title: HIF-1α and HIF-2α are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-1α-mediated fatty acid β-oxidation.
abstract: During periods of cellular hypoxia, hepatocytes adapt to consume less oxygen by shifting energy production from mitochondrial fatty acid β-oxidation to glycolysis. One of the earliest responses to pathologic hypoxia is the activation of the hypoxia-inducible factor (HIF). In the present study, we examined whether HIF-1 and HIF-2 were involved in the regulation of fatty acid synthesis and β-oxidation. We showed that hypoxia induced fat accumulation in the livers of mice and in HepG2 cells. These hypoxia-induced changes in fatty acid metabolism were mediated by suppressing fatty acid β-oxidation, without significantly influencing fatty acid synthesis. Exposing hepatocytes to 1% O2 reduced the mRNA expression of carnitine palmitoyltransferase 1 (CPT-1), which catalyzes the rate-limiting step in the mitochondrial import of fatty acids for β-oxidation. Moreover, hypoxia exposure reduced proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein levels, which plays an important role in regulation of β-oxidation. Exposure of HIF-1α or HIF-2α deficient hepatocytes to hypoxia abrogated the reduction in PGC-1α and CPT-1 expression and cellular lipid accumulation observed in normal hepatocytes exposed to hypoxia. These results suggest that both HIF-1α and HIF-2α are involved in hypoxia-induced lipid accumulation in hepatocytes via reducing PGC-1α mediated fatty acid β-oxidation.
authors: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China; Departments of Medicine and Pharmacology and Toxicology, University of Louisville, Louisville, KY USA.
authors: Yanlong
authors: Y
authors: Liu
authors: Departments of Medicine and Pharmacology and Toxicology, University of Louisville, Louisville, KY USA; First Hospital, Xi'an Jiaotong University, Xi'an, China.
authors: Zhenhua
authors: Z
authors: Ma
authors: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China; Departments of Medicine and Pharmacology and Toxicology, University of Louisville, Louisville, KY USA; Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors: Cuiqing
authors: C
authors: Zhao
authors: Departments of Medicine and Pharmacology and Toxicology, University of Louisville, Louisville, KY USA; College of Food Science and Engineering, Jilin Agricultural University, Changchun, China.
authors: Yuhua
authors: Y
authors: Wang
authors: Departments of Medicine and Pharmacology and Toxicology, University of Louisville, Louisville, KY USA; Chongqing Three Gorges Central Hospital, Chongqing, China.
authors: Guicheng
authors: G
authors: Wu
authors: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
authors: Jian
authors: J
authors: Xiao
authors: Departments of Medicine and Pharmacology and Toxicology, University of Louisville, Louisville, KY USA; Robley Rex Louisville VAMC, Louisville, KY USA.
authors: Craig J
authors: CJ
authors: McClain
authors: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
authors: Xiaokun
authors: X
authors: Li
authors: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China; Departments of Medicine and Pharmacology and Toxicology, University of Louisville, Louisville, KY USA. Electronic address: wenke.feng@louisville.edu.
authors: Wenke
authors: W
authors: Feng
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005227:Fatty Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D014157:Transcription Factors; D014280:Triglycerides; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; C486497:PPARGC1A protein, human
keywords: HIF; Hypoxia; Lipid accumulation; PGC-1α