PMID- 27062444 OWN - NLM STAT- MEDLINE DCOM- 20171219 LR - 20200326 IS - 1530-0277 (Electronic) IS - 0145-6008 (Print) IS - 0145-6008 (Linking) VI - 40 IP - 5 DP - 2016 May TI - Hepatic Peroxisome Proliferator-Activated Receptor Gamma Signaling Contributes to Alcohol-Induced Hepatic Steatosis and Inflammation in Mice. PG - 988-99 LID - 10.1111/acer.13049 [doi] AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) signaling has been shown to regulate lipogenesis and lipid accumulation. Previous studies have shown that hepatic PPARgamma is up-regulated in steatotic liver of both animal and human. However, the effects of hepatic PPARgamma signaling on alcoholic liver disease (ALD) remain elusive. METHODS: To determine the role of hepatic PPARgamma signaling on ALD, wild-type (WT) and hepatocyte-specific PPARgamma knockdown (PPARgamma∆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 PPARgamma 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 PPARgamma significantly alleviated alcohol-induced lipid accumulation and abolished the up-regulation of FASN, DGAT1, and DGAT2. Silencing of PPARgamma in FL83B cells significantly decreased ethanol (EtOH)-, linoleic acid-, and EtOH plus linoleic acid-induced lipid accumulation. Knockdown of hepatic PPARgamma 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 PPARgamma signaling contributes to alcohol-induced liver injury by promoting hepatic steatosis and inflammation. CI - Copyright (c) 2016 by the Research Society on Alcoholism. FAU - Zhang, Wenliang AU - Zhang W AD - Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina. FAU - Sun, Qian AU - Sun Q AD - Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina. AD - Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina. FAU - Zhong, Wei AU - Zhong W AD - Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina. FAU - Sun, Xinguo AU - Sun X AD - Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina. FAU - Zhou, Zhanxiang AU - Zhou Z AD - Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina. AD - Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina. LA - eng SI - GENBANK/NM_001163379 SI - GENBANK/NM_001199296 SI - GENBANK/NM_001291058 SI - GENBANK/NM_007381 SI - GENBANK/NM_007643 SI - GENBANK/NM_007981 SI - GENBANK/NM_007988 SI - GENBANK/NM_008149 SI - GENBANK/NM_008176 SI - GENBANK/NM_008509.2 SI - GENBANK/NM_008642 SI - GENBANK/NM_009512 SI - GENBANK/NM_009693 SI - GENBANK/NM_010011 SI - GENBANK/NM_010046 SI - GENBANK/NM_010130 SI - GENBANK/NM_011333 SI - GENBANK/NM_011977.3 SI - GENBANK/NM_011978 SI - GENBANK/NM_013495 SI - GENBANK/NM_013703.2 SI - GENBANK/NM_015729 SI - GENBANK/NM_017399 SI - GENBANK/NM_021274 SI - GENBANK/NM_026384 SI - GENBANK/NM_133360 SI - GENBANK/NM_172950 SI - GENBANK/NR_003278 SI - GENBANK/XM_001475753 GR - P30 DK056350/DK/NIDDK NIH HHS/United States GR - R01 AA018844/AA/NIAAA NIH HHS/United States GR - R01 AA020212/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20160408 PL - England TA - Alcohol Clin Exp Res JT - Alcoholism, clinical and experimental research JID - 7707242 RN - 0 (Chemokines) RN - 0 (Fatty Acid Transport Proteins) RN - 0 (Nuclear Proteins) RN - 0 (PPAR gamma) RN - 0 (Slc27a1 protein, mouse) RN - 3K9958V90M (Ethanol) RN - EC 2.3.1.20 (DGAT2 protein, mouse) RN - EC 2.3.1.20 (Dgat1 protein, mouse) RN - EC 2.3.1.20 (Diacylglycerol O-Acyltransferase) RN - EC 2.3.1.85 (Fatty Acid Synthases) RN - EC 3.1.3.4 (Lpin1 protein, mouse) RN - EC 3.1.3.4 (Phosphatidate Phosphatase) RN - EC 6.4.1.2 (Acetyl-CoA Carboxylase) SB - IM MH - Acetyl-CoA Carboxylase/biosynthesis MH - Animals MH - Cells, Cultured MH - Chemokines/metabolism MH - Diacylglycerol O-Acyltransferase/biosynthesis MH - Ethanol/*toxicity MH - Fatty Acid Synthases/biosynthesis MH - Fatty Acid Transport Proteins/biosynthesis MH - Fatty Liver, Alcoholic/enzymology/*metabolism MH - Gene Knockdown Techniques MH - Inflammation/enzymology/*metabolism MH - Liver/*metabolism MH - Liver Diseases, Alcoholic/enzymology/*metabolism MH - Male MH - Mice MH - Nuclear Proteins/biosynthesis MH - PPAR gamma/deficiency/genetics/*metabolism MH - Phosphatidate Phosphatase/biosynthesis MH - Signal Transduction/*drug effects MH - Up-Regulation PMC - PMC5742869 MID - NIHMS762222 OTO - NOTNLM OT - Alcoholic Liver Disease OT - Hepatic Inflammation OT - Hepatic Lipogenesis OT - Peroxisome Proliferator-Activated Receptor Gamma COIS- Conflict of Interest: None. EDAT- 2016/04/12 06:00 MHDA- 2017/12/20 06:00 PMCR- 2017/12/26 CRDT- 2016/04/11 06:00 PHST- 2016/02/10 00:00 [received] PHST- 2016/02/18 00:00 [accepted] PHST- 2016/04/11 06:00 [entrez] PHST- 2016/04/12 06:00 [pubmed] PHST- 2017/12/20 06:00 [medline] PHST- 2017/12/26 00:00 [pmc-release] AID - 10.1111/acer.13049 [doi] PST - ppublish SO - Alcohol Clin Exp Res. 2016 May;40(5):988-99. doi: 10.1111/acer.13049. Epub 2016 Apr 8.