Abstract
Background & Aims: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation and inflammation. Currently, the underlying mechanisms, leading to hepatic inflammation, are still unknown. The breakdown of free cholesterol inside Kupffer cells (KCs) by the mitochondrial enzyme CYP27A1 produces 27-hydroxycholesterol (27HC). We recently demonstrated that administration of 27HC to hyperlipidemic mice reduced hepatic inflammation. In line, hematopoietic deletion of Cyp27a1 resulted in increased hepatic inflammation. In the current manuscript, the effect of hematopoietic overexpression of Cyp27a1 on the development of NASH and cholesterol trafficking was investigated. We hypothesized that Cyp27a1 overexpression in KCs will lead to reduced hepatic inflammation., Methods: Irradiated Ldlr(-/-) mice were transplanted (tp) with bone marrow from mice overexpressing Cyp27a1 (Cyp27a1(over)) and wild type (Wt) mice and fed either chow or a high-fat, high-cholesterol (HFC) diet for 3 months. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) from Cyp27a1(over) and Wt mice., Results: In line with our hypothesis, hepatic inflammation in HFC-fed Cyp27a1(over)-tp mice was reduced and KCs were less foamy compared to Wt-tp mice. Remarkably, these changes occurred even though plasma and liver levels of 27HC did not differ between both groups. BMDM from Cyp27a1(over) mice revealed reduced inflammatory gene expression and increased expression of cholesterol transporters compared to Wt BMDM after lipopolysaccharide (LPS) stimulation., Conclusions: Our data suggest that overexpression of Cyp27a1 in KCs reduces hepatic inflammation independently of 27HC levels in plasma and liver, further pointing towards KCs as specific target for improving the therapy of NASH., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
33. Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet.
- Author
-
Sheedfar F, Vermeer M, Pazienza V, Villarroya J, Rappa F, Cappello F, Mazzoccoli G, Villarroya F, van der Molen H, Hofker MH, Koonen DP, and Vinciguerra M
- Subjects
- Adipogenesis, Animals, Cell Line, Diet, High-Fat, Disease Models, Animal, Histones genetics, Insulin Resistance genetics, Mice, Models, Molecular, Adipose Tissue, Brown metabolism, Energy Metabolism, Histones metabolism, Thinness metabolism
- Abstract
Background/objectives: In the context of obesity, epigenetic mechanisms regulate cell-specific chromatin plasticity, perpetuating gene expression responses to nutrient excess. MacroH2A1, a variant of histone H2A, emerged as a key chromatin regulator sensing small nutrients during cell proliferation and differentiation. Mice genetically ablated for macroH2A1 (knockout (KO)) do not show overt phenotypes under a standard diet. Our objective was to analyse the in vivo role of macroH2A1 in response to nutritional excess., Methods: Twelve-week-old whole-body macroH2A1 KO male mice were given a high-fat diet (60% energy from lard) for 12 weeks until being killed, and examined for glucose and insulin tolerance, and for body fat composition. Energy expenditure was assessed using metabolic cages and by measuring the expression levels of genes involved in thermogenesis in the brown adipose tissue (BAT) or in adipogenesis in the visceral adipose tissue (VAT)., Results: Under a chow diet, macroH2A1 KO mice did not differ from their wild-type (WT) littermates for body weight, and for sensitivity to glucose or insulin. However, KO mice displayed decreased heat production (P<0.05), and enhanced total activity during the night (P<0.01). These activities related to protection against diet-induced obesity in KO mice, which displayed decreased body weight owing to a specific decrease in fat mass (P<0.05), increased tolerance to glucose (P<0.05), and enhanced total activity during the day (P<0.05), compared with WT mice. KO mice displayed increased expression of thermogenic genes (Ucp1, P<0.05; Glut4, P<0.05; Cox4, P<0.01) in BAT and a decreased expression of adipogenic genes (Pparγ, P<0.05; Fabp4, P<0.05; Glut4, P<0.05) in VAT compared with WT mice, indicative of augmented energy expenditure., Conclusions: Genetic eviction of macroH2A1 confers protection against diet-induced obesity and metabolic derangements in mice. Inhibition of macroH2A1 might be a helpful strategy for epigenetic therapy of obesity.
- Published
- 2015
- Full Text
- View/download PDF
34. Systematic annotation of celiac disease loci refines pathological pathways and suggests a genetic explanation for increased interferon-gamma levels.
- Author
-
Kumar V, Gutierrez-Achury J, Kanduri K, Almeida R, Hrdlickova B, Zhernakova DV, Westra HJ, Karjalainen J, Ricaño-Ponce I, Li Y, Stachurska A, Tigchelaar EF, Abdulahad WH, Lähdesmäki H, Hofker MH, Zhernakova A, Franke L, Lahesmaa R, Wijmenga C, and Withoff S
- Subjects
- Celiac Disease metabolism, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Interferon-gamma genetics, Molecular Sequence Annotation, Celiac Disease genetics, Interferon-gamma metabolism, Polymorphism, Single Nucleotide, Quantitative Trait Loci
- Abstract
Although genome-wide association studies and fine mapping have identified 39 non-HLA loci associated with celiac disease (CD), it is difficult to pinpoint the functional variants and susceptibility genes in these loci. We applied integrative approaches to annotate and prioritize functional single nucleotide polymorphisms (SNPs), genes and pathways affected in CD. CD-associated SNPs were intersected with regulatory elements categorized by the ENCODE project to prioritize functional variants, while results from cis-expression quantitative trait loci (eQTL) mapping in 1469 blood samples were combined with co-expression analyses to prioritize causative genes. To identify the key cell types involved in CD, we performed pathway analysis on RNA-sequencing data from different immune cell populations and on publicly available expression data on non-immune tissues. We discovered that CD SNPs are significantly enriched in B-cell-specific enhancer regions, suggesting that, besides T-cell processes, B-cell responses play a major role in CD. By combining eQTL and co-expression analyses, we prioritized 43 susceptibility genes in 36 loci. Pathway and tissue-specific expression analyses on these genes suggested enrichment of CD genes in the Th1, Th2 and Th17 pathways, but also predicted a role for four genes in the intestinal barrier function. We also discovered an intricate transcriptional connectivity between CD susceptibility genes and interferon-γ, a key effector in CD, despite the absence of CD-associated SNPs in the IFNG locus. Using systems biology, we prioritized the CD-associated functional SNPs and genes. By highlighting a role for B cells in CD, which classically has been described as a T-cell-driven disease, we offer new insights into the mechanisms and pathways underlying CD., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
- Full Text
- View/download PDF
35. Cholesterol-induced hepatic inflammation does not underlie the predisposition to insulin resistance in dyslipidemic female LDL receptor knockout mice.
- Author
-
Gruben N, Funke A, Kloosterhuis NJ, Schreurs M, Sheedfar F, Havinga R, Houten SM, Shiri-Sverdlov R, van de Sluis B, Kuivenhoven JA, Koonen DP, and Hofker MH
- Subjects
- Adipose Tissue metabolism, Animals, Blood Glucose metabolism, Cholesterol blood, Dyslipidemias genetics, Dyslipidemias metabolism, Female, Gas Chromatography-Mass Spectrometry, Glucose Clamp Technique, Glucose Tolerance Test, Lipids chemistry, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, LDL metabolism, Risk Factors, Triglycerides metabolism, Cholesterol adverse effects, Inflammation metabolism, Insulin Resistance genetics, Liver metabolism, Receptors, LDL genetics
- Abstract
Chronic inflammation is considered a causal risk factor predisposing to insulin resistance. However, evidence is accumulating that inflammation confined to the liver may not be causal to metabolic dysfunction. To investigate this, we assessed if hepatic inflammation explains the predisposition towards insulin resistance in low-density lipoprotein receptor knock-out (Ldlr (-/-)) mice. For this, wild type (WT) and Ldlr (-/-) mice were fed a chow diet, a high fat (HF) diet, or a high fat, high cholesterol (HFC) diet for 2 weeks. Plasma lipid levels were elevated in chow-fed Ldlr (-/-) mice compared to WT mice. Although short-term HF or HFC feeding did not result in body weight gain and adipose tissue inflammation, dyslipidemia was worsened in Ldlr (-/-) mice compared to WT mice. In addition, dyslipidemic HF-fed Ldlr (-/-) mice had a higher hepatic glucose production rate than HF-fed WT mice, while peripheral insulin resistance was unaffected. This suggests that HF-fed Ldlr (-/-) mice suffered from hepatic insulin resistance. While HFC-fed Ldlr (-/-) mice displayed the anticipated increased hepatic inflammation, this did neither exacerbate systemic nor hepatic insulin resistance. Therefore, our results show that hepatic insulin resistance is unrelated to cholesterol-induced hepatic inflammation in Ldlr (-/-) mice, indicating that hepatic inflammation may not contribute to metabolic dysfunction per se.
- Published
- 2015
- Full Text
- View/download PDF
36. Plasma IL-1 receptor antagonist levels correlate with the development of non-alcoholic steatohepatitis.
- Author
-
Hendrikx T, Walenbergh SM, Jeurissen ML, Houben T, van Gorp PJ, Lindsey PJ, Koek GH, Kalhan S, Pihlajamaki J, Hofker MH, and Shiri-Sverdlov R
- Subjects
- Adult, Case-Control Studies, Female, Humans, Inflammation blood, Inflammation complications, Liver pathology, Male, Middle Aged, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease diagnosis, Obesity blood, Obesity complications, ROC Curve, Interleukin 1 Receptor Antagonist Protein blood, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease pathology
- Abstract
Aim: Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by lipid accumulation and inflammation. Here, we aimed to evaluate plasma IL-1Ra as a marker for NASH and to determine whether diagnosis of NASH can be further improved by adding IL-1Ra measurements., Materials & Methods: Therefore, plasma concentrations of IL-1Ra were measured from 146 subjects of a biopsy-proven NASH cohort with matched controls., Results: NASH patients had higher levels of plasma IL-1Ra compared with patients with steatosis or healthy controls., Conclusion: Our data confirm that IL-1Ra can be a useful tool in the diagnosis of hepatic inflammation and suggest that measuring plasma IL-1Ra levels in addition to ALT will improve the diagnosis for NASH at all stages of the disease.
- Published
- 2015
- Full Text
- View/download PDF
37. A cell-type-specific role for murine Commd1 in liver inflammation.
- Author
-
Bartuzi P, Wijshake T, Dekker DC, Fedoseienko A, Kloosterhuis NJ, Youssef SA, Li H, Shiri-Sverdlov R, Kuivenhoven JA, de Bruin A, Burstein E, Hofker MH, and van de Sluis B
- Abstract
The transcription factor NF-κB plays a critical role in the inflammatory response and it has been implicated in various diseases, including non-alcoholic fatty liver disease (NAFLD). Although transient NF-κB activation may protect tissues from stress, a prolonged NF-κB activation can have a detrimental effect on tissue homeostasis and therefore accurate termination is crucial. Copper Metabolism MURR1 Domain-containing 1 (COMMD1), a protein with functions in multiple pathways, has been shown to suppress NF-κB activity. However, its action in controlling liver inflammation has not yet been investigated. To determine the cell-type-specific contribution of Commd1 to liver inflammation, we used hepatocyte and myeloid-specific Commd1-deficient mice. We also used a mouse model of NAFLD to study low-grade chronic liver inflammation: we fed the mice a high fat, high cholesterol (HFC) diet, which results in hepatic lipid accumulation accompanied by liver inflammation. Depletion of hepatocyte Commd1 resulted in elevated levels of the NF-κB transactivation subunit p65 (RelA) but, surprisingly, the level of liver inflammation was not aggravated. In contrast, deficiency of myeloid Commd1 exacerbated diet-induced liver inflammation. Unexpectedly we observed that hepatic and myeloid Commd1 deficiency in the mice both augmented hepatic lipid accumulation. The elevated levels of proinflammatory cytokines in myeloid Commd1-deficient mice might be responsible for the increased level of steatosis. This increase was not seen in hepatocyte Commd1-deficient mice, in which increased lipid accumulation appeared to be independent of inflammation. Our mouse models demonstrate a cell-type-specific role for Commd1 in suppressing liver inflammation and in the progression of NAFLD., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
38. Nonalcoholic fatty liver disease: A main driver of insulin resistance or a dangerous liaison?
- Author
-
Gruben N, Shiri-Sverdlov R, Koonen DP, and Hofker MH
- Abstract
Insulin resistance is one of the key components of the metabolic syndrome and it eventually leads to the development of type 2 diabetes, making it one of the biggest medical problems of modern society. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are tightly associated with insulin resistance. While it is fairly clear that insulin resistance causes hepatic steatosis, it is not known if NAFLD causes insulin resistance. Hepatic inflammation and lipid accumulation are believed to be the main drivers of hepatic insulin resistance in NAFLD. Here we give an overview of the evidence linking hepatic lipid accumulation to the development of insulin resistance, including the accumulation of triacylglycerol and lipid metabolites, such as diacylglycerol and ceramides. In particular, we discuss the role of obesity in this relation by reviewing the current evidence in terms of the reported changes in body weight and/or adipose tissue mass. We further discuss whether the activation or inhibition of inflammatory pathways, Kupffer cells and other immune cells influences the development of insulin resistance. We show that, in contrast to what is commonly believed, neither hepatic steatosis nor hepatic inflammation is sufficient to cause insulin resistance. Many studies show that obesity cannot be ignored as an underlying factor in this relationship and NAFLD is therefore less likely to be one of the main drivers of insulin resistance., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
39. A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease.
- Author
-
Holmes MV, Frikke-Schmidt R, Melis D, Luben R, Asselbergs FW, Boer JM, Cooper J, Palmen J, Horvat P, Engmann J, Li KW, Onland-Moret NC, Hofker MH, Kumari M, Keating BJ, Hubacek JA, Adamkova V, Kubinova R, Bobak M, Khaw KT, Nordestgaard BG, Wareham N, Humphries SE, Langenberg C, Tybjaerg-Hansen A, and Talmud PJ
- Subjects
- Adult, Aged, Alleles, Cohort Studies, Female, Gene-Environment Interaction, Heterozygote, Humans, Male, Middle Aged, Risk Factors, Apolipoprotein E4 genetics, Coronary Disease genetics, Genotype, Smoking adverse effects
- Abstract
Background: Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD)., Methods and Results: We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test. In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification., Conclusions: In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
40. Genetic and epigenetic regulation of gene expression in fetal and adult human livers.
- Author
-
Bonder MJ, Kasela S, Kals M, Tamm R, Lokk K, Barragan I, Buurman WA, Deelen P, Greve JW, Ivanov M, Rensen SS, van Vliet-Ostaptchouk JV, Wolfs MG, Fu J, Hofker MH, Wijmenga C, Zhernakova A, Ingelman-Sundberg M, Franke L, and Milani L
- Subjects
- Adult, DNA Methylation, Fetus embryology, Gene Expression Regulation, Developmental, Humans, Organ Specificity, Polymorphism, Single Nucleotide, Quantitative Trait Loci genetics, Epigenesis, Genetic, Epigenomics, Fetus metabolism, Gene Expression Profiling, Liver growth & development, Liver metabolism
- Abstract
Background: The liver plays a central role in the maintenance of homeostasis and health in general. However, there is substantial inter-individual variation in hepatic gene expression, and although numerous genetic factors have been identified, less is known about the epigenetic factors., Results: By analyzing the methylomes and transcriptomes of 14 fetal and 181 adult livers, we identified 657 differentially methylated genes with adult-specific expression, these genes were enriched for transcription factor binding sites of HNF1A and HNF4A. We also identified 1,000 genes specific to fetal liver, which were enriched for GATA1, STAT5A, STAT5B and YY1 binding sites. We saw strong liver-specific effects of single nucleotide polymorphisms on both methylation levels (28,447 unique CpG sites (meQTL)) and gene expression levels (526 unique genes (eQTL)), at a false discovery rate (FDR) < 0.05. Of the 526 unique eQTL associated genes, 293 correlated significantly not only with genetic variation but also with methylation levels. The tissue-specificities of these associations were analyzed in muscle, subcutaneous adipose tissue and visceral adipose tissue. We observed that meQTL were more stable between tissues than eQTL and a very strong tissue-specificity for the identified associations between CpG methylation and gene expression., Conclusions: Our analyses generated a comprehensive resource of factors involved in the regulation of hepatic gene expression, and allowed us to estimate the proportion of variation in gene expression that could be attributed to genetic and epigenetic variation, both crucial to understanding differences in drug response and the etiology of liver diseases.
- Published
- 2014
- Full Text
- View/download PDF
41. The genome revolution and its role in understanding complex diseases.
- Author
-
Hofker MH, Fu J, and Wijmenga C
- Abstract
The completion of the human genome sequence in 2003 clearly marked the beginning of a new era for biomedical research. It spurred technological progress that was unprecedented in the life sciences, including the development of high-throughput technologies to detect genetic variation and gene expression. The study of genetics has become "big data science". One of the current goals of genetic research is to use genomic information to further our understanding of common complex diseases. An essential first step made towards this goal was by the identification of thousands of single nucleotide polymorphisms showing robust association with hundreds of different traits and diseases. As insight into common genetic variation has expanded enormously and the technology to identify more rare variation has become available, we can utilize these advances to gain a better understanding of disease etiology. This will lead to developments in personalized medicine and P4 healthcare. Here, we review some of the historical events and perspectives before and after the completion of the human genome sequence. We also describe the success of large-scale genetic association studies and how these are expected to yield more insight into complex disorders. We show how we can now combine gene-oriented research and systems-based approaches to develop more complex models to help explain the etiology of common diseases. This article is part of a Special Issue entitled: From Genome to Function., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
42. Pleiotropic effects of lipid genes on plasma glucose, HbA1c, and HOMA-IR levels.
- Author
-
Li N, van der Sijde MR, Bakker SJ, Dullaart RP, van der Harst P, Gansevoort RT, Elbers CC, Wijmenga C, Snieder H, Hofker MH, and Fu J
- Subjects
- Blood Glucose genetics, Cohort Studies, Dyslipidemias genetics, Fasting blood, Genetic Predisposition to Disease, Homeostasis, Humans, Insulin Resistance physiology, Lipids blood, Models, Biological, Polymorphism, Single Nucleotide, Triglycerides blood, Blood Glucose metabolism, Glycated Hemoglobin metabolism, Insulin Resistance genetics, Lipids genetics
- Abstract
Dyslipidemia is strongly associated with raised plasma glucose levels and insulin resistance (IR), and genome-wide association studies have identified 95 loci that explain a substantial proportion of the variance in blood lipids. However, the loci's effects on glucose-related traits are largely unknown. We have studied these lipid loci and tested their association collectively and individually with fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and IR in two independent cohorts: 10,995 subjects from LifeLines Cohort Study and 2,438 subjects from Prevention of Renal and Vascular Endstage Disease (PREVEND) study. In contrast to the positive relationship between dyslipidemia and glucose traits, the genetic predisposition to dyslipidemia showed a pleiotropic lowering effect on glucose traits. Specifically, the genetic risk score related to higher triglyceride level was correlated with lower levels of FPG (P = 9.6 × 10(-10) and P = 0.03 in LifeLines and PREVEND, respectively), HbA1c (P = 4.2 × 10(-7) in LifeLines), and HOMA of estimated IR (P = 6.2 × 10(-4) in PREVEND), after adjusting for blood lipid levels. At the single nucleotide polymorphism level, 15 lipid loci showed a pleiotropic association with glucose traits (P < 0.01), of which eight (CETP, MLXIPL, PLTP, GCKR, APOB, APOE-C1-C2, CYP7A1, and TIMD4) had opposite allelic directions of effect on dyslipidemia and glucose levels. Our findings suggest a complex genetic regulation and metabolic interplay between lipids and glucose., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
- Published
- 2014
- Full Text
- View/download PDF
43. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.
- Author
-
Holmes MV, Dale CE, Zuccolo L, Silverwood RJ, Guo Y, Ye Z, Prieto-Merino D, Dehghan A, Trompet S, Wong A, Cavadino A, Drogan D, Padmanabhan S, Li S, Yesupriya A, Leusink M, Sundstrom J, Hubacek JA, Pikhart H, Swerdlow DI, Panayiotou AG, Borinskaya SA, Finan C, Shah S, Kuchenbaecker KB, Shah T, Engmann J, Folkersen L, Eriksson P, Ricceri F, Melander O, Sacerdote C, Gamble DM, Rayaprolu S, Ross OA, McLachlan S, Vikhireva O, Sluijs I, Scott RA, Adamkova V, Flicker L, Bockxmeer FM, Power C, Marques-Vidal P, Meade T, Marmot MG, Ferro JM, Paulos-Pinheiro S, Humphries SE, Talmud PJ, Mateo Leach I, Verweij N, Linneberg A, Skaaby T, Doevendans PA, Cramer MJ, van der Harst P, Klungel OH, Dowling NF, Dominiczak AF, Kumari M, Nicolaides AN, Weikert C, Boeing H, Ebrahim S, Gaunt TR, Price JF, Lannfelt L, Peasey A, Kubinova R, Pajak A, Malyutina S, Voevoda MI, Tamosiunas A, Maitland-van der Zee AH, Norman PE, Hankey GJ, Bergmann MM, Hofman A, Franco OH, Cooper J, Palmen J, Spiering W, de Jong PA, Kuh D, Hardy R, Uitterlinden AG, Ikram MA, Ford I, Hyppönen E, Almeida OP, Wareham NJ, Khaw KT, Hamsten A, Husemoen LL, Tjønneland A, Tolstrup JS, Rimm E, Beulens JW, Verschuren WM, Onland-Moret NC, Hofker MH, Wannamethee SG, Whincup PH, Morris R, Vicente AM, Watkins H, Farrall M, Jukema JW, Meschia J, Cupples LA, Sharp SJ, Fornage M, Kooperberg C, LaCroix AZ, Dai JY, Lanktree MB, Siscovick DS, Jorgenson E, Spring B, Coresh J, Li YR, Buxbaum SG, Schreiner PJ, Ellison RC, Tsai MY, Patel SR, Redline S, Johnson AD, Hoogeveen RC, Hakonarson H, Rotter JI, Boerwinkle E, de Bakker PI, Kivimaki M, Asselbergs FW, Sattar N, Lawlor DA, Whittaker J, Davey Smith G, Mukamal K, Psaty BM, Wilson JG, Lange LA, Hamidovic A, Hingorani AD, Nordestgaard BG, Bobak M, Leon DA, Langenberg C, Palmer TM, Reiner AP, Keating BJ, Dudbridge F, and Casas JP
- Subjects
- Adult, Aged, Alcohol Drinking adverse effects, Biomarkers blood, Coronary Disease blood, Coronary Disease genetics, Female, Genetic Markers, Genotype, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Models, Statistical, Stroke blood, Stroke genetics, Alcohol Dehydrogenase genetics, Alcohol Drinking genetics, Coronary Disease etiology, Polymorphism, Single Nucleotide, Stroke etiology
- Abstract
Objective: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease., Design: Mendelian randomisation meta-analysis of 56 epidemiological studies., Participants: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers., Main Outcome Measures: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption., Results: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95))., Conclusions: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health., (© Holmes et al 2014.)
- Published
- 2014
- Full Text
- View/download PDF
44. Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations.
- Author
-
Yoneyama S, Guo Y, Lanktree MB, Barnes MR, Elbers CC, Karczewski KJ, Padmanabhan S, Bauer F, Baumert J, Beitelshees A, Berenson GS, Boer JM, Burke G, Cade B, Chen W, Cooper-Dehoff RM, Gaunt TR, Gieger C, Gong Y, Gorski M, Heard-Costa N, Johnson T, Lamonte MJ, McDonough C, Monda KL, Onland-Moret NC, Nelson CP, O'Connell JR, Ordovas J, Peter I, Peters A, Shaffer J, Shen H, Smith E, Speilotes L, Thomas F, Thorand B, Monique Verschuren WM, Anand SS, Dominiczak A, Davidson KW, Hegele RA, Heid I, Hofker MH, Huggins GS, Illig T, Johnson JA, Kirkland S, König W, Langaee TY, McCaffery J, Melander O, Mitchell BD, Munroe P, Murray SS, Papanicolaou G, Redline S, Reilly M, Samani NJ, Schork NJ, Van Der Schouw YT, Shimbo D, Shuldiner AR, Tobin MD, Wijmenga C, Yusuf S, Hakonarson H, Lange LA, Demerath EW, Fox CS, North KE, Reiner AP, Keating B, and Taylor KC
- Subjects
- Adiposity, Adult, Aged, Aged, 80 and over, Body Mass Index, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Waist-Hip Ratio, White People, Young Adult, Waist Circumference genetics
- Abstract
Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
- Published
- 2014
- Full Text
- View/download PDF
45. Lysosomal cholesterol accumulation: driver on the road to inflammation during atherosclerosis and non-alcoholic steatohepatitis.
- Author
-
Hendrikx T, Walenbergh SM, Hofker MH, and Shiri-Sverdlov R
- Subjects
- Animals, Disease Models, Animal, Humans, Macrophages metabolism, Atherosclerosis physiopathology, Cholesterol metabolism, Inflammation physiopathology, Lysosomes metabolism, Non-alcoholic Fatty Liver Disease physiopathology
- Abstract
Many studies show an association between the accumulation of cholesterol inside lysosomes and the progression towards inflammatory disease states that are closely related to obesity. While in the past, the knowledge regarding lysosomal cholesterol accumulation was limited to its association with plaque severity during atherosclerosis, recently, a growing body of evidence indicates a causal link between lysosomal cholesterol accumulation and inflammation. These findings make lysosomal cholesterol accumulation an important target for intervention in metabolic diseases that are characterized by the presence of an inflammatory response. In this review, we aim to show the importance of cholesterol trapping inside lysosomes to the development of inflammation by focusing upon cardiovascular disease and non-alcoholic steatohepatitis (NASH) in particular. We summarize current data supporting the hypothesis that lysosomal cholesterol accumulation plays a key role in the development of inflammation during atherosclerosis and NASH. In addition, potential mechanisms by which disturbed lysosomal function can trigger the inflammatory response, the challenges in improving cholesterol trafficking in macrophages and recent successful research directions will be discussed., (© 2014 The Authors. obesity reviews © 2014 International Association for the Study of Obesity.)
- Published
- 2014
- Full Text
- View/download PDF
46. Chemokine-like receptor 1 deficiency does not affect the development of insulin resistance and nonalcoholic fatty liver disease in mice.
- Author
-
Gruben N, Aparicio Vergara M, Kloosterhuis NJ, van der Molen H, Stoelwinder S, Youssef S, de Bruin A, Delsing DJ, Kuivenhoven JA, van de Sluis B, Hofker MH, and Koonen DP
- Subjects
- Animals, Body Weight, Fatty Liver pathology, Gene Deletion, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Non-alcoholic Fatty Liver Disease, Receptors, Chemokine, Fatty Liver genetics, Insulin Resistance genetics, Liver pathology, Receptors, G-Protein-Coupled genetics
- Abstract
The adipokine chemerin and its receptor, chemokine-like receptor 1 (Cmklr1), are associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD), which covers a broad spectrum of liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). It is possible that chemerin and/or Cmklr1 exert their effects on these disorders through inflammation, but so far the data have been controversial. To gain further insight into this matter, we studied the effect of whole-body Cmklr1 deficiency on insulin resistance and NAFLD. In view of the primary role of macrophages in hepatic inflammation, we also transplanted bone marrow from Cmklr1 knock-out (Cmklr1-/-) mice and wild type (WT) mice into low-density lipoprotein receptor knock-out (Ldlr-/-) mice, a mouse model for NASH. All mice were fed a high fat, high cholesterol diet containing 21% fat from milk butter and 0.2% cholesterol for 12 weeks. Insulin resistance was assessed by an oral glucose tolerance test, an insulin tolerance test, and by measurement of plasma glucose and insulin levels. Liver pathology was determined by measuring hepatic inflammation, fibrosis, lipid accumulation and the NAFLD activity score (NAS). Whole-body Cmklr1 deficiency did not affect body weight gain or food intake. In addition, we observed no differences between WT and Cmklr1-/- mice for hepatic inflammatory and fibrotic gene expression, immune cell infiltration, lipid accumulation or NAS. In line with this, we detected no differences in insulin resistance. In concordance with whole-body Cmklr1 deficiency, the absence of Cmklr1 in bone marrow-derived cells in Ldlr-/- mice did not affect their insulin resistance or liver pathology. Our results indicate that Cmklr1 is not involved in the pathogenesis of insulin resistance or NAFLD. Thus, we recommend that the associations reported between Cmklr1 and insulin resistance or NAFLD should be interpreted with caution.
- Published
- 2014
- Full Text
- View/download PDF
47. The Copper Metabolism MURR1 domain protein 1 (COMMD1) modulates the aggregation of misfolded protein species in a client-specific manner.
- Author
-
Vonk WI, Kakkar V, Bartuzi P, Jaarsma D, Berger R, Hofker MH, Klomp LW, Wijmenga C, Kampinga HH, and van de Sluis B
- Subjects
- Amyotrophic Lateral Sclerosis metabolism, Animals, HEK293 Cells, HeLa Cells, Humans, Mice, Molecular Weight, Mutant Proteins metabolism, Peptides chemistry, Peptides metabolism, Protein Binding, Protein Multimerization, Superoxide Dismutase metabolism, Superoxide Dismutase-1, Ubiquitin-Protein Ligases chemistry, Ubiquitin-Protein Ligases metabolism, Adaptor Proteins, Signal Transducing chemistry, Adaptor Proteins, Signal Transducing metabolism, Protein Aggregates, Protein Folding
- Abstract
The Copper Metabolism MURR1 domain protein 1 (COMMD1) is a protein involved in multiple cellular pathways, including copper homeostasis, NF-κB and hypoxia signalling. Acting as a scaffold protein, COMMD1 mediates the levels, stability and proteolysis of its substrates (e.g. the copper-transporters ATP7B and ATP7A, RELA and HIF-1α). Recently, we established an interaction between the Cu/Zn superoxide dismutase 1 (SOD1) and COMMD1, resulting in a decreased maturation and activation of SOD1. Mutations in SOD1, associated with the progressive neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS), cause misfolding and aggregation of the mutant SOD1 (mSOD1) protein. Here, we identify COMMD1 as a novel regulator of misfolded protein aggregation as it enhances the formation of mSOD1 aggregates upon binding. Interestingly, COMMD1 co-localizes to the sites of mSOD1 inclusions and forms high molecular weight complexes in the presence of mSOD1. The effect of COMMD1 on protein aggregation is client-specific as, in contrast to mSOD1, COMMD1 decreases the abundance of mutant Parkin inclusions, associated with Parkinson's disease. Aggregation of a polyglutamine-expanded Huntingtin, causative of Huntington's disease, appears unaltered by COMMD1. Altogether, this study offers new research directions to expand our current knowledge on the mechanisms underlying aggregation disease pathologies.
- Published
- 2014
- Full Text
- View/download PDF
48. Increased hepatic CD36 expression with age is associated with enhanced susceptibility to nonalcoholic fatty liver disease.
- Author
-
Sheedfar F, Sung MM, Aparicio-Vergara M, Kloosterhuis NJ, Miquilena-Colina ME, Vargas-Castrillón J, Febbraio M, Jacobs RL, de Bruin A, Vinciguerra M, García-Monzón C, Hofker MH, Dyck JR, and Koonen DP
- Subjects
- Adult, Aged, Aging, Animals, Cell Membrane metabolism, Female, Humans, Immunoblotting, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Middle Aged, Real-Time Polymerase Chain Reaction, Young Adult, CD36 Antigens biosynthesis, Hepatocytes metabolism, Liver metabolism, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
CD36 has been associated with obesity and diabetes in human liver diseases, however, its role in age-associated nonalcoholic fatty liver disease (NAFLD) is unknown. Therefore, liver biopsies were collected from individuals with histologically normal livers (n=30), and from patients diagnosed with simple steatosis (NAS; n=26). Patients were divided into two groups according to age and liver biopsy samples were immunostained for CD36. NAFLD parameters were examined in young (12-week) and middle-aged (52-week) C57BL/6J mice, some fed with chow-diet and some fed with low-fat (LFD; 10% kcal fat) or high-fat diet (HFD; 60% kcal fat) for 12-weeks. CD36 expression was positively associated with age in individuals with normal livers but not in NAS patients. However, CD36 was predominantly located at the plasma membrane of hepatocytes in aged NAS patients as compared to young. In chow-fed mice, aging, despite an increase in hepatic CD36 expression, was not associated with the development of NAFLD. However, middle-aged mice did exhibit the development of HFD-induced NAFLD, mediated by an increase of CD36 on the membrane. Enhanced CD36-mediated hepatic fat uptake may contribute to an accelerated progression of NAFLD in mice and humans. Therapies to prevent the increase in CD36 expression and/or CD36 from anchoring at the membrane may prevent the development of NAFLD.
- Published
- 2014
- Full Text
- View/download PDF
49. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.
- Author
-
Tragante V, Barnes MR, Ganesh SK, Lanktree MB, Guo W, Franceschini N, Smith EN, Johnson T, Holmes MV, Padmanabhan S, Karczewski KJ, Almoguera B, Barnard J, Baumert J, Chang YP, Elbers CC, Farrall M, Fischer ME, Gaunt TR, Gho JM, Gieger C, Goel A, Gong Y, Isaacs A, Kleber ME, Mateo Leach I, McDonough CW, Meijs MF, Melander O, Nelson CP, Nolte IM, Pankratz N, Price TS, Shaffer J, Shah S, Tomaszewski M, van der Most PJ, Van Iperen EP, Vonk JM, Witkowska K, Wong CO, Zhang L, Beitelshees AL, Berenson GS, Bhatt DL, Brown M, Burt A, Cooper-DeHoff RM, Connell JM, Cruickshanks KJ, Curtis SP, Davey-Smith G, Delles C, Gansevoort RT, Guo X, Haiqing S, Hastie CE, Hofker MH, Hovingh GK, Kim DS, Kirkland SA, Klein BE, Klein R, Li YR, Maiwald S, Newton-Cheh C, O'Brien ET, Onland-Moret NC, Palmas W, Parsa A, Penninx BW, Pettinger M, Vasan RS, Ranchalis JE, M Ridker P, Rose LM, Sever P, Shimbo D, Steele L, Stolk RP, Thorand B, Trip MD, van Duijn CM, Verschuren WM, Wijmenga C, Wyatt S, Young JH, Zwinderman AH, Bezzina CR, Boerwinkle E, Casas JP, Caulfield MJ, Chakravarti A, Chasman DI, Davidson KW, Doevendans PA, Dominiczak AF, FitzGerald GA, Gums JG, Fornage M, Hakonarson H, Halder I, Hillege HL, Illig T, Jarvik GP, Johnson JA, Kastelein JJ, Koenig W, Kumari M, März W, Murray SS, O'Connell JR, Oldehinkel AJ, Pankow JS, Rader DJ, Redline S, Reilly MP, Schadt EE, Kottke-Marchant K, Snieder H, Snyder M, Stanton AV, Tobin MD, Uitterlinden AG, van der Harst P, van der Schouw YT, Samani NJ, Watkins H, Johnson AD, Reiner AP, Zhu X, de Bakker PI, Levy D, Asselbergs FW, Munroe PB, and Keating BJ
- Subjects
- Arterial Pressure, Computational Biology methods, Europe, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide, Quality Control, Quantitative Trait Loci, Risk Factors, Blood Pressure, Diastole, Genetics, Population, Systole, White People genetics
- Abstract
Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
50. Are hypertriglyceridemia and low HDL causal factors in the development of insulin resistance?
- Author
-
Li N, Fu J, Koonen DP, Kuivenhoven JA, Snieder H, and Hofker MH
- Subjects
- Cholesterol, HDL metabolism, Dyslipidemias complications, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hypertriglyceridemia complications, Insulin Resistance genetics, Metabolic Syndrome complications, Diabetes Mellitus, Type 2 prevention & control, Insulin Resistance physiology
- Abstract
Insulin resistance often occurs with dyslipidemia as part of the metabolic syndrome and the current dominant paradigm is that insulin resistance leads to dyslipidemia. However, dyslipidemia may also cause insulin resistance; this was postulated 30 years ago, but has never been substantiated. Establishing whether dyslipidemia plays a causal role in the etiology of insulin resistance is important since it could reveal new avenues for combating type 2 diabetes. In this review we summarize recent evidence from epidemiological, genetic and intervention studies to re-address this old hypothesis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.