title: Regulation of sterol regulatory element-binding transcription factor 1a by human chorionic gonadotropin and insulin in cultured rat theca-interstitial cells.
abstract: Theca-interstitial (T-I) cells of the ovary synthesize androgens in response to luteinizing hormone (LH). In pathological conditions such as polycystic ovarian syndrome, T-I cells are hyperactive in androgen production in response to LH and insulin. Because cholesterol is an essential substrate for androgen production, we examined the effect of human chorionic gonadotropin (hCG) and insulin on signaling pathways that are known to increase cholesterol accumulation in steroidogenic cells. Specifically, the effect of hCG and insulin on sterol regulatory element-binding transcription factor 1a (SREBF1a) required for cholesterol biosynthesis and uptake was examined. Primary cultures of T-I cells isolated from 25-day-old rat ovaries responded to hCG and insulin to increase the active/processed form of SREBF1a. The hCG and insulin significantly reduced insulin-induced gene 1 (INSIG1) protein, a negative regulator of SREBF processing. Furthermore, an increase in the expression of selected SREBF target genes, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) and mevalonate kinase (Mvk), was also observed. Protein kinase A (PRKA) inhibitor completely abolished the hCG-induced increase in SREBF1a, while increasing INSIG1. Although the hCG-induced depletion of total and free cholesterol was abolished by aminoglutethimide, the stimulatory effect on SREBF1a was not totally suppressed. Treatment with 25-hydroxycholesterol abrogated the effect of hCG on SREBF1a. Inhibition of the phosphatidylinositol 3-kinase pathway did not block the insulin-induced increase in SREBF1a, whereas mitogen-activated protein kinase inhibition reduced the insulin response. These results suggest that the increased androgen biosynthesis by T-I cells in response to hCG and insulin is regulated, at least in part, by increasing the expression of sterol response element-responsive genes by increasing SREBF1a.
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Murugesan
authors.initials: M
authors.lastname: Palaniappan
authors.forename: K M J
authors.initials: KM
authors.lastname: Menon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000616:Aminoglutethimide / Q000378:metabolism; D000704:Analysis of Variance; D000728:Androgens / Q000096:biosynthesis; D000735:Androstenedione / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006888:Hydroxycholesterols / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D013799:Theca Cells / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000728:Androgens; D006063:Chorionic Gonadotropin; D006888:Hydroxycholesterols; C491574:Insig1 protein, rat; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D000616:Aminoglutethimide; D000735:Androstenedione; C007997:25-hydroxycholesterol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013254:Steroid 17-alpha-Hydroxylase; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D019950:Mitogen-Activated Protein Kinase 1; D055372:AMP-Activated Protein Kinases