Regulation of HMG-CoA reductase expression by hypoxia.
The ability to maintain O(2) 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-1alpha (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-1alpha 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-1alpha even if a parallel action of SREBP-2 actively translocated to nucleus by the increased level of SCAP cannot be excluded.
Pallottini
Valentina
V
Department of Biology, University of Roma Tre, Viale Marconi, 446-00146 Rome, Italy. vpallott@uniroma3.it
Guantario
Barbara
B
Martini
Chiara
C
Totta
Pierangela
P
Filippi
Irene
I
Carraro
Fabio
F
Trentalance
Anna
A
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis* / Q000235:genetics; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020218:Response Elements; D013997:Time Factors; D014158:Transcription, Genetic
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D010100:Oxygen