title: Hypoxia-inducible factor-1 (HIF-1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia.
abstract: Metabolism under hypoxia is significantly different from that under normoxia. It has been well elucidated that HIF-1 (hypoxia-inducible factor-1) plays a central role in regulating glucose metabolism under hypoxia; however, the role of HIF-1 in lipid metabolism has not yet been well addressed. In the present study we demonstrate that HIF-1 promotes LDL (low-density lipoprotein) and VLDL (very-LDL) uptake through regulation of VLDLR (VLDL receptor) gene expression under hypoxia. Increased VLDLR mRNA and protein levels were observed under hypoxic or DFO (deferoxamine mesylate salt) treatment in MCF7, HepG2 and HeLa cells. Using dual-luciferase reporter and ChIP (chromatin immunoprecipitation) assays we confirmed a functional HRE (hypoxia-response element) which is localized at +405 in exon 1 of the VLDLR gene. Knockdown of HIF1A (the α subunit of HIF-1) and VLDLR, but not HIF2A (the α subunit of HIF-2), attenuated hypoxia-induced lipid accumulation through affecting LDL and VLDL uptake. Additionally we also observed a correlation between HIF-1 activity and VLDLR expression in hepatocellular carcinoma specimens. The results of the present study suggest that HIF-1-mediated VLDLR induction influences intracellular lipid accumulation through regulating LDL and VLDL uptake under hypoxia.
authors.affiliation: Department of Biochemistry and Molecular Biology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Shen
authors.forename: Ying-Ze
authors.initials: YZ
authors.lastname: Zhao
authors.forename: Ming-Tai
authors.initials: MT
authors.lastname: Chen
authors.forename: Feng-Lin
authors.initials: FL
authors.lastname: Zhang
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Chang-Zheng
authors.initials: CZ
authors.lastname: Liu
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.forename: Jun-Wu
authors.initials: JW
authors.lastname: Zhang
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D011973:Receptors, LDL / Q000096:biosynthesis*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; C036053:VLDL receptor