Hypoxia inducible factor (HIF1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia

Hypoxia inducible factor (HIF1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia
 
Guo-Min Shen, Ying-Ze Zhao,　Ming-Tai Chen,　Feng-Lin Zhang, Xiao-Ling Liu, Yi Wang, Chang-Zheng Liu, Jia Yu, Jun-Wu Zhang

Biochemistry J 441(2):675-683, 2012

The metabolism under hypoxia is significantly different from that under normoxia. It has been well elucidated that hypoxia inducible factor 1 (HIF1) plays a central role in regulating glucose metabolism under hypoxia. However, the role of HIF1 in lipid metabolism has not been well addressed yet. Here we demonstrated that HIF1 promotes low density lipoprotein (LDL) and very low density lipoprotein (VLDL) uptake through regulating very low density lipoprotein receptor gene (VLDLR) expression under hypoxia. Increased VLDLR mRNA and protein levels were observed under hypoxic or DFO treatment in MCF7, HepG2, and HeLa cells. By dual luciferase reporter assay and ChIP assay we confirmed a functional HRE which is localized at +405 in the exon1 of VLDLR gene. Knockdown of HIF1α and VLDLR, but not HIF2α, attenuates hypoxia-induced lipid accumulation through affecting LDL and VLDL uptake. Additionally we also observed a correlation between HIF1 activity and VLDLR expression in hepatocellular carcinoma specimens. These results suggest that the HIF-1-mediated VLDLR induction influences intracellular lipid accumulation through regulating LDL and VLDL uptake under hypoxia.