Contribution of steroidogenic factor 1 to the regulation of cholesterol synthesis

Steroidogenic factor 1 (SF-1) is an orphan member of the nuclear receptor f amily expressed in steroidogenic tissues, where it has an essential role in the regulation of the steroid hormone biosynthesis, adrenal and gonadal de velopment and endocrine responses fundamental for reproduction. Here we sho w that SF-1 regulates the transcription of cytosolic 3-hydroxy-3-methyl-glu taryl-CoA (HMG-CoA) synthase gene, which is essential for the endogenous sy nthesis of cholesterol. We have identified an element located 365 bp upstre am of the gene for cytosolic HMG-CoA synthase; SF-1 binds as a monomer to t his element and confers SF-1 responsiveness to homologous and heterologous promoters. It has been shown that in tissues with a high demand for cholest erol to be used in steroid synthesis, there is a lack of correlation betwee n the cholesterol levels and the activity of the limiting enzymes of the me valonate pathway. In accord with those results, we observed that cholestero l synthesis from acetate and either cytosolic HMG-CoA mRNA expression or tr anscriptional activity were not changed in response to 25-hydroxycholestero l in the SF-1-expressing steroidogenic Leydig tumour MA-10 cells. Moreover, the overexpression of SF-1 in nonsteroidogenic CV-1 cells renders them les s sensitive to the regulatory effects of cholesterol. This observation led to the hypothesis that in steroidogenic tissues the expression of SF-1 perm its high levels of endogenous synthesis of cholesterol irrespective of the intracellular levels of this metabolite.