41 results on '"Lestavel S"'
Search Results
2. Influence of Roux-en-Y gastric bypass on plasma bile acid profiles: a comparative study between rats, pigs and humans
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Spinelli, V, Lalloyer, F, Baud, G, Osto, E, Kouach, M, Daoudi, M, Vallez, E, Raverdy, V, Goossens, J-F, Descat, A, Doytcheva, P, Hubert, T, Lutz, T A, Lestavel, S, Staels, B, Pattou, F, and Tailleux, A
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- 2016
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3. CYS127S (FH-Kairouan) and D245N (FH-Tozeur) mutations in the LDL receptor gene in Tunisian families with familial hypercholesterolaemia
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Slimane, M N, Lestavel, S, Clavey, V, Maatouk, F, Ben Fahrat, M H, Fruchart, J C, Hammami, M, and Benlian, P
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- 2002
4. Activation of intestinal peroxisome proliferator-activated receptor- increases high-density lipoprotein production
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Colin, S., primary, Briand, O., additional, Touche, V., additional, Wouters, K., additional, Baron, M., additional, Pattou, F., additional, Hanf, R., additional, Tailleux, A., additional, Chinetti, G., additional, Staels, B., additional, and Lestavel, S., additional
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- 2012
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5. Peroxisome proliferator-activated receptor α controls cellular cholesterol trafficking in macrophages
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Chinetti-Gbaguidi, G., primary, Rigamonti, E., additional, Helin, L., additional, Mutka, A.L., additional, Lepore, M., additional, Fruchart, J.C., additional, Clavey, V., additional, Ikonen, E., additional, Lestavel, S., additional, and Staels, B., additional
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- 2005
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6. Liver X Receptor Activation Controls Intracellular Cholesterol Trafficking and Esterification in Human Macrophages
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Rigamonti, E., primary, Helin, L., additional, Lestavel, S., additional, Mutka, A.L., additional, Lepore, M., additional, Fontaine, C., additional, Bouhlel, M.A., additional, Bultel, S., additional, Fruchart, J.C., additional, Ikonen, E., additional, Clavey, V., additional, Staels, B., additional, and Chinetti-Gbaguidi, G., additional
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- 2005
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7. Peroxisome Proliferator-Activated Receptor α Reduces Cholesterol Esterification in Macrophages
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Chinetti, G., primary, Lestavel, S., additional, Fruchart, J.-C., additional, Clavey, V., additional, and Staels, B., additional
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- 2003
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8. PPAR (peroxisome proliferator-activated receptors) et paroi vasculaire : implications dans l'athérosclérose.
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Lestavel, S, primary, Chinetti, G, additional, Bocher, V, additional, Fruchart, JC, additional, Clavey, V, additional, and Staels, B, additional
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- 2001
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9. A High Concentration of Melatonin Inhibits In Vitro LDL Peroxidation But Not Oxidized LDL Toxicity Toward Cultured Endothelial Cells
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Walters-Laporte, E., primary, Furman, C., additional, Fouquet, S., additional, Martin-Nizard, F., additional, Lestavel, S., additional, Gozzo, A., additional, Lesieur, D., additional, Fruchart, J. C., additional, Duriez, P., additional, and Teissier, E., additional
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- 1998
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10. Immunological and functional properties of in vitro oxidized low density lipoprotein.
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Harduin, P, primary, Tailleux, A, additional, Lestavel, S, additional, Clavey, V, additional, Fruchart, J C, additional, and Fievet, C, additional
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- 1995
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11. Corrigendum to "Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis" [Mol Metab 69 (2023) 1-13].
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Dehondt H, Marino A, Butruille L, Mogilenko DA, Nzoussi Loubota AC, Chávez-Talavera O, Dorchies E, Vallez E, Haas J, Derudas B, Bongiovanni A, Tardivel M, Kuipers F, Lefebvre P, Lestavel S, Tailleux A, Dombrowicz D, Caron S, and Staels B
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- 2024
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12. Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis.
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Dehondt H, Marino A, Butruille L, Mogilenko DA, Nzoussi Loubota AC, Chávez-Talavera O, Dorchies E, Vallez E, Haas J, Derudas B, Bongiovanni A, Tardivel M, Kuipers F, Lefebvre P, Lestavel S, Tailleux A, Dombrowicz D, Caron S, and Staels B
- Subjects
- Animals, Mice, Adipocytes metabolism, Adipose Tissue metabolism, Glucose metabolism, Homeostasis, Inflammation metabolism, Oxidative Stress, Receptors, Cytoplasmic and Nuclear metabolism, Insulin Resistance physiology
- Abstract
Objective: Obesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. The bile acid (BA)-activated nuclear Farnesoid X Receptor (FXR) controls systemic glucose and lipid metabolism. Here, we studied the role of FXR in adipose tissue function., Methods: We first investigated the immune phenotype of epididymal WAT (eWAT) from high fat diet (HFD)-fed whole-body FXR-deficient (FXR
-/- ) mice by flow cytometry and gene expression analysis. We then generated adipocyte-specific FXR-deficient (Ad-FXR-/- ) mice and analyzed systemic and eWAT metabolism and immune phenotype upon HFD feeding. Transcriptomic analysis was done on mature eWAT adipocytes from HFD-fed Ad-FXR-/- mice., Results: eWAT from HFD-fed whole-body FXR-/- and Ad-FXR-/- mice displayed decreased pro-inflammatory macrophage infiltration and inflammation. Ad-FXR-/- mice showed lower blood glucose concentrations, improved systemic glucose tolerance and WAT insulin sensitivity and oxidative stress. Transcriptomic analysis identified Gsta4, a modulator of oxidative stress in WAT, as the most upregulated gene in Ad-FXR-/- mouse adipocytes. Finally, chromatin immunoprecipitation analysis showed that FXR binds the Gsta4 gene promoter., Conclusions: These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)- Published
- 2023
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13. Oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of sodium-glucose co-transporter 1 in enterocytes.
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Zubiaga L, Briand O, Auger F, Touche V, Hubert T, Thevenet J, Marciniak C, Quenon A, Bonner C, Peschard S, Raverdy V, Daoudi M, Kerr-Conte J, Pasquetti G, Koepsell H, Zdzieblo D, Mühlemann M, Thorens B, Delzenne ND, Bindels LB, Deprez B, Vantyghem MC, Laferrère B, Staels B, Huglo D, Lestavel S, and Pattou F
- Abstract
Metformin (MET) is the most prescribed antidiabetic drug, but its mechanisms of action remain elusive. Recent data point to the gut as MET's primary target. Here, we explored the effect of MET on the gut glucose transport machinery. Using human enterocytes (Caco-2/TC7 cells) in vitro , we showed that MET transiently reduced the apical density of sodium-glucose transporter 1 (SGLT1) and decreased the absorption of glucose, without changes in the mRNA levels of the transporter. Administered 1 h before a glucose challenge in rats (Wistar, GK), C57BL6 mice and mice pigs, oral MET reduced the post-prandial glucose response (PGR). This effect was abrogated in SGLT1-KO mice. MET also reduced the luminal clearance of 2-(
18 F)-fluoro-2-deoxy-D-glucose after oral administration in rats. In conclusion, oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of SGLT1 in enterocytes, which may contribute to the clinical effects of the drug., Competing Interests: The authors declare no competing interests., (© 2023.)- Published
- 2023
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14. An Exploratory Study of the Role of Dietary Proteins in the Regulation of Intestinal Glucose Absorption.
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Dugardin C, Fleury L, Touche V, Ahdach F, Lesage J, Tenenbaum M, Everaert N, Briand O, Lestavel S, Ravallec R, and Cudennec B
- Abstract
Several studies have demonstrated that high protein diets improve glucose homeostasis. Nevertheless, the mechanisms underlying this effect remain elusive. This exploratory study aims to screen and compare the acute effects of dietary proteins from different sources on intestinal glucose absorption. Six dietary proteins from various sources were thus selected and digested thanks to the INFOGEST static gastrointestinal digestion protocol. The digested proteins were able to decrease intestinal glucose absorption in vitro and ex vivo . Moreover, acute ingestion of casein and fish gelatin led to improved glucose tolerance in Wistar rats without significant effect on insulin secretion. In parallel, GLUT2 mRNA expression in enterocytes was decreased following short-term incubation with some of the digested proteins. These results strengthen the evidence that digested protein-derived peptides and amino acids are key regulators of glucose homeostasis and highlight their role in intestinal glucose absorption., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dugardin, Fleury, Touche, Ahdach, Lesage, Tenenbaum, Everaert, Briand, Lestavel, Ravallec and Cudennec.)
- Published
- 2022
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15. Farnesoid X Receptor Activation in Brain Alters Brown Adipose Tissue Function via the Sympathetic System.
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Deckmyn B, Domenger D, Blondel C, Ducastel S, Nicolas E, Dorchies E, Caron E, Charton J, Vallez E, Deprez B, Annicotte JS, Lestavel S, Tailleux A, Magnan C, Staels B, and Bantubungi K
- Abstract
The nuclear bile acid (BA) receptor farnesoid X receptor (FXR) is a major regulator of metabolic/energy homeostasis in peripheral organs. Indeed, enterohepatic-expressed FXR controls metabolic processes (BA, glucose and lipid metabolism, fat mass, body weight). The central nervous system (CNS) regulates energy homeostasis in close interaction with peripheral organs. While FXR has been reported to be expressed in the brain, its function has not been studied so far. We studied the role of FXR in brain control of energy homeostasis by treating wild-type and FXR-deficient mice by intracerebroventricular (ICV) injection with the reference FXR agonist GW4064. Here we show that pharmacological activation of brain FXR modifies energy homeostasis by affecting brown adipose tissue (BAT) function. Brain FXR activation decreases the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and consequently the sympathetic tone. FXR activation acts by inhibiting hypothalamic PKA-CREB induction of TH expression. These findings identify a function of brain FXR in the control of energy homeostasis and shed new light on the complex control of energy homeostasis by BA through FXR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer DV declared a shared affiliation, though no other collaboration, with several of the authors, KB, BDc, DD, CB, SD, EN, ED, EC, JC, EV, J-SA, AT, BS, BDp, SL., (Copyright © 2022 Deckmyn, Domenger, Blondel, Ducastel, Nicolas, Dorchies, Caron, Charton, Vallez, Deprez, Annicotte, Lestavel, Tailleux, Magnan, Staels and Bantubungi.)
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- 2022
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16. Characterization of one anastomosis gastric bypass and impact of biliary and common limbs on bile acid and postprandial glucose metabolism in a minipig model.
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Marciniak C, Chávez-Talavera O, Caiazzo R, Hubert T, Zubiaga L, Baud G, Quenon A, Descat A, Vallez E, Goossens JF, Kouach M, Vangelder V, Gobert M, Daoudi M, Derudas B, Pigny P, Klein A, Gmyr V, Raverdy V, Lestavel S, Laferrère B, Staels B, Tailleux A, and Pattou F
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- Anastomosis, Surgical methods, Animals, Bile Acids and Salts blood, Biliary Tract metabolism, Biliary Tract Surgical Procedures methods, Blood Glucose metabolism, Common Bile Duct metabolism, Common Bile Duct surgery, Female, Models, Animal, Obesity, Morbid metabolism, Obesity, Morbid surgery, Postprandial Period, Random Allocation, Swine, Swine, Miniature, Weight Loss physiology, Bile Acids and Salts metabolism, Biliary Tract pathology, Common Bile Duct pathology, Gastric Bypass methods, Glucose metabolism
- Abstract
The alimentary limb has been proposed to be a key driver of the weight-loss-independent metabolic improvements that occur upon bariatric surgery. However, the one anastomosis gastric bypass (OAGB) procedure, consisting of one long biliary limb and a short common limb, induces similar beneficial metabolic effects compared to Roux-en-Y Gastric Bypass (RYGB) in humans, despite the lack of an alimentary limb. The aim of this study was to assess the role of the length of biliary and common limbs in the weight loss and metabolic effects that occur upon OAGB. OAGB and sham surgery, with or without modifications of the length of either the biliary limb or the common limb, were performed in Gottingen minipigs. Weight loss, metabolic changes, and the effects on plasma and intestinal bile acids (BAs) were assessed 15 days after surgery. OAGB significantly decreased body weight, improved glucose homeostasis, increased postprandial GLP-1 and fasting plasma BAs, and qualitatively changed the intestinal BA species composition. Resection of the biliary limb prevented the body weight loss effects of OAGB and attenuated the postprandial GLP-1 increase. Improvements in glucose homeostasis along with changes in plasma and intestinal BAs occurred after OAGB regardless of the biliary limb length. Resection of only the common limb reproduced the glucose homeostasis effects and the changes in intestinal BAs. Our results suggest that the changes in glucose metabolism and BAs after OAGB are mainly mediated by the length of the common limb, whereas the length of the biliary limb contributes to body weight loss. NEW & NOTEWORTHY Common limb mediates postprandial glucose metabolism change after gastric bypass whereas biliary limb contributes to weight loss.
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- 2021
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17. Inflammation-induced cholestasis in cancer cachexia.
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Thibaut MM, Sboarina M, Roumain M, Pötgens SA, Neyrinck AM, Destrée F, Gillard J, Leclercq IA, Dachy G, Demoulin JB, Tailleux A, Lestavel S, Rastelli M, Everard A, Cani PD, Porporato PE, Loumaye A, Thissen JP, Muccioli GG, Delzenne NM, and Bindels LB
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- Animals, Cytokines, Humans, Mice, Cachexia etiology, Cholestasis etiology, Inflammation complications, Neoplasms complications
- Abstract
Background: Cancer cachexia is a debilitating metabolic syndrome contributing to cancer death. Organs other than the muscle may contribute to the pathogenesis of cancer cachexia. This work explores new mechanisms underlying hepatic alterations in cancer cachexia., Methods: We used transcriptomics to reveal the hepatic gene expression profile in the colon carcinoma 26 cachectic mouse model. We performed bile acid, tissue mRNA, histological, biochemical, and western blot analyses. Two interventional studies were performed using a neutralizing interleukin 6 antibody and a bile acid sequestrant, cholestyramine. Our findings were evaluated in a cohort of 94 colorectal cancer patients with or without cachexia (43/51)., Results: In colon carcinoma 26 cachectic mice, we discovered alterations in five inflammatory pathways as well as in other pathways, including bile acid metabolism, fatty acid metabolism, and xenobiotic metabolism (normalized enrichment scores of -1.97, -2.16, and -1.34, respectively; all Padj < 0.05). The hepatobiliary transport system was deeply impaired in cachectic mice, leading to increased systemic and hepatic bile acid levels (+1512 ± 511.6 pmol/mg, P = 0.01) and increased hepatic inflammatory cytokines and neutrophil recruitment to the liver of cachectic mice (+43.36 ± 16.01 neutrophils per square millimetre, P = 0.001). Adaptive mechanisms were set up to counteract this bile acid accumulation by repressing bile acid synthesis and by enhancing alternative routes of basolateral bile acid efflux. Targeting bile acids using cholestyramine reduced hepatic inflammation, without affecting the hepatobiliary transporters (e.g. tumour necrosis factor α signalling via NFκB and inflammatory response pathways, normalized enrichment scores of -1.44 and -1.36, all Padj < 0.05). Reducing interleukin 6 levels counteracted the change in expression of genes involved in the hepatobiliary transport, bile acid synthesis, and inflammation. Serum bile acid levels were increased in cachectic vs. non-cachectic cancer patients (e.g. total bile acids, +5.409 ± 1.834 μM, P = 0.026) and were strongly correlated to systemic inflammation (taurochenodeoxycholic acid and C-reactive protein: ρ = 0.36, Padj = 0.017)., Conclusions: We show alterations in bile acid metabolism and hepatobiliary secretion in cancer cachexia. In this context, we demonstrate the contribution of systemic inflammation to the impairment of the hepatobiliary transport system and the role played by bile acids in the hepatic inflammation. This work paves the way to a better understanding of the role of the liver in cancer cachexia., (© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)
- Published
- 2021
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18. The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids.
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Ducastel S, Touche V, Trabelsi MS, Boulinguiez A, Butruille L, Nawrot M, Peschard S, Chávez-Talavera O, Dorchies E, Vallez E, Annicotte JS, Lancel S, Briand O, Bantubungi K, Caron S, Bindels LB, Delzenne NM, Tailleux A, Staels B, and Lestavel S
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- Animals, Colon drug effects, Glucagon-Like Peptide 1 metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Colon metabolism, Fatty Acids, Volatile pharmacology, Glucagon-Like Peptide 1 antagonists & inhibitors, Microbiota, Receptors, Cytoplasmic and Nuclear physiology
- Abstract
The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.
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- 2020
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19. Food-Derived Hemorphins Cross Intestinal and Blood-Brain Barriers In Vitro .
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Domenger D, Cudennec B, Kouach M, Touche V, Landry C, Lesage J, Gosselet F, Lestavel S, Goossens JF, Dhulster P, and Ravallec R
- Abstract
A qualitative study is presented, where the main question was whether food-derived hemorphins, i.e., originating from digested alimentary hemoglobin, could pass the intestinal barrier and/or the blood-brain barrier (BBB). Once absorbed, hemorphins are opioid receptor (OR) ligands that may interact with peripheral and central OR and have effects on food intake and energy balance regulation. LLVV-YPWT (LLVV-H4), LVV-H4, VV-H4, VV-YPWTQRF (VV-H7), and VV-H7 hemorphins that were previously identified in the 120 min digest resulting from the simulated gastrointestinal digestion of hemoglobin have been synthesized to be tested in in vitro models of passage of IB and BBB. LC-MS/MS analyses yielded that all hemorphins, except the LLVV-H4 sequence, were able to cross intact the human intestinal epithelium model with Caco-2 cells within 5-60 min when applied at 5 mM. Moreover, all hemorphins crossed intact the human BBB model with brain-like endothelial cells (BLEC) within 30 min when applied at 100 µM. Fragments of these hemorphins were also detected, especially the YPWT common tetrapeptide that retains OR-binding capacity. A cAMP assay performed in Caco-2 cells indicates that tested hemorphins behave as OR agonists in these cells by reducing cAMP production. We further provide preliminary results regarding the effects of hemorphins on tight junction proteins, specifically here the claudin-4 that is involved in paracellular permeability. All hemorphins at 100 µM, except the LLVV-H4 peptide, significantly decreased claudin-4 mRNA levels in the Caco-2 intestinal model. This in vitro study is a first step toward demonstrating food-derived hemorphins bioavailability which is in line with the growing body of evidence supporting physiological functions for food-derived peptides.
- Published
- 2018
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20. Ffar2 expression regulates leukaemic cell growth in vivo.
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Bindels LB, Porporato PE, Ducastel S, Sboarina M, Neyrinck AM, Dewulf EM, Feron O, Lestavel S, Cani PD, Staels B, Sonveaux P, and Delzenne NM
- Subjects
- Animals, Apoptosis, Biomarkers, Tumor metabolism, Female, Leukemia, Experimental metabolism, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Tumor Cells, Cultured, Cell Proliferation, Leukemia, Experimental pathology, Receptors, G-Protein-Coupled physiology
- Abstract
Background: Activation of free fatty acid receptor 2 (FFAR2) by microbiota-derived metabolites (e.g., propionate) reduces leukaemic cell proliferation in vitro. This study aims to test whether Ffar2 expression per se also influences leukaemia cell growth in vivo., Methods: Bcr-Abl-expressing BaF cells were used as a leukaemia model and the role of Ffar2 was evaluated in Balb/c mice after lentiviral shRNA transduction., Results: Our data formally establish that reduced leukaemic cell proliferation is associated with increased Ffar2 expression in vivo and in vitro. Going beyond association, we point out that decreasing Ffar2 expression fosters cancer cell growth in vitro and in vivo., Conclusions: Our data demonstrate the role of Ffar2 in the control of leukaemic cell proliferation in vivo and indicate that a modulation of Ffar2 expression through nutritional tools or pharmacological agents may constitute an attractive therapeutic approach to tackle leukaemia progression in humans.
- Published
- 2017
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21. Bile Acid Alterations Are Associated With Insulin Resistance, but Not With NASH, in Obese Subjects.
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Legry V, Francque S, Haas JT, Verrijken A, Caron S, Chávez-Talavera O, Vallez E, Vonghia L, Dirinck E, Verhaegen A, Kouach M, Lestavel S, Lefebvre P, Van Gaal L, Tailleux A, Paumelle R, and Staels B
- Subjects
- Adult, Case-Control Studies, Female, Gene Expression Regulation, Humans, Liver metabolism, Male, Middle Aged, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease epidemiology, Obesity complications, Obesity epidemiology, Bile Acids and Salts metabolism, Insulin Resistance, Non-alcoholic Fatty Liver Disease metabolism, Obesity metabolism
- Abstract
Context: Bile acids (BAs) are signaling molecules controlling energy homeostasis that can be both toxic and protective for the liver. BA alterations have been reported in obesity, insulin resistance (IR), and nonalcoholic steatohepatitis (NASH). However, whether BA alterations contribute to NASH independently of the metabolic status is unclear., Objective: To assess BA alterations associated with NASH independently of body mass index and IR., Design and Setting: Patients visiting the obesity clinic of the Antwerp University Hospital (a tertiary referral facility) were recruited from 2006 to 2014., Patients: Obese patients with biopsy-proven NASH (n = 32) and healthy livers (n = 26) were matched on body mass index and homeostasis model assessment of IR., Main Outcome Measures: Transcriptomic analyses were performed on liver biopsies. Plasma concentrations of 21 BA species and 7α-hydroxy-4-cholesten-3-one, a marker of BA synthesis, were determined by liquid chromatography-tandem mass spectrometry. Plasma fibroblast growth factor 19 was measured by enzyme-linked immunosorbent assay., Results: Plasma BA concentrations did not correlate with any hepatic lesions, whereas, as previously reported, primary BA strongly correlated with IR. Transcriptomic analyses showed unaltered hepatic BA metabolism in NASH patients. In line, plasma 7α-hydroxy-4-cholesten-3-one was unchanged in NASH. Moreover, no sign of hepatic BA accumulation or activation of BA receptors-farnesoid X, pregnane X, and vitamin D receptors-was found. Finally, plasma fibroblast growth factor 19, secondary-to-primary BA, and free-to-conjugated BA ratios were similar, suggesting unaltered intestinal BA metabolism and signaling., Conclusions: In obese patients, BA alterations are related to the metabolic phenotype associated with NASH, especially IR, but not liver necroinflammation., (Copyright © 2017 Endocrine Society)
- Published
- 2017
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22. Intestinal bile acid receptors are key regulators of glucose homeostasis.
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Trabelsi MS, Lestavel S, Staels B, and Collet X
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- Animals, Biomedical Research education, Biomedical Research methods, Biomedical Research trends, Blood Glucose metabolism, Congresses as Topic, Diabetes Mellitus, Type 2 blood, Humans, Nutritional Sciences education, Nutritional Sciences methods, Nutritional Sciences trends, Obesity blood, Societies, Scientific, Diabetes Mellitus, Type 2 metabolism, Energy Metabolism, Intestinal Mucosa metabolism, Obesity metabolism, RNA-Binding Proteins metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
In addition to their well-known function as dietary lipid detergents, bile acids have emerged as important signalling molecules that regulate energy homeostasis. Recent studies have highlighted that disrupted bile acid metabolism is associated with metabolism disorders such as dyslipidaemia, intestinal chronic inflammatory diseases and obesity. In particular, type 2 diabetes (T2D) is associated with quantitative and qualitative modifications in bile acid metabolism. Bile acids bind and modulate the activity of transmembrane and nuclear receptors (NR). Among these receptors, the G-protein-coupled bile acid receptor 1 (TGR5) and the NR farnesoid X receptor (FXR) are implicated in the regulation of bile acid, lipid, glucose and energy homeostasis. The role of these receptors in the intestine in energy metabolism regulation has been recently highlighted. More precisely, recent studies have shown that FXR is important for glucose homeostasis in particular in metabolic disorders such as T2D and obesity. This review highlights the growing importance of the bile acid receptors TGR5 and FXR in the intestine as key regulators of glucose metabolism and their potential as therapeutic targets.
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- 2017
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23. Liver X Receptor Regulates Triglyceride Absorption Through Intestinal Down-regulation of Scavenger Receptor Class B, Type 1.
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Briand O, Touche V, Colin S, Brufau G, Davalos A, Schonewille M, Bovenga F, Carrière V, de Boer JF, Dugardin C, Riveau B, Clavey V, Tailleux A, Moschetta A, Lasunción MA, Groen AK, Staels B, and Lestavel S
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- Animals, Apolipoprotein B-100 metabolism, Apolipoproteins B metabolism, Benzoates pharmacology, Benzylamines pharmacology, Caco-2 Cells, Cholesterol, Dietary metabolism, Chylomicrons metabolism, DEAD-box RNA Helicases deficiency, DEAD-box RNA Helicases genetics, Down-Regulation, Humans, Hydrocarbons, Fluorinated pharmacology, Intestinal Mucosa drug effects, Jejunum drug effects, Liver X Receptors, Male, Mice, Inbred C57BL, Mice, Knockout, MicroRNAs genetics, MicroRNAs metabolism, Orphan Nuclear Receptors agonists, Protein Transport, RNA Interference, Ribonuclease III deficiency, Ribonuclease III genetics, Scavenger Receptors, Class B deficiency, Scavenger Receptors, Class B genetics, Signal Transduction, Sulfonamides pharmacology, Transcription, Genetic, Transfection, Intestinal Absorption drug effects, Intestinal Mucosa metabolism, Jejunum metabolism, Orphan Nuclear Receptors metabolism, Scavenger Receptors, Class B metabolism, Triglycerides metabolism
- Abstract
Background & Aims: Reducing postprandial triglyceridemia may be a promising strategy to lower the risk of cardiovascular disorders associated with obesity and type 2 diabetes. In enterocytes, scavenger receptor class B, type 1 (SR-B1, encoded by SCARB1) mediates lipid-micelle sensing to promote assembly and secretion of chylomicrons. The nuclear receptor subfamily 1, group H, members 2 and 3 (also known as liver X receptors [LXRs]) regulate genes involved in cholesterol and fatty acid metabolism. We aimed to determine whether intestinal LXRs regulate triglyceride absorption., Methods: C57BL/6J mice were either fed a cholesterol-enriched diet or given synthetic LXR agonists (GW3965 or T0901317). We measured the production of chylomicrons and localized SR-B1 by immunohistochemistry. Mechanisms of postprandial triglyceridemia and SR-B1 regulation were studied in Caco-2/TC7 cells incubated with LXR agonists., Results: In mice and in the Caco-2/TC7 cell line, LXR agonists caused localization of intestinal SR-B1 from apical membranes to intracellular organelles and reduced chylomicron secretion. In Caco-2/TC7 cells, LXR agonists reduced SR-B1-dependent lipidic-micelle-induced Erk phosphorylation. LXR agonists also reduced intracellular trafficking of the apical apolipoprotein B pool toward secretory compartments. LXR reduced levels of SR-B1 in Caco-2/TC7 cells via a post-transcriptional mechanism that involves microRNAs., Conclusion: In Caco-2/TC7 cells and mice, intestinal activation of LXR reduces the production of chylomicrons by a mechanism dependent on the apical localization of SR-B1., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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24. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells.
- Author
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Trabelsi MS, Daoudi M, Prawitt J, Ducastel S, Touche V, Sayin SI, Perino A, Brighton CA, Sebti Y, Kluza J, Briand O, Dehondt H, Vallez E, Dorchies E, Baud G, Spinelli V, Hennuyer N, Caron S, Bantubungi K, Caiazzo R, Reimann F, Marchetti P, Lefebvre P, Bäckhed F, Gribble FM, Schoonjans K, Pattou F, Tailleux A, Staels B, and Lestavel S
- Subjects
- Animals, Anticholesteremic Agents pharmacology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Bile Acids and Salts metabolism, Blood Glucose metabolism, Colesevelam Hydrochloride pharmacology, Colon cytology, Colon metabolism, Diet, High-Fat, Glucagon-Like Peptide 1 metabolism, Glycolysis, Humans, Ileum cytology, Ileum metabolism, Insulin metabolism, Insulin Secretion, Insulin-Secreting Cells metabolism, Intestines cytology, Jejunum cytology, Jejunum metabolism, Mice, Mice, Knockout, Mice, Obese, Nuclear Proteins metabolism, Obesity genetics, Obesity metabolism, Proglucagon drug effects, Proglucagon genetics, Proglucagon metabolism, Receptors, G-Protein-Coupled genetics, Sequestering Agents pharmacology, Signal Transduction, Transcription Factors metabolism, Enteroendocrine Cells metabolism, Glucagon-Like Peptide 1 genetics, Intestinal Mucosa metabolism, RNA, Messenger metabolism, Receptors, Cytoplasmic and Nuclear genetics
- Abstract
Bile acids are signalling molecules, which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex bile acids in the intestinal lumen and decrease intestinal FXR activity. The BAS-BA complex also induces glucagon-like peptide-1 (GLP-1) production by L cells which potentiates β-cell glucose-induced insulin secretion. Whether FXR is expressed in L cells and controls GLP-1 production is unknown. Here, we show that FXR activation in L cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycaemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes.
- Published
- 2015
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25. Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production.
- Author
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Colin S, Briand O, Touche V, Wouters K, Baron M, Pattou F, Hanf R, Tailleux A, Chinetti G, Staels B, and Lestavel S
- Subjects
- Animals, Apolipoproteins B metabolism, Butyrates pharmacology, Caco-2 Cells, Cells, Cultured, Chalcones pharmacology, Enterocytes metabolism, Esterification physiology, Fatty Acids metabolism, Female, Humans, Jejunum metabolism, Mice, Mice, Knockout, PPAR alpha antagonists & inhibitors, Phenylurea Compounds pharmacology, Propionates pharmacology, Lipoproteins, HDL metabolism, PPAR alpha physiology
- Abstract
Aims: Peroxisome proliferator-activated receptor (PPAR)-α is a transcription factor controlling lipid metabolism in liver, heart, muscle, and macrophages. Peroxisome proliferator-activated receptor-α activation increases plasma HDL cholesterol and exerts hypotriglyceridaemic actions via the liver. However, the intestine expresses PPAR-α, produces HDL and chylomicrons, and is exposed to diet-derived PPAR-α ligands. Therefore, we examined the effects of PPAR-α activation on intestinal lipid and lipoprotein metabolism., Methods and Results: The impact of PPAR-α activation was evaluated in term of HDL-related gene expression in mice, ex vivo in human jejunal biopsies and in Caco-2/TC7 cells. Apolipoprotein-AI/HDL secretion, cholesterol esterification, and trafficking were also studied in vitro. In parallel to improving plasma lipid profiles and increasing liver and intestinal expression of fatty acid oxidation genes, treatment with the dual PPAR-α/δ ligand GFT505 resulted in a more pronounced increase in plasma HDL compared with fenofibrate in mice. GFT505, but not fenofibrate, increased the expression of HDL production genes such as apolipoprotein-AI and ATP-binding cassette A1 transporter in murine intestines. A similar increase was observed upon PPAR-α activation of human biopsies and Caco-2/TC7 cells. Additionally, HDL secretion by Caco-2/TC7 cells increased. Moreover, PPAR-α activation decreased the cholesterol esterification capacity of Caco-2/TC7 cells, modified cholesterol trafficking, and reduced apolipoprotein-B secretion., Conclusion: Peroxisome proliferator-activated receptor-α activation reduces cholesterol esterification, suppresses chylomicron, and increases HDL secretion by enterocytes. These results identify the intestine as a target organ of PPAR-α ligands with entero-hepatic tropism to reduce atherogenic dyslipidaemia.
- Published
- 2013
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26. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity.
- Author
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Prawitt J, Abdelkarim M, Stroeve JH, Popescu I, Duez H, Velagapudi VR, Dumont J, Bouchaert E, van Dijk TH, Lucas A, Dorchies E, Daoudi M, Lestavel S, Gonzalez FJ, Oresic M, Cariou B, Kuipers F, Caron S, and Staels B
- Subjects
- Adipose Tissue drug effects, Adipose Tissue metabolism, Animals, Bile Acids and Salts blood, Disease Models, Animal, Homeostasis, Hypertriglyceridemia etiology, Insulin pharmacology, Insulin Resistance, Lipid Metabolism, Male, Mice, Mice, Obese, Weight Gain physiology, Glucose metabolism, Obesity metabolism, Receptors, Cytoplasmic and Nuclear deficiency
- Abstract
Objective: Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed., Research Design and Methods: Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity., Results: FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism., Conclusions: Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis., (© 2011 by the American Diabetes Association.)
- Published
- 2011
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27. PPARβ/δ activation induces enteroendocrine L cell GLP-1 production.
- Author
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Daoudi M, Hennuyer N, Borland MG, Touche V, Duhem C, Gross B, Caiazzo R, Kerr-Conte J, Pattou F, Peters JM, Staels B, and Lestavel S
- Subjects
- Animals, Blood Glucose metabolism, Blotting, Western, Cells, Cultured, Diabetes Mellitus, Experimental pathology, Disease Models, Animal, Enteroendocrine Cells pathology, Glucagon-Like Peptide 1 genetics, Humans, Male, Mice, Polymerase Chain Reaction, RNA, Messenger biosynthesis, Rats, Diabetes Mellitus, Experimental metabolism, Enteroendocrine Cells metabolism, Gene Expression Regulation, Glucagon-Like Peptide 1 biosynthesis, PPAR-beta metabolism, RNA, Messenger genetics
- Abstract
Background & Aims: Glucagon-like peptide (GLP)-1, an intestinal incretin produced by L cells through proglucagon processing, is secreted after nutrient ingestion and acts on endocrine pancreas beta cells to enhance insulin secretion. Peroxisome proliferator-activated receptor (PPAR) β/δ is a nuclear receptor that improves glucose homeostasis and pancreas islet function in diabetic animal models. Here, we investigated whether PPARβ/δ activation regulates L cell GLP-1 production., Methods: Proglucagon regulation and GLP-1 release were evaluated in murine GLUTag and human NCI-H716 L cells and in vivo using wild-type, PPARβ/δ-null, and ob/ob C57Bl/6 mice treated with the PPARβ/δ synthetic agonists GW501516 or GW0742., Results: PPARβ/δ activation increased proglucagon expression and enhanced glucose- and bile acid-induced GLP-1 release by intestinal L cells in vitro and ex vivo in human jejunum. In vivo treatment with GW0742 increased proglucagon messenger RNA levels in the small intestine in wild-type but not in PPARβ/δ-deficient mice. Treatment of wild-type and ob/ob mice with GW501516 enhanced the increase in plasma GLP-1 level after an oral glucose load and improved glucose tolerance. Concomitantly, proglucagon and GLP-1 receptor messenger RNA levels increased in the small intestine and pancreas, respectively. Finally, PPARβ/δ agonists activate the proglucagon gene transcription by interfering with the β-catenin/TCF-4 pathway., Conclusions: Our data show that PPARβ/δ activation potentiates GLP-1 production by the small intestine. Pharmacologic targeting of PPARβ/δ is a promising approach in the treatment of patients with type 2 diabetes mellitus, especially in combination with dipeptidyl peptidase IV inhibitors., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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28. Rexinoid bexarotene modulates triglyceride but not cholesterol metabolism via gene-specific permissivity of the RXR/LXR heterodimer in the liver.
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Lalloyer F, Pedersen TA, Gross B, Lestavel S, Yous S, Vallez E, Gustafsson JA, Mandrup S, Fiévet C, Staels B, and Tailleux A
- Subjects
- Animals, Bexarotene, DNA-Binding Proteins chemistry, Dimerization, Female, Homeostasis, Lipogenesis, Liver X Receptors, Mice, Mice, Inbred C57BL, Orphan Nuclear Receptors, Receptors, Cytoplasmic and Nuclear chemistry, Retinoid X Receptors chemistry, Cholesterol metabolism, DNA-Binding Proteins physiology, Liver metabolism, Receptors, Cytoplasmic and Nuclear physiology, Retinoid X Receptors physiology, Tetrahydronaphthalenes pharmacology, Triglycerides metabolism
- Abstract
Objective: Bexarotene (Targretin) is a clinically used antitumoral agent which exerts its action through binding to and activation of the retinoid-X-receptor (RXR). The most frequent side-effect of bexarotene administration is an increase in plasma triglycerides, an independent risk factor of cardiovascular disease. The molecular mechanism behind this hypertriglyceridemia remains poorly understood., Methods and Results: Using wild-type and LXR alpha/beta-deficient mice, we show here that bexarotene induces hypertriglyceridemia and activates hepatic LXR-target genes of lipogenesis in an LXR-dependent manner, hence exerting a permissive effect on RXR/LXR heterodimers. Interestingly, RNA analysis and Chromatin Immunoprecipitation assays performed in the liver reveal that the in vivo permissive effect of bexarotene on the RXR/LXR heterodimer is restricted to lipogenic genes without modulation of genes controlling cholesterol homeostasis., Conclusions: These findings demonstrate that the hypertriglyceridemic action of bexarotene occurs via the RXR/LXR heterodimer and show that RXR heterodimers can act with a selective permissivity on target genes of specific metabolic pathways in the liver.
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- 2009
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29. Liver X receptor activation induces the uptake of cholesteryl esters from high density lipoproteins in primary human macrophages.
- Author
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Bultel S, Helin L, Clavey V, Chinetti-Gbaguidi G, Rigamonti E, Colin M, Fruchart JC, Staels B, and Lestavel S
- Subjects
- Apolipoprotein A-I metabolism, Atherosclerosis etiology, Atherosclerosis metabolism, Biological Transport, Active, Caveolin 1 genetics, Caveolin 1 metabolism, Cells, Cultured, Cholesterol, HDL metabolism, DNA-Binding Proteins agonists, Humans, Hydrocarbons, Fluorinated pharmacology, Liver X Receptors, Macrophages cytology, Macrophages drug effects, Membrane Microdomains metabolism, Orphan Nuclear Receptors, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Cytoplasmic and Nuclear agonists, Scavenger Receptors, Class B genetics, Scavenger Receptors, Class B metabolism, Sulfonamides pharmacology, Cholesterol Esters metabolism, DNA-Binding Proteins metabolism, Lipoproteins, HDL metabolism, Macrophages metabolism, Receptors, Cytoplasmic and Nuclear metabolism
- Abstract
Objective: Liver X receptors (LXRs) are oxysterol-activated nuclear receptors regulating reverse cholesterol transport, in part by modulating cholesterol efflux from macrophages to apoAI and HDL via the ABCA1 and ABCG1/ABCG4 pathways. Moreover, LXR activation increases intracellular cholesterol trafficking via the induction of NPC1 and NPC2 expression. However, implication of LXRs in the selective uptake of cholesteryl esters from lipoproteins in human macrophages has never been reported., Methods and Results: Our results show that (1) selective CE uptake from HDL(3) is highly efficient in human monocyte-derived macrophages; (2) surprisingly, HDL(3)-CE uptake is strongly increased by LXR activation despite antiatherogenic effects of LXRs; (3) HDL(3)-CE uptake increase is not linked to SR-BI expression modulation but it is dependent of proteoglycan interactions; (4) HDL(3)-CE uptake increase is associated with increased expression and secretion of apoE and LPL, two proteins interacting with proteoglycans; (5) HDL(3)-CE uptake increase depends on the integrity of raft domains and is associated with an increased caveolin-1 expression., Conclusions: Our study identifies a new role for LXRs in the control of cholesterol homeostasis in human macrophages. LXR activation results in enhanced dynamic intracellular cholesterol fluxes through an increased CE uptake from HDL and leads to an increased cholesterol availability to efflux to apoAI and HDL.
- Published
- 2008
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30. Intestine-specific regulation of PPARalpha gene transcription by liver X receptors.
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Colin S, Bourguignon E, Boullay AB, Tousaint JJ, Huet S, Caira F, Staels B, Lestavel S, Lobaccaro JM, and Delerive P
- Subjects
- Animals, Benzoates pharmacology, Benzylamines pharmacology, DNA-Binding Proteins agonists, DNA-Binding Proteins genetics, Gene Expression Regulation physiology, Homeostasis physiology, Hydrocarbons, Fluorinated, Lipid Metabolism physiology, Liver physiology, Liver X Receptors, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Organ Specificity, Orphan Nuclear Receptors, PPAR alpha metabolism, RNA, Messenger metabolism, Receptor Cross-Talk physiology, Receptors, Cytoplasmic and Nuclear agonists, Receptors, Cytoplasmic and Nuclear genetics, Sulfonamides pharmacology, Transcription, Genetic physiology, Transcriptional Activation, DNA-Binding Proteins metabolism, Intestines physiology, PPAR alpha genetics, Receptors, Cytoplasmic and Nuclear metabolism
- Abstract
Liver X receptor-alpha (LXRalpha) and LXRbeta are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They have been identified as key players in cholesterol homeostasis and lipid and glucose metabolism as well as immune and inflammatory responses. In the small intestine, LXRs have been shown not only to regulate cholesterol absorption and excretion but also to promote high-density lipoprotein biogenesis via the ATP-binding cassette A1 signaling pathway. Here, using gene expression assays, we identified PPARalpha as an intestine-specific LXR target gene. Chronic administration of LXR synthetic agonists led to a significant increase of PPARalpha mRNA levels in the small intestine but not in the liver. In addition, this specific PPARalpha gene up-regulation occurred in the duodenum, jejunum, and ileum in a dose-dependent manner and translated at the protein level as demonstrated by Western blot analysis. Furthermore, PPARalpha gene induction was completely abolished in LXR-deficient mice. Finally, the physiological relevance of LXR-mediated PPARalpha up-regulation in the small intestine was assessed in PPARalpha-deficient mice. Administration of a synthetic LXR agonist to wild-type mice led to the induction of several PPARalpha target genes including PDK4 and CPT1. Those effects were completely abolished in PPARalpha-deficient mice, demonstrating the biological relevance of this LXR-PPARalpha transcriptional cascade. Taken together, these results demonstrate that PPARalpha is an intestine-specific LXR target gene and suggest the existence of a transcriptional cross talk between those members of the nuclear receptor superfamily.
- Published
- 2008
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31. The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia.
- Author
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Lalloyer F, Fiévet C, Lestavel S, Torpier G, van der Veen J, Touche V, Bultel S, Yous S, Kuipers F, Paumelle R, Fruchart JC, Staels B, and Tailleux A
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 1, ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters metabolism, Animals, Apolipoprotein E2 genetics, Apolipoprotein E2 metabolism, Atherosclerosis metabolism, Bexarotene, CD13 Antigens genetics, CD13 Antigens metabolism, Disease Models, Animal, Dyslipidemias drug therapy, Dyslipidemias metabolism, Female, Gene Expression Regulation drug effects, Homeostasis physiology, Intestinal Absorption drug effects, Lipoproteins genetics, Lipoproteins metabolism, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Tetrahydronaphthalenes therapeutic use, Triglycerides blood, Atherosclerosis drug therapy, Atherosclerosis etiology, Cholesterol metabolism, Dyslipidemias complications, Homeostasis drug effects, Retinoid X Receptors agonists, Tetrahydronaphthalenes pharmacology
- Abstract
Objective: The activity of the antitumoral agent bexarotene (Targretin, Bexarotene) depends on its binding to the nuclear retinoid-X receptor (RXR) and subsequent transcriptional regulation of target genes. Through RXR activation, bexarotene may modulate numerous metabolic pathways involved in atherosclerosis. Here, we investigated the effect of bexarotene on atherosclerosis progression in a dyslipidemic murine model, the human apolipoprotein E2 knockin mouse, that develops essentially macrophage-laden lesions., Methods and Results: Atherosclerotic lesions together with different metabolic pathways involved in atherosclerosis were investigated in mice treated or not with bexarotene. Bexarotene protects from atherosclerosis development in mice, at least in part by improving the circulating cholesterol distribution profile likely via a marked decrease of dietary cholesterol absorption caused by modulation of intestinal expression of genes recently identified as major players in this process, Niemann-Pick-C1-Like1 (NPC1L1) and CD13. This atheroprotection appears despite a strong hypertriglyceridemia. Moreover, bexarotene treatment only modestly modulates inflammatory gene expression in the vascular wall, but markedly enhanced the capacity of macrophages to efflux cellular lipids., Conclusions: These data provide evidence of a favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, likely via a beneficial action on intestinal absorption and macrophage efflux.
- Published
- 2006
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32. Peroxisome proliferator-activated receptor alpha controls cellular cholesterol trafficking in macrophages.
- Author
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Chinetti-Gbaguidi G, Rigamonti E, Helin L, Mutka AL, Lepore M, Fruchart JC, Clavey V, Ikonen E, Lestavel S, and Staels B
- Subjects
- Biological Transport, Carrier Proteins genetics, Cell Differentiation, Cell Membrane drug effects, Cell Membrane metabolism, Cells, Cultured, Gene Expression Regulation, Glycoproteins genetics, Humans, Intracellular Signaling Peptides and Proteins, Lipoproteins, LDL pharmacology, Macrophages cytology, Membrane Glycoproteins genetics, Niemann-Pick C1 Protein, PPAR alpha genetics, Progesterone pharmacology, RNA, Messenger genetics, RNA, Small Interfering genetics, Vesicular Transport Proteins, Cholesterol metabolism, Macrophages metabolism, PPAR alpha metabolism
- Abstract
The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant that governs its availability for efflux to extracellular acceptors. NPC1 and NPC2 are proteins localized in the late endosome and control cholesterol transport from the lysosome to the plasma membrane. Here, we report that NPC1 and NPC2 gene expression is induced by oxidized LDL (OxLDL) in human macrophages. Because OxLDLs contain natural activators of peroxisome proliferator-activated receptor alpha (PPARalpha), a fatty acid-activated nuclear receptor, the regulation of NPC1 and NPC2 by PPARalpha and the consequences on cholesterol trafficking were further studied. NPC1 and NPC2 expression is induced by synthetic PPARalpha ligands in human macrophages. Furthermore, PPARalpha activation leads to an enrichment of cholesterol in the plasma membrane. By contrast, incubation with progesterone, which blocks postlysosomal cholesterol trafficking, as well as NPC1 and NPC2 mRNA depletion using small interfering RNA, abolished ABCA1-dependent cholesterol efflux induced by PPARalpha activators. These observations identify a novel regulatory role for PPARalpha in the control of cholesterol availability for efflux that, associated with its ability to inhibit cholesterol esterification and to stimulate ABCA1 and scavenger receptor class B type I expression, may contribute to the stimulation of reverse cholesterol transport.
- Published
- 2005
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33. Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1.
- Author
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van der Veen JN, Kruit JK, Havinga R, Baller JF, Chimini G, Lestavel S, Staels B, Groot PH, Groen AK, and Kuipers F
- Subjects
- ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters metabolism, Animals, Caco-2 Cells drug effects, Cholesterol blood, Cholesterol, HDL blood, Cholesterol, HDL drug effects, Female, Humans, Intestinal Absorption drug effects, Intestines drug effects, Macrophages metabolism, Membrane Proteins drug effects, Membrane Proteins genetics, Membrane Transport Proteins drug effects, Membrane Transport Proteins genetics, Mice, Mice, Inbred DBA, Mice, Knockout, PPAR delta agonists, Proteins drug effects, Proteins genetics, RNA, Messenger drug effects, RNA, Messenger genetics, Sterols metabolism, Thiazoles pharmacology, Time Factors, Cholesterol metabolism, Cholesterol, HDL metabolism, Intestinal Absorption physiology, Intestinal Mucosa metabolism, Membrane Transport Proteins metabolism, PPAR delta metabolism
- Abstract
Peroxisome proliferator-activated receptors (PPARs) control the transcription of genes involved in lipid metabolism. Activation of PPARdelta may have antiatherogenic effects through the increase of plasma HDL, theoretically promoting reverse cholesterol transport from peripheral tissues toward the liver for removal via bile and feces. Effects of PPARdelta activation by GW610742 were evaluated in wild-type and Abca1-deficient (Abca1(-/-)) mice that lack HDL. Treatment with GW610742 resulted in an approximately 50% increase of plasma HDL-cholesterol in wild-type mice, whereas plasma cholesterol levels remained extremely low in Abca1(-/-) mice. Yet, biliary cholesterol secretion rates were similar in untreated wild-type and Abca1(-/-) mice and unaltered upon treatment. Unexpectedly, PPARdelta activation led to enhanced fecal neutral sterol loss in both groups without any changes in intestinal Abca1, Abcg5, Abcg8, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase expression. Moreover, GW610742 treatment resulted in a 43% reduction of fractional cholesterol absorption in wild-type mice, coinciding with a significantly reduced expression of the cholesterol absorption protein Niemann-Pick C1-like 1 (Npc1l1) in the intestine. PPARdelta activation is associated with increased plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression. Thus, PPARdelta is a promising target for drugs aimed to treat or prevent atherosclerosis.
- Published
- 2005
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34. Peroxisome proliferator-activated receptor alpha reduces cholesterol esterification in macrophages.
- Author
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Chinetti G, Lestavel S, Fruchart JC, Clavey V, and Staels B
- Subjects
- Carnitine O-Palmitoyltransferase genetics, Carnitine O-Palmitoyltransferase metabolism, Cells, Cultured, Cholesterol Esters metabolism, Enzyme Activation drug effects, Esterification drug effects, Foam Cells cytology, Foam Cells drug effects, Foam Cells metabolism, Gene Expression drug effects, Homeostasis drug effects, Humans, Ligands, Macrophages cytology, Macrophages drug effects, Peroxisome Proliferators pharmacology, Pyrimidines pharmacology, RNA, Messenger metabolism, Receptors, Cytoplasmic and Nuclear drug effects, Sphingomyelin Phosphodiesterase metabolism, Sterol O-Acyltransferase genetics, Sterol O-Acyltransferase metabolism, Transcription Factors drug effects, Tumor Necrosis Factor-alpha pharmacology, Cholesterol metabolism, Macrophages metabolism, Receptors, Cytoplasmic and Nuclear metabolism, Transcription Factors metabolism
- Abstract
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor activated by fatty acid derivatives and hypolipidemic drugs of the fibrate class. PPARalpha is expressed in monocytes, macrophages, and foam cells, suggesting a role for this receptor in macrophage lipid homeostasis with consequences for atherosclerosis development. Recently, it was shown that PPARalpha activation promotes cholesterol efflux from macrophages via induction of the ABCA1 pathway. In the present study, the influence of PPARalpha activators on intracellular cholesterol homeostasis was investigated. In human macrophages and foam cells, treatment with fibrates, synthetic PPARalpha activators, led to a decrease in the cholesteryl ester (CE):free cholesterol (FC) ratio. In these cells, PPARalpha activation reduced cholesterol esterification rates and Acyl-CoA:cholesterol acyltransferase-1 (ACAT1) activity. However, PPARalpha activation did not alter ACAT1 gene expression, whereas mRNA levels of carnitine palmitoyltransferase type 1 (CPT-1), a key enzyme in mitochondrial fatty acid catabolism, were induced. Finally, PPARalpha activation blocked CE formation induced by TNF-alpha, possibly due to the inhibition of neutral sphingomyelinase activation by TNF-alpha. In conclusion, our results identify a role for PPARalpha in the control of cholesterol esterification in macrophages, resulting in an enhanced availability of FC for efflux through the ABCA1 pathway.
- Published
- 2003
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35. Lipid free apolipoprotein E binds to the class B Type I scavenger receptor I (SR-BI) and enhances cholesteryl ester uptake from lipoproteins.
- Author
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Bultel-Brienne S, Lestavel S, Pilon A, Laffont I, Tailleux A, Fruchart JC, Siest G, and Clavey V
- Subjects
- Binding Sites, Binding, Competitive, CD36 Antigens chemistry, Cell Line, Cell Membrane metabolism, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Glycosides metabolism, Humans, Hydrolysis, Ligands, Lipid Metabolism, Lipoproteins, HDL metabolism, Lipoproteins, LDL metabolism, Protein Binding, Receptors, Scavenger, Recombinant Proteins metabolism, Scavenger Receptors, Class B, Thrombin metabolism, Tumor Cells, Cultured, Apolipoproteins E metabolism, CD36 Antigens metabolism, Cholesterol Esters pharmacokinetics, Lipoproteins metabolism, Membrane Proteins, Receptors, Immunologic, Receptors, Lipoprotein
- Abstract
The Class B type I scavenger receptor I (SR-BI) is a physiologically relevant high density lipoprotein (HDL) receptor that can mediate selective cholesteryl ester (CE) uptake by cells. Direct interaction of apolipoprotein E (apoE) with this receptor has never been demonstrated, and its implication in CE uptake is still controversial. By using a human adrenal cell line (NCI-H295R), we have addressed the role of apoE in binding to SR-BI and in selective CE uptake from lipoproteins to cells. This cell line does not secrete apoE and SR-BI is its major HDL-binding protein. We can now provide evidence that 1) free apoE is a ligand for SR-BI, 2) apoE associated to lipids or in lipoproteins does not modulate binding or CE-selective uptake by the SR-BI pathway, and 3) the direct interaction of free apoE to SR-BI leads to an increase in CE uptake from lipoproteins of both low and high densities. We propose that this direct interaction could modify SR-BI structure in cell membranes and potentiate CE uptake.
- Published
- 2002
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36. Reconstitution of hepatitis C virus envelope glycoproteins into liposomes as a surrogate model to study virus attachment.
- Author
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Lambot M, Frétier S, Op De Beeck A, Quatannens B, Lestavel S, Clavey V, and Dubuisson J
- Subjects
- Dimerization, Electrophoresis, Polyacrylamide Gel, Viral Envelope Proteins isolation & purification, Viral Structural Proteins isolation & purification, Hepacivirus physiology, Liposomes, Membrane Fusion, Viral Envelope Proteins metabolism, Viral Structural Proteins metabolism
- Abstract
The envelope glycoproteins, E1 and E2, of hepatitis C virus (HCV) assemble intracellularly to form a noncovalent heterodimer that is expected to be essential for viral assembly and entry. However, due to the lack of a cell culture system supporting efficient HCV replication, it is very difficult to obtain relevant information on the functions of this glycoprotein oligomer. To get better insights into its biological and biochemical properties, HCV envelope glycoprotein heterodimer expressed by a vaccinia virus recombinant was purified by immunoaffinity. Purified E1E2 heterodimer was recognized by conformation-dependent monoclonal antibodies, showing that the proteins were properly folded. In addition, it interacted with human CD81, a putative HCV receptor, as well as with human low and very low density lipoproteins, which have been shown to be associated with infectious HCV particles isolated from patients. Purified E1E2 heterodimer was also reconstituted into liposomes. E1E2-liposomes were recognized by a conformation-dependent monoclonal antibody as well as by human CD81. Together, these data indicate that E1E2-liposomes are a valuable tool to study the molecular requirements for HCV binding to target cells.
- Published
- 2002
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37. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.
- Author
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Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB, Fruchart JC, Clavey V, and Staels B
- Subjects
- ATP Binding Cassette Transporter 1, Base Sequence, Biological Transport, Cells, Cultured, DNA Primers, Humans, ATP-Binding Cassette Transporters metabolism, Cholesterol metabolism, Foam Cells metabolism, Receptors, Cytoplasmic and Nuclear agonists, Transcription Factors agonists
- Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.
- Published
- 2001
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38. Apolipoprotein AII enrichment of HDL enhances their affinity for class B type I scavenger receptor but inhibits specific cholesteryl ester uptake.
- Author
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Pilon A, Briand O, Lestavel S, Copin C, Majd Z, Fruchart JC, Castro G, and Clavey V
- Subjects
- Adrenal Cortex Neoplasms metabolism, Animals, Apolipoprotein A-I pharmacology, Apolipoprotein A-II pharmacology, Binding, Competitive, CD36 Antigens, Humans, Lipoproteins chemistry, Lipoproteins metabolism, Lipoproteins, HDL chemistry, Mice, Phosphatidylcholines metabolism, Receptors, Scavenger, Scavenger Receptors, Class B, Tritium, Tumor Cells, Cultured, Apolipoprotein A-II metabolism, Cholesterol Esters metabolism, Lipoproteins, HDL metabolism, Membrane Proteins, Receptors, Immunologic metabolism, Receptors, Lipoprotein
- Abstract
Apolipoproteins of high density lipoprotein (HDL) and especially apolipoprotein (apo)AI and apoAII have been demonstrated as binding directly to the class B type I scavenger receptor (SR-BI), the HDL receptor that mediates selective cholesteryl ester uptake. However, the functional relevance of the binding capacity of each apolipoprotein is still unknown. The human adrenal cell line, NCI-H295R, spontaneously expresses a high level of SR-BI, the major apoAI binding protein in these cells. As previously described for murine SR-BI, free apoAI, palmitoyl-oleoyl-phosphatidylcholine (POPC)-AI, and HDL are good ligands for human SR-BI. In vitro displacement of apoAI by apoAII in HDLs or in Lp AI purified from HDL by immunoaffinity enhances their ability to compete with POPC-AI to bind to SR-BI and also enhances their direct binding capacity. The next step was to determine whether the higher affinity of apoAII for SR-BI correlated with the specific uptake of cholesteryl esters from these HDLs. Free apoAII and, to a lesser extent, free apoAI that were added to the cell medium during uptake experiments inhibited the specific uptake of [(3)H]cholesteryl esters from HDL, indicating that binding sites on cells were the same as cholesteryl ester uptake sites. In direct experiments, the uptake of [(3)H]cholesteryl esters from apoAII-enriched HDL was highly reduced compared with the uptake from native HDL. These results demonstrate that in the human adrenal cell line expressing SR-BI as the major HDL binding protein, efficient apoAII binding has an inhibitory effect on the delivery of cholesteryl esters to cells.
- Published
- 2000
- Full Text
- View/download PDF
39. Role of serum amyloid A during metabolism of acute-phase HDL by macrophages.
- Author
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Artl A, Marsche G, Lestavel S, Sattler W, and Malle E
- Subjects
- Animals, Cell Membrane immunology, Cell Membrane metabolism, Cells, Cultured, Cholesterol pharmacokinetics, Epitopes immunology, Ligands, Macrophages cytology, Mice, Phosphoproteins blood, Protein Binding immunology, Rabbits, Triglycerides blood, Tritium, Acute-Phase Reaction immunology, Apolipoproteins metabolism, Cholesterol, HDL metabolism, Macrophages immunology, Macrophages metabolism, Serum Amyloid A Protein metabolism
- Abstract
The serum amyloid A (SAA) family of proteins is encoded by multiple genes that display allelic variation and a high degree of homology in mammals. Triggered by inflammation after stimulation of hepatocytes by lymphokine-mediated processes, the concentrations of SAA may increase during the acute-phase reaction to levels 1000-fold greater than those found in the noninflammatory state. In addition to its role as an acute-phase reactant, SAA (104 amino acids, 12 kDa) is considered to be the precursor protein of secondary reactive amyloidosis, in which the N-terminal portion is incorporated into the bulk of amyloid fibrils. However, the association with lipoproteins of the high-density range and subsequent modulation of the metabolic properties of its physiological carrier appear to be the principal role of SAA. Because SAA may displace apolipoprotein A-I, the major protein component of native high density lipoprotein (HDL), during the acute-phase reaction, the present study was aimed at (1) investigating binding properties of native and acute-phase (SAA-enriched) HDL by J774 macrophages, (2) elucidating whether the presence of SAA on HDL particles affects selective uptake of HDL-associated cholesteryl esters, and (3) comparing cellular cholesterol efflux mediated by native and acute-phase HDL. Both the total and the specific binding at 4 degrees C of rabbit acute-phase HDL were approximately 2-fold higher than for native HDL. Nonlinear regression analysis revealed K(d) values of 7.0 x 10(-7) mol/L (native HDL) and 3.1 x 10(-7) mol/L (acute-phase HDL), respectively. The corresponding B(max) values were 203 ng of total lipoprotein per milligram of cell protein (native HDL) and 250 ng of total lipoprotein per milligram of cell protein (acute-phase HDL). At 37 degrees C, holoparticle turnover was slightly enhanced for acute-phase HDL, a fact reflected by 2-fold higher degradation rates. In contrast, the presence of SAA on HDL specifically increased (1. 7-fold) the selective uptake of HDL cholesteryl esters from acute-phase HDL by J774 macrophages, a widely used in vitro model to study foam cell formation and cholesterol efflux properties. Although ligand blotting experiments with solubilized J774 membrane proteins failed to identify the scavenger receptor-BI as a binding protein for both native and acute-phase HDL, 2 binding proteins with molecular masses of 100 and 72 kDa, the latter comigrating with CD55 (also termed decay-accelerating factor), were identified. During cholesterol efflux studies, it became apparent that the ability of acute-phase HDL with regard to cellular cholesterol removal was considerably lower than that for native HDL. This was reflected by a 1.7-fold increase in tau/2 values (22 versus 36 hours; native versus acute-phase HDL). Our observations of increased HDL cholesteryl ester uptake and reduced cellular cholesterol efflux (acute-phase versus native HDL) suggest that displacement of apolipoprotein A-I by SAA results in considerable altered metabolic properties of its main physiological carrier. These changes in the apolipoprotein moieties appear (at least in the in vitro system tested) to transform an originally antiatherogenic into a proatherogenic lipoprotein particle.
- Published
- 2000
- Full Text
- View/download PDF
40. Mutation screening of the LDLR gene and ApoB gene in patients with a phenotype of familial hypercholesterolemia and normal values in a functional LDL receptor/apolipoprotein B assay.
- Author
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Nissen H, Lestavel S, Hansen TS, Luc G, Bruckert E, and Clavey V
- Subjects
- Apolipoprotein B-100, Apolipoproteins B blood, DNA Mutational Analysis, HeLa Cells, Humans, Hyperlipoproteinemia Type II blood, Receptors, LDL blood, Apolipoproteins B genetics, Genetic Testing, Hyperlipoproteinemia Type II genetics, Mutation, Receptors, LDL genetics
- Abstract
Mutations in the LDL receptor (LDLR) or the apolipoprotein B-100 genes causing familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB), two of the most frequent inherited diseases, are the underlying genetic defects in a small proportion of patients suffering from premature atherosclerotic heart disease. Consequently, secure diagnostic tools for these conditions allowing early preventive measures are needed. Since clinical and biochemical diagnosis often is inaccurate, assays analyzing patient LDLR function and LDL affinity have been established. These assays are, however, not able clearly to differentiate between suspected FH/FDB samples and normal controls. To evaluate if this may be caused by other hitherto undescribed genetic defects or to failure of the functional assays, we undertook denaturing gradient gel electrophoresis based mutation screening of the LDLR gene and the codon 3456 3553 region of the apolipoprotein B gene in six French FH/FDB patients with normal outcomes on functional assays. In all six patients, pathogenic LDLR mutations were found, including three previously undescribed mutations, suggesting that failure of the functional assays explains the normal results found in some phenotypic FH/FDB patients and illustrating the need for DNA based screening techniques for routine genetic diagnosis in FH/FDB.
- Published
- 1998
- Full Text
- View/download PDF
41. High-density-lipoprotein subfraction 3 interaction with glycosylphosphatidylinositol-anchored proteins.
- Author
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Nion S, Briand O, Lestavel S, Torpier G, Nazih F, Delbart C, Fruchart JC, and Clavey V
- Subjects
- Biological Transport, Cells, Cultured, Fibroblasts metabolism, Humans, Phosphatidylinositol Diacylglycerol-Lyase, Phosphoinositide Phospholipase C, Protein Binding drug effects, Skin cytology, Skin metabolism, Type C Phospholipases pharmacology, Cell Membrane metabolism, Cholesterol metabolism, Endocytosis, Glycosylphosphatidylinositols metabolism, Lipoproteins, HDL metabolism
- Abstract
To elucidate further the binding of high-density-lipoprotein subfraction 3 (HDL3) to cells, the involvement of glycosylphosphatidylinositol-anchored proteins (GPI-proteins) was studied. Treatment of cultured cells, such as fibroblasts or SK-MES-1 cells, with a phosphatidylinositol-specific phospholipase C (PI-PLC) significantly decreases specific HDL3 binding. Moreover, PI-PLC treatment of cultured cells or cellular plasma membrane fractions results in releasing proteins. These proteins have a soluble form and can also bind HDL3, as revealed by ligand blotting experiments with HDL3. In order to obtain enriched GPI-proteins, we used a detergent-free purification method to prepare a caveolar membrane fraction. In the caveolar fraction, we obtained, by ligand blotting experiments, the enrichment of two HDL3-binding proteins with molecular masses of 120 and 80 kDa. These proteins were also revealed in a plasma membrane preparation with two other proteins, with molecular masses of 150 and 104 kDa, and were sensitive to PI-PLC treatment. Electron microscopy also showed the binding of Au-labelled HDL3 inside the caveolar membrane invaginations. In SK-MES-1 cells, HDL3 are internalized into a particular structure, resulting in the accumulation and concentration of such specific membrane domains. To sum up, a demonstration has been made of the implication of GPI-proteins as well as caveolae in the binding of HDL3 to cells.
- Published
- 1997
- Full Text
- View/download PDF
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