HIF-lα and HIF-2α are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-lα-mediated fatty acid β-oxidation

作者：Liu, Yanlong; Ma, Zhenhua; Zhao, Cuiqing; Wang, Yuhua; Wu, Guicheng; Xiao, Jian; McClain, Craig J.; Li, Xiaokun; Feng, Wenke^*

来源：Toxicology Letters, 2014, 226(2): 117-123.

DOI：10.1016/j.toxlet.2014.01.033

• Hypoxia
• HIF
• Lipid accumulation
• PGC-1 alpha

During periods of cellular hypoxia, hepatocytes adapt to consume less oxygen by shifting energy production from mitochondrial fatty acid beta-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 beta-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 beta-oxidation, without significantly influencing fatty acid synthesis. Exposing hepatocytes to 1% O-2 reduced the mRNA expression of carnitine palmitoyltransferase 1 (CPT-1), which catalyzes the rate-limiting step in the mitochondrial import of fatty acids for beta-oxidation. Moreover, hypoxia exposure reduced proliferator-activated receptor-gamma coactivator-alpha (PGC-1 alpha) protein levels, which plays an important role in regulation of beta-oxidation. Exposure of HIF-1 alpha. or HIF-2 alpha deficient hepatocytes to hypoxia abrogated the reduction in PGC-1 alpha. and CPT-1 expression and cellular lipid accumulation observed in normal hepatocytes exposed to hypoxia. These results suggest that both HIF-1 alpha. and HIF-2 alpha are involved in hypoxia-induced lipid accumulation in hepatocytes via reducing PGC-1 alpha mediated fatty acid beta-oxidation.

• 出版日期2014-4-21
• 单位吉林大学; 吉林农业大学; 西安交通大学; 温州医科大学