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.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/3101 |
| Date | 12 April 2006 |
| Creators | Tan, Qiulin |
| Contributors | Tian, Yanan |
| Publisher | Texas A&M University |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Thesis, text |
| Format | 495826 bytes, electronic, application/pdf, born digital |
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