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    Inhibition of cholesterol biosynthesis under hypoxia

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    etd-tamu-2005C-TOXI-Tan.pdf (484.2Kb)
    Date
    2006-04-12
    Author
    Tan, Qiulin
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    Abstract
    Oxygen balance is very important and tightly regulated in mammals. Under hypoxia, hypoxia inducible factor 1(HIF-1) dimerizes with hypoxia inducible factor 1± (HIF-) and activates expression of several genes. Using a mammalian two hybrid assay, we found that HIF-1 interacted with sterol response element binding protein 1a (SREBP1a). SREBP1a regulates transcription of HMG-CoA reductase via binding to the sterol response element (SRE) in the promoter region. HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis. The interaction between SREBP1a and HIF-1suggests that HIF-1 may play an important role in regulation of cholesterol biosynthesis. We tested the effects of hypoxia on the HMG-CoA reductase. We found that hypoxia caused suppression of SRE-driven luciferase reporter gene expression. HMG-CoA reductase mRNA levels decreased under hypoxia in both hepatoma cells and mouse primary hepatocytes. Electrophoretic mobility shift assay showed that HIF-1 blocked binding of SREBP1a to the SRE sequence in vitro. Ectopic expression of HIF-1 suppressed the SRE- driven luciferase reporter gene expression in BPR cells (HIF-1). Our results suggest that hypoxia inhibits cholesterol biosynthesis by suppressing SREBP1a-regulated gene expression and this suppression is caused by the blockage of SREBP1a binding to SRE sequence by HIF-1.
    URI
    http://hdl.handle.net/1969.1/3101
    Subject
    cholesterol
    hypoxia
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    • Electronic Theses, Dissertations, and Records of Study (2002– )
    Citation
    Tan, Qiulin (2005). Inhibition of cholesterol biosynthesis under hypoxia. Master's thesis, Texas A&M University. Texas A&M University. Available electronically from http : / /hdl .handle .net /1969 .1 /3101.

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