Regulation of steroid 5-alpha reductase type 2 (Srd5a2) by sterol regulatory element binding proteins and statin.
In this study, we show that sterol regulatory element binding proteins (SREBPs) regulate expression of Srd5a2, an enzyme that catalyzes the irreversible conversion of testosterone to dihydroxytestosterone in the male reproductive tract and is highly expressed in androgen-sensitive tissues such as the prostate and skin. We show that Srd5a2 is induced in livers and prostate from mice fed a chow diet supplemented with lovastatin plus ezitimibe (L/E), which increases the activity of nuclear SREBP-2. The three fold increase in Srd5a2 mRNA mediated by L/E treatment was accompanied by the induction of SREBP-2 binding to the Srd5a2 promoter detected by a ChIP-chip assay in liver. We identified a SREBP-2 responsive region within the first 300 upstream bases of the mouse Srd5a2 promoter by co-transfection assays which contain a site that bound SREBP-2 in vitro by an EMSA. Srd5a2 protein was also induced in cells over-expressing SREBP-2 in culture. The induction of Srd5a2 through SREBP-2 provides a mechanistic explanation for why even though statin therapy is effective in reducing cholesterol levels in treating hypercholesterolemia it does not compromise androgen production in clinical studies.
Seo
Young-Kyo
YK
Department of Molecular Biology and Biochemistry, 3244 McGaugh Hall, University of California, UC Irvine, Irvine, CA 92697-3900, USA.
Zhu
Bing
B
Jeon
Tae-Il
TI
Osborne
Timothy F
TF
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000069438:Ezetimibe; D015971:Gene Expression Regulation, Enzymologic; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D006903:Hydroxymethylglutaryl CoA Reductases / Q000494:pharmacology* / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000187:drug effects / Q000201:enzymology*; D011471:Prostatic Neoplasms / Q000201:enzymology; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D051782:Sterol Regulatory Element Binding Protein 2 / Q000819:agonists / Q000378:metabolism*; D014162:Transfection
D001384:Azetidines; D006538:Heptanoic Acids; D011758:Pyrroles; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D008148:Lovastatin; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D000069438:Ezetimibe