AbstractThe ability to maintain O2 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‐1α (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‐1α 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‐1α even if a parallel action of SREBP‐2 actively translocated to nucleus by the increased level of SCAP cannot be excluded. J. Cell. Biochem. 104: 701–709, 2008. © 2008 Wiley‐Liss, Inc.