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The transrepressive activity of peroxisome proliferator‐activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice
Author(s) -
Pawlak Michal,
Baugé Eric,
Bourguet William,
Bosscher Karolien,
Lalloyer Fanny,
Tailleux Anne,
Lebherz Corinna,
Lefebvre Philippe,
Staels Bart
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27297
Subject(s) - lipotoxicity , fibrosis , steatohepatitis , peroxisome proliferator activated receptor , nonalcoholic fatty liver disease , transrepression , medicine , steatosis , peroxisome proliferator activated receptor alpha , endocrinology , cirrhosis , inflammation , fatty liver , pioglitazone , hepatology , obeticholic acid , insulin resistance , biology , nuclear receptor , receptor , agonist , type 2 diabetes , diabetes mellitus , transcription factor , disease , insulin , biochemistry , transactivation , gene
Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple‐hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator‐activated receptor (PPAR)‐α agonism can efficiently oppose these symptoms. To dissect the relative contribution of antisteatotic versus anti‐inflammatory PPAR‐α activities in counteracting dietary‐induced liver fibrosis, we used a PPAR‐α mutant lacking its DNA‐binding‐dependent activity on fatty acid metabolism. Liver‐specific expression of wild‐type or a DNA‐binding‐deficient PPAR‐α in acute and chronic models of inflammation were used to study PPAR‐α's anti‐inflammatory versus metabolic activities in NASH and fibrosis. Pharmacologically activated PPAR‐α inhibited hepatic inflammatory responses and the transition from steatosis toward NASH and fibrosis through a direct, anti‐inflammatory mechanism independent of its lipid handling properties. Conclusion : The transrepression activity of PPAR‐α on chronic liver inflammation is sufficient to prevent progression of NASH to liver fibrosis. Dissociated PPAR‐α agonists, selectively modulating PPAR‐α transrepression activity, could thus be an option to prevent NASH and fibrosis progression. (H epatology 2014;60:1593–1606)