Inhibition of cholesterol biosynthesis under hypoxia
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.
Citation
Tan, Qiulin (2005). Inhibition of cholesterol biosynthesis under hypoxia. Master's thesis, Texas A&M University. Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /3101.