Up-regulation of steroid biosynthesis by retinoid signaling: Implications for aging

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• 作者：Pulak R. Manna^a ; ^d ; ^{pulak.manna@ttuhsc.edu" class="auth_mail" title="E-mail the corresponding author} ; Cloyce L. Stetson^b ; Carol Daugherty^b ; Ikue Shimizu^b ; Peter J. Syapin^c ; Ghislaine Garrel^e ; Joelle Cohen-Tannoudji^e ; ^f ; Ilpo Huhtaniemi^g ; Andrzej T. Slominski^h ; Kevin Pruitt^d ; Douglas M. Stocco^a
• 关键词：RA ; retinoic acid ; Retinoids ; RA and its derivatives ; atRA ; all-trans RA ; RAR ; retinoic acid receptor ; RXR ; retinoid X receptor ; LXR ; liver X receptor ; PKA ; protein kinase A ; (Bu)2cAMP ; dibutyryl adenosine 3&prime ; 5&prime ; cyclic monophosphate ; StAR ; steroidogenic acute regulatory protein ; CYP11A1 ; cytochrome P450scc ; siRNA ; small interfering RNA ; EMSA ; electrophoretic mobility shift assay ; NE ; nuclear extract ; ChIP ; chromatin immunoprecipitation ; RT-PCR ; reverse transcription polymerase chain
• 刊名：Mechanisms of Ageing and Development
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：150
• 期：Complete
• 页码：74-82
• 全文大小：859 K

文摘

Retinoids (vitamin A and its derivatives) are critical for a spectrum of developmental and physiological processes, in which steroid hormones also play indispensable roles. The StAR protein predominantly regulates steroid biosynthesis in steroidogenic tissues. We have reported that regulation of retinoid, especially atRA and 9-cis RA, responsive StAR transcription is largely mediated by an LXR–RXR/RAR heterodimeric motif in the mouse StAR promoter. Herein we demonstrate that retinoids are capable of enhancing StAR protein, P-StAR, and steroid production in granulosa, adrenocortical, glial, and epidermal cells. Whereas transient expression of RAR伪 and RXR伪 enhanced 9-cis RA induced StAR gene transcription, silencing of RXR伪 with siRNA, decreased StAR and steroid levels. An oligonucleotide probe encompassing an LXR–RXR/RAR motif bound to adrenocortical and epidermal keratinocyte nuclear proteins in EMSAs. ChIP studies revealed association of RAR伪 and RXR伪 with the StAR proximal promoter. Further studies demonstrated that StAR mRNA levels decreased in diseased and elderly men and women skin tissues and that atRA could restore steroidogenesis in epidermal keratinocytes of aged individuals. These findings provide novel insights into the relevance of retinoid signaling in the up-regulation of steroid biosynthesis in various target tissues, and indicate that retinoid therapy may have important implications in age-related complications and diseases.