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.
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Research Article|
December 21 2011
Hypoxia-inducible factor-1 (HIF-1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia
Guo-Min Shen;
Guo-Min Shen
*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
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Ying-Ze Zhao;
Ying-Ze Zhao
*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
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Ming-Tai Chen;
Ming-Tai Chen
*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
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Feng-Lin Zhang;
Feng-Lin Zhang
*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
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Xiao-Ling Liu;
Xiao-Ling Liu
*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
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Yi Wang;
Yi Wang
†Department of VIP, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China
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Chang-Zheng Liu;
Chang-Zheng Liu
*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
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Jia Yu;
Jia Yu
*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
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Jun-Wu Zhang
Jun-Wu Zhang
1
*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
1To whom correspondence should be addressed (email junwu_zhang@pumc.edu.cn).
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Publisher: Portland Press Ltd
Received:
July 28 2011
Revision Received:
October 04 2011
Accepted:
October 04 2011
Accepted Manuscript online:
October 04 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 441 (2): 675–683.
Article history
Received:
July 28 2011
Revision Received:
October 04 2011
Accepted:
October 04 2011
Accepted Manuscript online:
October 04 2011
Citation
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; Hypoxia-inducible factor-1 (HIF-1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia. Biochem J 15 January 2012; 441 (2): 675–683. doi: https://doi.org/10.1042/BJ20111377
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