PPARγ is essential for protection against nonalcoholic steatohepatitis

Top of pageAbstract Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that regulates lipid metabolism and inflammatory responses. Certain PPARγ ligands improve nonalcoholic steatohepatitis (NASH). The role of PPARγ itself in NASH remains poorly understood. The functional consequences of PPARγ in the development of steatohepatitis through gene deficiency or gene overexpression of PPARγ delivered by adenovirus (Ad-PPARγ) were examined. Our results show that PPARγ-deficient (PPARγ+/−) mice fed the methionine- and choline-deficient (MCD) diet developed more severe steatohepatitis than wild-type mice, and were unaffected by PPARγ ligand rosiglitazone. Overexpression of PPARγ delivered by Ad-PPARγ 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 PPARγ was also mediated via regulating adipokines through suppressing tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and inducing adiponectin. Moreover, PPARγ activation suppressed hepatic lipoperoxide and reduced hepatic pro-inflammatory cytokines (TNF-α and IL-6) production. In conclusion, PPARγ is an important endogenous regulator and potential therapeutic target for nutritional steatohepatitis. Keywords: PPARγ; nonalcoholic steatohepatitis; gene modulation; cytokines; animal experiment Abbreviations: ALT, alanine aminotransferase; aP2, fatty acid binding protein-4; FATP, fatty acid transport protein; CD36, fatty acid translocase; LPL, lipoprotein lipase; MCD, methionine and choline deficient; NASH, nonalcoholic steatohepatitis; PPARγ, peroxisome proliferator-activated receptor-γ; SCD-1, stearoyl-CoA desaturase isoform-1; SREBP-1, sterol regulatory element binding protein isoform-1; TG, triglyceride; WAT, white adipose tissue; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6