title: Hepatic Peroxisome Proliferator-Activated Receptor Gamma Signaling Contributes to Alcohol-Induced Hepatic Steatosis and Inflammation in Mice.
abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) signaling has been shown to regulate lipogenesis and lipid accumulation. Previous studies have shown that hepatic PPARγ is up-regulated in steatotic liver of both animal and human. However, the effects of hepatic PPARγ signaling on alcoholic liver disease (ALD) remain elusive.
  
  
  
  To determine the role of hepatic PPARγ signaling on ALD, wild-type (WT) and hepatocyte-specific PPARγ knockdown (PPARγ∆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.
  
  
  
  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 PPARγ 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 PPARγ significantly alleviated alcohol-induced lipid accumulation and abolished the up-regulation of FASN, DGAT1, and DGAT2. Silencing of PPARγ in FL83B cells significantly decreased ethanol (EtOH)-, linoleic acid-, and EtOH plus linoleic acid-induced lipid accumulation. Knockdown of hepatic PPARγ 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).
  
  
  
  The results suggest that hepatic PPARγ signaling contributes to alcohol-induced liver injury by promoting hepatic steatosis and inflammation.
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina.|Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina.
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Sun
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina.|Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina.
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000096:biosynthesis; D000431:Ethanol / Q000633:toxicity*; D064429:Fatty Acid Synthases / Q000096:biosynthesis; D050612:Fatty Acid Transport Proteins / Q000096:biosynthesis; D005235:Fatty Liver, Alcoholic / Q000201:enzymology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008108:Liver Diseases, Alcoholic / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D018925:Chemokines; D050612:Fatty Acid Transport Proteins; D009687:Nuclear Proteins; D047495:PPAR gamma; C493569:Slc27a1 protein, mouse; D000431:Ethanol; C516957:DGAT2 protein, mouse; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D064429:Fatty Acid Synthases; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; D000103:Acetyl-CoA Carboxylase
keywords: Alcoholic Liver Disease; Hepatic Inflammation; Hepatic Lipogenesis; Peroxisome Proliferator-Activated Receptor Gamma