Inhibition of cholesterol biosynthesis under hypoxia /
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| Format: | Thesis eBook |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University],
[2006]
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| Subjects: | |
| Online Access: | Link to OAK Trust copy |
| Abstract: | Oxygen balance is very important and tightly regulated in mammals. Under hypoxia, hypoxia inducible factor 1[beta] (HIF-1[beta]) dimerizes with hypoxia inducible factor 1 [alpha] (HIF-1 [alpha]) and activates expression of several genes. Using a mammalian two hybrid assay, we found that HIF-1 [beta] 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-1[beta]suggests that HIF-1[beta] 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[beta] blocked binding of SREBP1a to the SRE sequence in vitro. Ectopic expression of HIF-1[beta] suppressed the SRE- driven luciferase reporter gene expression in BPR cells (HIF-1[beta]-/-). 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 [beta]. |
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| Item Description: | "Major Subject: Toxicology" Title from author supplied metadata (automated record created on Apr. 14, 2006.) Vita. Abstract. Electronic resource. |
| Format: | Mode of access: World Wide Web. System requirements: World Wide Web access and Adobe Acrobat Reader. |
| Bibliography: | Includes bibliographical references. |