HIF-1α induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice.

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.

• Authors: Yasumasa Nishiyama, Nobuhito Goda, Mai Kanai, Daisuke Niwa, Kota Osanai, Yu Yamamoto, Nanami Senoo-Matsuda, Randall S Johnson, Soichiro Miura, Yasuaki Kabe, Makoto Suematsu
• Journal: Journal of hepatology (J Hepatol) Vol. 56 Issue 2 Pg. 441-7 (Feb 2012) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 21896344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Amino Acids, Dicarboxylic
• Basic Helix-Loop-Helix Transcription Factors
• Bhlhe40 protein, mouse
• Hif1a protein, mouse
• Homeodomain Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Ethanol
• Acetyl-CoA Carboxylase
• oxalylglycine

Topics

• 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, metabolism, prevention & control)
• Gene Expression (drug effects)
• Homeodomain Proteins (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, deficiency, genetics)
• Lipid Metabolism
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Knockout
• Sterol Regulatory Element Binding Protein 1 (genetics, metabolism)