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

Yasumasa Nishiyama, Nobuhito Goda, Mai Kanai, Daisuke Niwa, Kota Osanai, Yu Yamamoto, Nanami Senoo-Matsuda, Randall S. Johnson, Soichiro Miura, Yasuaki Kabe, Makoto Suematsu

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)441-447
Number of pages7
JournalJournal of Hepatology
Volume56
Issue number2
DOIs
Publication statusPublished - 2012 Feb

Fingerprint

Alcoholic Fatty Liver
Hypoxia-Inducible Factor 1
Lipids
Ethanol
Liver
Fatty Liver
Sterol Regulatory Element Binding Protein 1
Lipid Metabolism
Hepatocytes
Anaerobiosis
Genes
Diet
Acetyl-CoA Carboxylase
Hypertriglyceridemia
Mixed Function Oxygenases
Oxygen Consumption
Alcohols

Keywords

  • Alcoholic fatty liver
  • DEC1
  • HIF-1
  • SREBP-1c

ASJC Scopus subject areas

  • Hepatology

Cite this

HIF-1α induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice. / Nishiyama, Yasumasa; Goda, Nobuhito; Kanai, Mai; Niwa, Daisuke; Osanai, Kota; Yamamoto, Yu; Senoo-Matsuda, Nanami; Johnson, Randall S.; Miura, Soichiro; Kabe, Yasuaki; Suematsu, Makoto.

In: Journal of Hepatology, Vol. 56, No. 2, 02.2012, p. 441-447.

Research output: Contribution to journalArticle

Nishiyama, Y, Goda, N, Kanai, M, Niwa, D, Osanai, K, Yamamoto, Y, Senoo-Matsuda, N, Johnson, RS, Miura, S, Kabe, Y & Suematsu, M 2012, 'HIF-1α induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice', Journal of Hepatology, vol. 56, no. 2, pp. 441-447. https://doi.org/10.1016/j.jhep.2011.07.024
Nishiyama, Yasumasa ; Goda, Nobuhito ; Kanai, Mai ; Niwa, Daisuke ; Osanai, Kota ; Yamamoto, Yu ; Senoo-Matsuda, Nanami ; Johnson, Randall S. ; Miura, Soichiro ; Kabe, Yasuaki ; Suematsu, Makoto. / HIF-1α induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice. In: Journal of Hepatology. 2012 ; Vol. 56, No. 2. pp. 441-447.
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AU - Osanai, Kota

AU - Yamamoto, Yu

AU - Senoo-Matsuda, Nanami

AU - Johnson, Randall S.

AU - Miura, Soichiro

AU - Kabe, Yasuaki

AU - Suematsu, Makoto

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