1. Hepatic Peroxisome Proliferator-Activated Receptor Gamma Signaling Contributes to Alcohol-Induced Hepatic Steatosis and Inflammation in Mice.
- Author
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Zhang, Wenliang, Sun, Qian, Zhong, Wei, Sun, Xinguo, and Zhou, Zhanxiang
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ALCOHOLIC liver diseases , *ANALYSIS of variance , *ANIMAL experimentation , *BIOLOGICAL assay , *CARRIER proteins , *CELL culture , *CELLULAR signal transduction , *CHEMOKINES , *ETHANOL , *GENE expression , *GENETIC techniques , *GLUCANS , *IMMUNOHISTOCHEMISTRY , *INFLAMMATION , *LIPIDS , *MICE , *POLYMERASE chain reaction , *PROBABILITY theory , *RESEARCH funding , *STATISTICS , *T-test (Statistics) , *TRANSFERASES , *WESTERN immunoblotting , *DATA analysis , *DATA analysis software , *PEROXISOME proliferator-activated receptors , *DESCRIPTIVE statistics - Abstract
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∆ Hep) mice were fed a modified Lieber- De Carli 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 ( FATP1), acetyl- Co A 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 γ significantly alleviated alcohol-induced lipid accumulation and abolished the up-regulation of FASN, DGAT1, and DGAT2. Silencing of PPAR γ in FL83 B cells significantly decreased ethanol ( Et OH)-, linoleic acid-, and Et OH plus linoleic acid-induced lipid accumulation. Knockdown of hepatic PPAR γ 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 [ Ly6 G], and F4/80). Conclusions The results suggest that hepatic PPAR γ signaling contributes to alcohol-induced liver injury by promoting hepatic steatosis and inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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