title: Mechanism for HIF-1 activation by cholesterol under normoxia: a redox signaling pathway for liver damage.
abstract: Cholesterol and chronic activation of hypoxia-inducible factor-1 (HIF-1) have been separately implicated in the pathogenesis and progression of liver diseases. In AML12 hepatocytes increased HIF-1α protein accumulation was evident after 2 h of incubation with cholesterol, whereas enhanced HIF-1 transcriptional activity was observed after 6 h. Investigations into the molecular mechanism have shown that cholesterol inhibited HIF-1α degradation. Mitochondrial dysfunction and enhanced mitochondrial reactive oxygen species (ROS) generation were observed in 2-h cholesterol-treated cells along with augmented nitric oxide (NO) levels. Further analysis indicated that HIF-1α stabilization at later time (6h), but not after 2h, of incubation with cholesterol was dependent on NO production. To elucidate the role of mitochondrial dysfunction in HIF-1α stabilization, mitochondrial DNA-depleted hepatocytes were prepared. In these cells the ability of cholesterol to activate the HIF-1 pathway was abolished. Similarly, catalase overexpression also attenuated cholesterol-induced HIF-1α accumulation. These results demonstrate that cholesterol promotes HIF-1 activation in a ROS- and NO-dependent manner. Chronic liver activation of HIF-1 by cholesterol may mediate its deleterious effects in the liver.
authors.affiliation: The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
authors.forename: Sarit
authors.initials: S
authors.lastname: Anavi
authors.affiliation: The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Hahn-Obercyger
authors.affiliation: The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
authors.forename: Zecharia
authors.initials: Z
authors.lastname: Madar
authors.affiliation: The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address: oren.tirosh@mail.huji.ac.il.
authors.forename: Oren
authors.initials: O
authors.lastname: Tirosh
mesh_terms: D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004272:DNA, Mitochondrial; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D002784:Cholesterol; D002374:Catalase
keywords: Free radicals; Inflammation; Lipids; Nonalcoholic steatohepatitis; Oxidative stress; Redox signaling