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Regulation of Sterol Regulatory Element Binding Transcription Factor 1a by Human Chorionic Gonadotropin and Insulin in Cultured Rat Theca-Interstitial Cells.

Authors: Palaniappan, M  Menon, KM 
Citation: Palaniappan M and Menon KM, Biol Reprod. 2009 Mar 18.
Pubmed: (View Article at PubMed) PMID:19299314
DOI: Full-text: DOI:10.1095/biolreprod.108.074351

Theca-interstitial (T-I) cells of the ovary synthesize androgens in response to luteinizing hormone (LH). In pathological conditions such as polycystic ovarian syndrome (PCOS), the T-I cells are hyperactive in androgen production in response to LH and insulin. Since 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. 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. While the hCG-induced depletion of total and free cholesterol was abolished by aminoglutethimide (AGM), the stimulatory effect on SREBF1a was not totally suppressed. Treatment with 25-hydroxycholesterol (25-OHC) abrogated the hCG effect on SREBF1a. Inhibition of the phosphatidylinositol 3-kinase pathway did not block the insulin-induced increase in SREBF1a, whereas MAP kinase inhibition reduced the insulin response. These results suggest that the increased androgen biosynthesis by the T-I cells in response to hCG and insulin, at least in part, is regulated by increasing the expression of SRE responsive genes by increasing SREBF1a.


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CRRD Object Information
CRRD ID: 2308854
Created: 2009-06-11
Species: All species
Last Modified: 2009-06-11
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.