Regulation of HMG-CoA reductase expression by hypoxia

The ability to maintainO2 homeostasis is essential to the survival of all invertebrate and vertebrate species. The transcriptional factor, hypoxia inducible factor 1 (HIF-1), is the principal regulator of oxygen homeostasis. Under hypoxic condition HIF-1 induces the transcription of several hypoxia-responsive genes by binding to hypoxia-response elements (HRE) in their promoters. In recent years it has been demonstrated that hypoxia could be related to metabolic variations such as hyper-cholesterolemia in mouse models. On the basis of this observation, the present study was performed to verify the involvement of HIF-1, and in particular the effect of chemical and environmental induction of HIF- 1a (the oxygen sensitive isoform) accumulation in 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoAR, the key and rate limiting enzyme of cholesterol biosynthetic pathway) regulation. Our results show that HIF-1a accumulation is able to increase level and activity of HMG-CoAR by stimulating its transcription. The raised transcription of the reductase could be related to an induction by HIF-1a even if a parallel action of SREBP-2 actively translocated to nucleus by the increased level of SCAP cannot be excluded.