HIF 1 inhibits STAR transcription and testosterone synthesis in murine Leydig cells

Wang, Xueting; Zou, Zhiran; Yang, Zhihui; Jiang, Shan; Lu, Yapeng; Wang, Dan; Dong, Zhangji; Xu, Sha; Zhu, Li

doi:10.1530/jme-18-0148

Cited by 24 publications

(21 citation statements)

References 48 publications

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“…The expression of STAR was shown to be induced by HIF1 in mouse KK1 cells 18 . Conversely, the inhibitory action of HIF1 on STAR expression is documented in mouse Leydig cells 45 . Similar reports can be found that HIF1 could increase HSD3B expression in Leydig cells 46 , while others suggest that it may inhibit HSD3B and progesterone production in canine luteal cells 47 .…”

Section: Discussionmentioning

confidence: 98%

HIF1 driven transcriptional activity regulates steroidogenesis and proliferation of bovine granulosa cells

Baddela

Sharma

Michaelis

et al. 2020

Sci Rep

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Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor, consisting of a constitutively expressed β-subunit (HIF1B) and a regulated α-subunit (HIF1A). In the present study, we analyzed the HIF1 driven transcriptional activity in bovine granulosa cells (GC). Treatment of GC with FSH (follicle stimulating hormone) and IGF1 (insulin-like growth factor 1) resulted in the upregulation of HIF1A mRNA expression under normoxia. Immunohistochemistry of bovine ovarian sections showed distinct staining of HIF1A in the GC layer of different staged ovarian follicles. Suppression of HIF1 using echinomycin and gene knockdown procedures revealed that HIF1 transcriptionally regulates the genes associated with steroidogenesis (STAR, HSD3B and CYP19A1) and proliferation (CCND2 and PCNA) of GC. Further, our data suggest that CYP19A1, the key gene of estradiol production, is one of the plausible downstream targets of HIF1 in bovine GC as shown by gene expression, radioimmunoassay, and chromatin precipitation analysis. Based on these results, we propose that HIF1 driven transcriptional activity plays a crucial role in GC functionality, especially steroidogenesis and proliferation in developing bovine ovarian follicles.

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Section: Discussionmentioning

confidence: 98%

HIF1 driven transcriptional activity regulates steroidogenesis and proliferation of bovine granulosa cells

Baddela

Sharma

Michaelis

et al. 2020

Sci Rep

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“…3 e, f, g and Table 2 ). For the selected genes expressed in testis, we observed that the expression levels of Pem (a well-defined androgen target gene) (Wang, et al, 2006 ) and Star (the first rate-limiting enzyme in testosterone synthesis) (Wang, et al, 2018 ) were reduced upon STAC3 ablation, whereas transcriptional levels of other rate-limiting enzymes (namely Hsd3b and Cyp11a1 ) were comparable in Ctrl sh and Stac3 sh-treated testes (Fig. 3 h).…”

Section: Resultsmentioning

confidence: 99%

“…The primers used were: mouse Stac3 (NM_177707.4), 5′-CCC ACT CTA CAG CGA CCA AC-3′ and 5′-GAC TCT GGC TCC TCC TCC AT-3′; rat stac3 (NM_001130558.1), 5′-ACT TCA GCT CTA CCA CCA CG-3′ and 5′-CTC CAT CTC GGT TGT CTC TGG-3′; human STAC3 (NM_145064.3), 5′-TTT CAG CCC TGA CAC CAA GG-3′ and 5′-ACT TTG CCG AGT CTC TGC TG-3′; human 18S (M10098.1, also applied to mouse and rat 18 s), 5′-AAT CAG GGT TCG ATT CCG GA-3′ and 5′-GTG GAC TCA TTC CAA TTA CAG-3′. Primers used for Pem, Star, Hsd3b and Cyp11a1 have been reported elsewhere (Wang, et al, 2006(Wang, et al, , 2018.…”

Section: Rt-qpcrmentioning

confidence: 99%

Testicular STAC3 regulates Leydig cell steroidogenesis through potentiating mitochondrial membrane potential and StAR processing

Bi¹,

Liu²,

Xu³

et al. 2021

Cell Tissue Res

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SH3 and cysteine-rich protein 3 (STAC3), a small adapter protein originally identified as a core component of excitation–contraction coupling machinery, regulates the voltage-induced Ca2+ release in skeletal muscle. However, the possibility of additional, as yet unknown, non-muscle effects of STAC3 cannot be ruled out. Herein, we provide the evidence for the expression and functional involvement of STAC3 in spermatogenesis. STAC3 expression was localized in the testicular interstitium of rodent and human testes. By using the cytotoxic drug ethylene dimethane sulfonate (EDS), STAC3 expression was observed to be decreased sharply in rat testis after selective withdrawal of Leydig cells (LCs), and reappeared immediately after LCs repopulation, indicating that testicular expression of STAC3 mainly stems from LCs. From a functional standpoint, in vivo lentiviral vector–mediated suppression of STAC3 resulted in a significant decrease in testosterone production, and thereafter caused impairment of male fertility by inducing oligozoospermia and asthenospermia. The indispensible involvement of STAC3 in testicular steroidogenesis was validated using the in vivo knockdown model with isolated primary LCs as well as in vitro experiments with primary LCs. By generating the TM3Stac3−/− cells, we further revealed that STAC3 depletion attenuated mitochondrial membrane potential and StAR processing in db-cAMP-stimulated LCs. Thus, the inhibitory effect of STAC3 deficiency on testicular steroidogenesis may be ascribed to a disturbed mitochondrial homeostasis. Collectively, the present results strongly suggest that STAC3 may function as a novel regulator linking mitochondrial homeostasis and testicular steroidogenesis in LCs. Our data underscore an unexpected reproductive facet of this muscle-derived factor.

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“…Previous in vitro studies and reports on HIF1α alterations in zebrafish larvae have suggested negative regulation of StAR, the mitochondrial cholesterol transporter (7,17,20). However, data on the effects of HPP alterations in adrenal cortex of mice is scant at best.…”

Section: Loss Of Phd2/hif1α In Adrenocortical Cells Impacts Gene Exprmentioning

confidence: 99%

“…Recent in vitro and zebrafish studies have revealed a continuous cross talk between HIF and steroidogenesis pathways, along with potential interference in the production of aldosterone and glucocorticoids (17)(18)(19)(20). There is also evidence suggesting a role for the hypoxia pathway in modulating glucocorticoid/glucocorticoid receptor (GR) signaling (21,22).…”

Section: Introductionmentioning

confidence: 99%

HIF1α is an essential regulator of steroidogenesis in the adrenal gland

Watts

Stein

Meneses

et al. 2020

Preprint

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AbstractEndogenous steroid hormones, especially glucocorticoids and mineralocorticoids, are essential for life regulating numerous physiological and pathological processes. These hormones derive from the adrenal cortex, and drastic or sustained changes in their circulatory levels affect multiple organ systems. Although a role for hypoxia pathway proteins (HPP) in steroidogenesis has been suggested, knowledge on the true impact of the HIFs (Hypoxia Inducible Factors) and oxygen sensors (HIF-prolyl hydroxylase domain-containing enzymes; PHDs) in the adrenocortical cells of vertebrates is scant. By creating a unique set of transgenic mouse lines, we reveal a prominent role for HIF1α in the synthesis of virtually all steroids under steady state conditions. Specifically, mice deficient in HIF1α in a part of the adrenocortical cells displayed enhanced levels of enzymes responsible for steroidogenesis and a cognate increase in circulatory steroid levels. These changes resulted in cytokine alterations and changes in the profile of circulatory mature hematopoietic cells. Conversely, HIF1α overexpression due to combined PHD2 and PHD3 deficiency in the adrenal cortex resulted in the opposite phenotype of insufficient steroid production due to impaired transcription of necessary enzymes. Based on these results, we propose HIF1α to be a central and vital regulator of steroidogenesis as its modulation in adrenocortical cells dramatically impacts hormone synthesis with systemic consequences. Additionally, these mice can have potential clinical significances as they may serve as essential tools to understand the pathophysiology of hormone modulations in a number of diseases associated with metabolic syndrome, auto-immunity or even cancer.

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HIF 1 inhibits STAR transcription and testosterone synthesis in murine Leydig cells

Cited by 24 publications

References 48 publications

HIF1 driven transcriptional activity regulates steroidogenesis and proliferation of bovine granulosa cells

HIF1 driven transcriptional activity regulates steroidogenesis and proliferation of bovine granulosa cells

Testicular STAC3 regulates Leydig cell steroidogenesis through potentiating mitochondrial membrane potential and StAR processing

HIF1α is an essential regulator of steroidogenesis in the adrenal gland

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