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

• Published in: Journal of hepatology Vol. 56; no. 2; pp. 441 - 447
• Main Authors: Nishiyama, Yasumasa, Goda, Nobuhito, Kanai, Mai, Niwa, Daisuke, Osanai, Kota, Yamamoto, Yu, Senoo-Matsuda, Nanami, Johnson, Randall S, Miura, Soichiro, Kabe, Yasuaki, Suematsu, Makoto
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.02.2012; Elsevier
• Subjects: Acetyl-CoA Carboxylase - metabolism; Addictive behaviors; Adult and adolescent clinical studies; Alcoholic fatty liver; Alcoholism; Alcoholism and acute alcohol poisoning; Amino Acids, Dicarboxylic - pharmacology; Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; DEC1; Disease Susceptibility; Ethanol - administration & dosage; Fatty Liver, Alcoholic - genetics; Fatty Liver, Alcoholic - metabolism; Fatty Liver, Alcoholic - prevention & control; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression - drug effects; HIF-1; 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; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Knockout; Other diseases. Semiology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; SREBP-1c; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Toxicology; DMOG; CPT; hypoxia inducible factor; MTP; carnithine palmitoyltransferase; total cholesterol; alcoholic liver diseases; IκB kinase; DEC1; NF-κB; hepatocyte-specific HIF-1α-null; PPAR; helix-loop-helix; NEFA; RT-PCR; VLDL; Tchol; von Hippel–Lindau; MCAD; nuclear factor kappa-light-chain-enhancer of activated B cells; SREBP; non-esterified fatty acid; stearoyl CoA desaturase; TCA; dimethyloxalylglycine; fatty acid synthase; very low density lipoprotein; sterol regulatory element-binding protein; triglyceride; medium chain acyl CoA dehydrogenase; HLH; microsomal triglyceride transfer protein; stimulated with retinoic acid; acetyl-CoA carboxylase; nicotinamide adenine dinucleotide; HIF-1; NADH; diacylglycerol acyltransferase; Alcoholic fatty liver; Stra; peroxisome proliferator-activated receptor; VHL; WT; ACC; DEC; tricarboxylic acid; HIF; VEGF; H-HIFKO; differentiated embryo chondrocyte; IKK; DGAT; AOX; SREBP-1c; acyl CoA oxidase; TG; SCD; vascular endothelial growth factor; reverse transcription polymerase chain reaction; ALD; FAS; LCAD; long chain acyl CoA dehydrogenase; wild-type; Alcoholism; Rodentia; Hepatic disease; Lipids; Accumulation; Vertebrata; Mammalia; Fatty liver; Mouse; Animal; Gastroenterology; Digestive diseases
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2011.07.024

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.