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PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells.
Toxicol Appl Pharmacol. 2014 Apr 01; 276(1):73-81.TA

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.

CONCLUSION

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+Show Affiliations

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.Inserm UMR 991, 35043 Rennes Cedex, France; Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex, France.Inserm UMR 991, 35043 Rennes Cedex, France; Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex, France.Technologie Servier, Orléans, France.Institut de Recherches Servier, Courbevoie, France.Biologie Servier, Gidy, France.Biologie Servier, Gidy, France.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.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24534255

Citation

Rogue, Alexandra, et al. "PPAR Agonists Reduce Steatosis in Oleic Acid-overloaded HepaRG Cells." Toxicology and Applied Pharmacology, vol. 276, no. 1, 2014, pp. 73-81.
Rogue A, Anthérieu S, Vluggens A, et al. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells. Toxicol Appl Pharmacol. 2014;276(1):73-81.
Rogue, A., Anthérieu, S., Vluggens, A., Umbdenstock, T., Claude, N., de la Moureyre-Spire, C., Weaver, R. J., & Guillouzo, A. (2014). PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells. Toxicology and Applied Pharmacology, 276(1), 73-81. https://doi.org/10.1016/j.taap.2014.02.001
Rogue A, et al. PPAR Agonists Reduce Steatosis in Oleic Acid-overloaded HepaRG Cells. Toxicol Appl Pharmacol. 2014 Apr 1;276(1):73-81. PubMed PMID: 24534255.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells. AU - Rogue,Alexandra, AU - Anthérieu,Sébastien, AU - Vluggens,Aurore, AU - Umbdenstock,Thierry, AU - Claude,Nancy, AU - de la Moureyre-Spire,Catherine, AU - Weaver,Richard J, AU - Guillouzo,André, Y1 - 2014/02/15/ PY - 2013/07/26/received PY - 2013/12/04/revised PY - 2014/02/06/accepted PY - 2014/2/19/entrez PY - 2014/2/19/pubmed PY - 2014/5/17/medline KW - Fatty acid overload KW - Fatty acid oxidation KW - Hepatocytes KW - Hepatotoxicity KW - Non-alcoholic steatohepatitis SP - 73 EP - 81 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 276 IS - 1 N2 - UNLABELLED: 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. CONCLUSION: 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. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/24534255/PPAR_agonists_reduce_steatosis_in_oleic_acid_overloaded_HepaRG_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(14)00038-6 DB - PRIME DP - Unbound Medicine ER -