title: PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells.
abstract: Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis.
  
  
  CONCLUSIONS
  Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients.
authors.affiliation: Inserm UMR 991, 35043 Rennes Cedex, France; Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex, France; Biologie Servier, Gidy, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rogue
authors.affiliation: Inserm UMR 991, 35043 Rennes Cedex, France; Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Anthérieu
authors.affiliation: Inserm UMR 991, 35043 Rennes Cedex, France; Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Vluggens
authors.affiliation: Technologie Servier, Orléans, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Umbdenstock
authors.affiliation: Institut de Recherches Servier, Courbevoie, France.
authors.forename: Nancy
authors.initials: N
authors.lastname: Claude
authors.affiliation: Biologie Servier, Gidy, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: de la Moureyre-Spire
authors.affiliation: Biologie Servier, Gidy, France.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weaver
authors.affiliation: Inserm UMR 991, 35043 Rennes Cedex, France; Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex, France. Electronic address: Andre.Guillouzo@univ-rennes1.fr.
authors.forename: André
authors.initials: A
authors.lastname: Guillouzo
mesh_terms: D002460:Cell Line; D000090702:Constitutive Androstane Receptor; D004353:Drug Evaluation, Preclinical; D005230:Fatty Acids, Nonesterified / Q000009:adverse effects; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D050155:Lipogenesis / Q000187:drug effects; D008082:Lipotropic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D065626:Non-alcoholic Fatty Liver Disease; D019301:Oleic Acid / Q000009:adverse effects; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000090702:Constitutive Androstane Receptor; D005230:Fatty Acids, Nonesterified; D005998:Glycine; D008082:Lipotropic Agents; D000071518:Liver X Receptors; D019301:Oleic Acid; D057093:Orphan Nuclear Receptors; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C000605213:NR1H3 protein, human; C500085:muraglitazar
keywords: Fatty acid overload; Fatty acid oxidation; Hepatocytes; Hepatotoxicity; Non-alcoholic steatohepatitis