Affiliation:
1. 1Geriatric Research, Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA
2. 2Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, California, USA
Abstract
miR-132 is hormonally regulated in steroidogenic cells of the adrenal gland, ovary and testis. Here, we examined the potential role of miR-132 in the control of steroidogenesis. Transfection of Y1 adrenal cells with miR-132 increased mRNAs of 3β-HSD and 20α-HSD enzymes, which catalyze the sequential conversion of pregnenolone to progesterone to biologically inactive 20α-hydroxyprogesterone (20α-OHP). Overexpression of miR-132 reduced MeCP2 and StAR protein expression, basal progestin (progesterone and 20α-OHP) production, but enhanced their production in response to cAMP stimulation. Use of [3H] pregnenolone and free-diffusible 22(R)-hydroxycholesterol further confirmed that miR-132 promotes the production of 20α-OHP by upregulating 3β-HSD and 20α-HSD. Evidence is also presented that StAR is a direct target of miR-132. Transient transfection of Y1 cells with miR-132 demonstrated that miR-132 induction of 3β-HSD and 20α-HSD was accompanied by significant suppression of one of its target gene products, MeCP2. In contrast, co-expression of miR-132 plus MeCP2 protein partially blocked the ability of miR-132 to upregulate the expression and function of 3β-HSD and 20α-HSD. Moreover, suppression of MeCP2 protein with siRNA resulted in increased expression of 3β-HSD and 20α-HSD, further demonstrating that miR-132 induces the expression of these two enzymes via inhibition of MeCP2. Likewise, overexpression of miR-132 increased 20α-OHP production with and without HDL loading, while knockdown of miR-132 resulted in a significant decrease of 20α-OHP production by granulosa cells. In conclusion, our data suggest that miR-132 attenuates steroidogenesis by repressing StAR expression and inducing 20α-HSD via inhibition of MeCP2 to generate a biologically inactive 20α-OHP.
Subject
Endocrinology,Molecular Biology
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