Hepatic Peroxisome Proliferator-Activated Receptor Gamma Signaling Contributes to Alcohol-Induced Hepatic Steatosis and Inflammation in Mice

Background: Peroxisome proliferator-activated receptor gamma (PPAR gamma) signaling has been shown to regulate lipogenesis and lipid accumulation. Previous studies have shown that hepatic PPAR gamma is up-regulated in steatotic liver of both animal and human. However, the effects of hepatic PPAR gamma signaling on alcoholic liver disease (ALD) remain elusive. Methods: To determine the role of hepatic PPAR gamma signaling on ALD, wild-type (WT) and hepatocyte-specific PPAR gamma knockdown (PPAR gamma Delta Hep) mice were fed a modified Lieber-DeCarli alcohol or isocaloric maltose dextrin control liquid diet for 8 weeks to induce ALD. Blood parameters, hepatic steatosis, and inflammation were measured after 8-week alcohol feeding. Results: Alcohol feeding to WT mice resulted in liver damage (alanine aminotransferase [ALT], 94.68 +/- 17.05 U/L; aspartate aminotransferase [AST], 55.87 +/- 11.29 U/L), which was significantly alleviated by hepatic PPAR gamma knockdown (ALT, 57.36 +/- 14.98 U/L; AST, 38.06 +/- 3.35 U/L). Alcohol feeding led to marked lipid accumulation and up-regulation of lipogenic genes including fatty acid transport protein 1 (FATP1), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), lipin1 (LIPIN1), diacylglycerol acyltransferase 1 (DGAT1), and diacylglycerol acyltransferase 2 (DGAT2) in the livers of WT mice. Knockdown of hepatic PPAR gamma significantly alleviated alcohol-induced lipid accumulation and abolished the up-regulation of FASN, DGAT1, and DGAT2. Silencing of PPAR gamma in FL83B cells significantly decreased ethanol (EtOH)-, linoleic acid-, and EtOH plus linoleic acid-induced lipid accumulation. Knockdown of hepatic PPAR gamma also significantly reduced alcohol-induced inflammatory chemokine (monocyte chemotactic protein 1 [MCP1], keratinocyte-derived chemokine [KC], interferon gamma-induced protein 10 [IP-10]) and inflammatory infiltration (lymphocyte antigen 6 complex, locus G [Ly6G], and F4/80). Conclusions: The results suggest that hepatic PPAR gamma signaling contributes to alcohol-induced liver injury by promoting hepatic steatosis and inflammation.