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

The peroxisome proliferator-activated receptor system is exciting much interest as a novel point of therapeutic intervention in inflammation. Here, the effect of a peroxisome proliferator-activated receptor alpha agonist, [4-chloro-6-(2,3-xylidine)-pyrimidinylthio]acetic acid (Wy14,643), was examined in arachidonic acid-induced murine ear inflammation. 3-[1-(4-Chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK886, a 5-lipoxygenase inhibitor) and indomethacin (a cyclo-oxygenase inhibitor) were used as reference compounds. Wy14,643 dose dependently inhibited ear swelling and polymorphonuclear leukocyte influx, as did MK886, associated with reduced tissue leukotriene B4 but not prostaglandin E2 levels. Unlike MK886, Wy14,643 did not inhibit ex vivo leukotriene B4 production. However, Wy14,643, but not MK886, induced peroxisomal enzyme activity. Indomethacin was less effective, though tissue prostaglandin E2 but not leukotriene B4 levels were reduced. Again, unlike indomethacin, Wy14,643 did not reduce ex vivo prostaglandin E2 production. However, indomethacin did increase peroxisomal enzyme activity but to a lesser extent than Wy14,643. This study demonstrates that peroxisome proliferator-activated receptor alpha activation can inhibit arachidonic acid-induced inflammation in part by enhancing degradation of leukotriene B4.