RRC ID 28593
Author Nishiyama Y, Goda N, Kanai M, Niwa D, Osanai K, Yamamoto Y, Senoo-Matsuda N, Johnson RS, Miura S, Kabe Y, Suematsu M.
Title HIF-1α induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice.
Journal J Hepatol
Abstract BACKGROUND & AIMS:Chronic alcohol intake stimulates hepatic oxygen consumption and subsequently causes liver hypoxia, leading to activation of hypoxia inducible factor-1 (HIF-1). Although HIF-1 plays a crucial role in the metabolic switch from aerobic to anaerobic metabolism in response to hypoxia, its roles in the regulation of lipid metabolism in alcoholic fatty liver remain unknown.
METHODS:Wild-type and hepatocyte-specific HIF-1α-null mice were subjected to a 6% ethanol-containing liquid diet for 4 weeks, and functional effects of loss of the HIF-1α gene on lipid metabolism were examined in the liver.
RESULTS:Hepatocyte-specific HIF-1α-null mice developed severe hypertriglyceridemia with enhanced accumulation of lipids in the liver of mice exposed to a 6% ethanol-containing liquid diet for 4 weeks. Sterol regulatory element-binding protein 1c (SREBP-1c) and its downstream target acetyl-CoA carboxylase were greatly activated as the hepatic steatosis progressed, and these alterations were inversely correlated with the expression of the HIF-1-regulated gene DEC1. Overexpression of DEC1 in the mutant liver abrogated the detrimental effects of loss of HIF-1α gene on ethanol-induced fatty liver with reduced SREBP-1c expression. Conversely, co-administration of the HIF hydroxylase inhibitor dimethyloxalylglycine for the last 2 weeks improved markedly the ethanol-induced fatty liver in mice.
CONCLUSIONS:The current results provide direct evidence for protective roles of HIF-1 induction in the development of ethanol-induced fatty liver via activation of the HIF-1-regulated transcriptional repressor DEC1.
Volume 56(2)
Pages 441-7
Published 2012-2-1
DOI 10.1016/j.jhep.2011.07.024
PII S0168-8278(11)00659-3
PMID 21896344
MeSH Acetyl-CoA Carboxylase / metabolism Amino Acids, Dicarboxylic / pharmacology Animals Basic Helix-Loop-Helix Transcription Factors / metabolism Disease Susceptibility Ethanol / administration & dosage Fatty Liver, Alcoholic / genetics Fatty Liver, Alcoholic / metabolism* Fatty Liver, Alcoholic / prevention & control* Gene Expression / drug effects Homeodomain Proteins / metabolism Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis* Hypoxia-Inducible Factor 1, alpha Subunit / deficiency Hypoxia-Inducible Factor 1, alpha Subunit / genetics Lipid Metabolism* Liver / drug effects Liver / metabolism Male Mice Mice, Knockout Sterol Regulatory Element Binding Protein 1 / genetics Sterol Regulatory Element Binding Protein 1 / metabolism
IF 20.582
Times Cited 57
DNA material mDEC1-FLAG in pCAGGS (RDB08473)