PPARgamma is essential for protection against nonalcoholic steatohepatitis

Abstract

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that regulates lipid metabolism and inflammatory responses. Certain PPARgamma ligands improve nonalcoholic steatohepatitis (NASH). The role of PPARgamma itself in NASH remains poorly understood. The functional consequences of PPARgamma in the development of steatohepatitis through gene deficiency or gene overexpression of PPARgamma delivered by adenovirus (Ad-PPARgamma) were examined. Our results show that PPARgamma-deficient (PPARgamma(+/-)) mice fed the methionine- and choline-deficient (MCD) diet developed more severe steatohepatitis than wild-type mice, and were unaffected by PPARgamma ligand rosiglitazone. Overexpression of PPARgamma delivered by Ad-PPARgamma attenuated steatohepatitis. This effect was associated with redistribution of fatty acid from liver to adipose tissue by enhancing expression of fatty acid uptake genes (fatty acid binding protein-4 (aP2), fatty acid translocase (CD36), lipoprotein lipase (LPL) and fatty acid transport protein-1 (FATP-1)) and lipogenic genes (sterol regulatory element binding protein isoform-1 (SREBP-1) and stearoyl-CoA desaturase isoform-1 (SCD-1)) in adipose tissue and to a lesser extent in liver. The anti-steatohepatitis action of PPARgamma was also mediated via regulating adipokines through suppressing tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and inducing adiponectin. Moreover, PPARgamma activation suppressed hepatic lipoperoxide and reduced hepatic pro-inflammatory cytokines (TNF-alpha and IL-6) production. In conclusion, PPARgamma is an important endogenous regulator and potential therapeutic target for nutritional steatohepatitis.