PPAR gamma is essential for protection against nonalcoholic steatohepatitis

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a transcription factor that regulates lipid metabolism and inflammatory responses. Certain PPAR gamma ligands improve nonalcoholic steatohepatitis (NASH). The role of PPAR gamma itself in NASH remains poorly understood. The functional consequences of PPAR gamma in the development of steatohepatitis through gene deficiency or gene overexpression of PPAR gamma delivered by adenovirus (Ad-PPAR gamma) were examined. Our results show that PPAR gamma-deficient (PPAR gamma(+/)) mice fed the methionine- and choline-deficient (MCD) diet developed more severe steatohepatitis than wild-type mice, and were unaffected by PPAR gamma ligand rosiglitazone. Overexpression of PPAR gamma delivered by Ad-PPAR gamma 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 PPAR gamma was also mediated via regulating adipokines through suppressing tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and inducing adiponectin. Moreover, PPAR gamma activation suppressed hepatic lipoperoxide and reduced hepatic pro-inflammatory cytokines (TNF-alpha and IL-6) production. In conclusion, PPAR gamma is an important endogenous regulator and potential therapeutic target for nutritional steatohepatitis. Gene Therapy (2010) 17, 790-798; doi: 10.1038/gt.2010.41; published online 8 April 2010