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

Background Peroxisome proliferator‐activated receptor gamma ( PPAR γ ) signaling has been shown to regulate lipogenesis and lipid accumulation. Previous studies have shown that hepatic PPAR γ is up‐regulated in steatotic liver of both animal and human. However, the effects of hepatic PPAR γ signaling on alcoholic liver disease ( ALD ) remain elusive. Methods To determine the role of hepatic PPAR γ signaling on ALD , wild‐type ( WT ) and hepatocyte‐specific PPAR γ knockdown ( PPAR γ ∆ H ep) mice were fed a modified L ieber‐ D e C arli 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 γ 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 ( FATP 1), acetyl‐ C o A carboxylase ( ACC ), fatty acid synthase ( FASN ), lipin1 (LIPIN1), diacylglycerol acyltransferase 1 ( DGAT 1), and diacylglycerol acyltransferase 2 ( DGAT 2) in the livers of WT mice. Knockdown of hepatic PPAR γ significantly alleviated alcohol‐induced lipid accumulation and abolished the up‐regulation of FASN , DGAT 1, and DGAT 2. Silencing of PPAR γ in FL 83 B cells significantly decreased ethanol ( E t OH )–, linoleic acid–, and E t OH plus linoleic acid–induced lipid accumulation. Knockdown of hepatic PPAR γ also significantly reduced alcohol‐induced inflammatory chemokine (monocyte chemotactic protein 1 [ MCP 1], keratinocyte‐derived chemokine [ KC ], interferon gamma‐induced protein 10 [ IP ‐10]) and inflammatory infiltration (lymphocyte antigen 6 complex, locus G [ L y6 G ], and F 4/80). Conclusions The results suggest that hepatic PPAR γ signaling contributes to alcohol‐induced liver injury by promoting hepatic steatosis and inflammation.