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

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 4weeks, 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 4weeks. 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 2weeks 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.

Abbreviations: ACC, acetyl-CoA carboxylase, ALD, alcoholic liver diseases, AOX, acyl CoA oxidase, CPT, carnithine palmitoyltransferase, DEC, differentiated embryo chondrocyte, DGAT, diacylglycerol acyltransferase, DMOG, dimethyloxalylglycine, FAS, fatty acid synthase, H-HIFKO, hepatocyte-specific HIF-1α-null, HIF, hypoxia inducible factor, HLH, helix-loop-helix, IKK, IκB kinase, LCAD, long chain acyl CoA dehydrogenase, MCAD, medium chain acyl CoA dehydrogenase, MTP, microsomal triglyceride transfer protein, NADH, nicotinamide adenine dinucleotide, NEFA, non-esterified fatty acid, NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells, PPAR, peroxisome proliferator-activated receptor, RT-PCR, reverse transcription polymerase chain reaction, SCD, stearoyl CoA desaturase, SREBP, sterol regulatory element-binding protein, Stra, stimulated with retinoic acid, TCA, tricarboxylic acid, Tchol, total cholesterol, TG, triglyceride, VEGF, vascular endothelial growth factor, VHL, von Hippel–Lindau, VLDL, very low density lipoprotein, WT, wild-type

Keywords: Alcoholic fatty liver, HIF-1, SREBP-1c, DEC1