title: HIF-1α induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice.
abstract: OBJECTIVE
  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.
authors: Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan.
authors: Yasumasa
authors: Y
authors: Nishiyama
authors: Nobuhito
authors: N
authors: Goda
authors: Mai
authors: M
authors: Kanai
authors: Daisuke
authors: D
authors: Niwa
authors: Kota
authors: K
authors: Osanai
authors: Yu
authors: Y
authors: Yamamoto
authors: Nanami
authors: N
authors: Senoo-Matsuda
authors: Randall S
authors: RS
authors: Johnson
authors: Soichiro
authors: S
authors: Miura
authors: Yasuaki
authors: Y
authors: Kabe
authors: Makoto
authors: M
authors: Suematsu
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D004198:Disease Susceptibility; D000431:Ethanol / Q000008:administration & dosage; D005235:Fatty Liver, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000103:Acetyl-CoA Carboxylase; D000600:Amino Acids, Dicarboxylic; D051792:Basic Helix-Loop-Helix Proteins; D000431:Ethanol; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051780:Sterol Regulatory Element Binding Protein 1; C491539:Bhlhe40 protein, mouse; C497443:Hif1a protein, mouse; C497388:Srebf1 protein, mouse; C040947:oxalylglycine