HIF-1alpha and HIF-2alpha are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-1alpha-mediated fatty acid beta-oxidation.
Article Details
- CitationCopy to clipboard
Liu Y, Ma Z, Zhao C, Wang Y, Wu G, Xiao J, McClain CJ, Li X, Feng W
HIF-1alpha and HIF-2alpha are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-1alpha-mediated fatty acid beta-oxidation.
Toxicol Lett. 2014 Apr 21;226(2):117-23. doi: 10.1016/j.toxlet.2014.01.033. Epub 2014 Feb 3.
- PubMed ID
- 24503013 [ View in PubMed]
- Abstract
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% 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 beta-oxidation. Moreover, hypoxia exposure reduced proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) protein levels, which plays an important role in regulation of beta-oxidation. Exposure of HIF-1alpha or HIF-2alpha deficient hepatocytes to hypoxia abrogated the reduction in PGC-1alpha and CPT-1 expression and cellular lipid accumulation observed in normal hepatocytes exposed to hypoxia. These results suggest that both HIF-1alpha and HIF-2alpha are involved in hypoxia-induced lipid accumulation in hepatocytes via reducing PGC-1alpha mediated fatty acid beta-oxidation.