Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.8
5.6
Journals
IJMS
Special Issues
Molecular Mechanisms of Steroid Hormone Biosynthesis and Action
ijms-logo
Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

► Journal Menu

Journal Browser

► Journal Browser
share announcement

Molecular Mechanisms of Steroid Hormone Biosynthesis and Action

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (1 November 2022) | Viewed by 35479

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Jacques J. Tremblay

E-Mail Website
Guest Editor
1. Reproduction, Mother and Child Health, Room T3-67, CHU de Québec—Université Laval Research Centre, Québec, QC G1V 4G2, Canada
2. Centre for Research in Reproduction, Development and Intergenerational Health, Department of Obstetrics, Gynecology and Reproduction, Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada
Interests: leydig cells; steroidogenesis; gene expression; hormone action; male sex differentiation; transcription factors; endocrine disruptors

Special Issue Information

Dear Colleagues,

Steroids are essential hormones that are needed to regulate biological processes across the lifespan. Steroid hormone production and action must be tightly controlled; otherwise, there can be detrimental effects on physiological function leading to disease.  

The biosynthesis of steroids and their actions in target tissues and cells are complex; however, coordinated processes that rely on a series of diverse cellular and molecular events, ranging from proper steroidogenic cell differentiation and gene expression to hormone transport, hormone processing, and hormone action via interaction with specific receptors. The regulation of these events requires the concerted action of various hormones, growth factors, transcription factors, and other signaling and regulatory molecules that are needed to ensure adequate genomic, cellular, and/or physiological responses. Many of these processes are also targets for endocrine disruption.

This Special Issue on the “Molecular mechanisms of steroid hormone biosynthesis and action” welcomes original research and review articles in this field. Potential topics of interest may include, but are not limited, to the following:

  1. Mechanisms of steroidogenic cell differentiation.
  2. Steroid hormone biosynthesis, including substrate availability, mechanism of steroidogenic enzyme action via the classical and backdoor pathways.
  3. Molecular and cellular regulation of steroidogenesis, including steroidogenic cell response to hormone stimulation, signaling pathways, kinases, transcription factors, and gene expression.
  4. Mechanisms of steroid hormone action on target cells, including genomic and non-genomic pathways.
  5. Molecular mechanisms of endocrine disruptor action on steroidogenic cells.
  6. New tools and approaches to study steroidogenesis and steroid hormone action.

This Special Issue aims to gather experts at the cutting edge of their fields to disseminate their latest work to a broad range of readership.

Dr. Jacques J. Tremblay
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Leydig cells
  • adrenal cortex
  • ovary
  • placenta
  • steroidogenesis
  • hormone action
  • steroid hormone receptors
  • endocrine disruptors
  • transcription factors
  • HPG and HPA axes
  • non-classical steroidogenic tissues

Published Papers (19 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

21 pages, 5956 KiB  
Article
Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes
by Casandra Walker, Annie Boisvert, Priyanka Malusare and Martine Culty
Int. J. Mol. Sci. 2023, 24(2), 1211; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021211 - 07 Jan 2023
Cited by 4 | Viewed by 2030
Abstract
Perinatal exposure to endocrine disrupting chemicals (EDCs) has been shown to affect male reproductive functions. However, the effects on male reproduction of exposure to EDC mixtures at doses relevant to humans have not been fully characterized. In previous studies, we found that in [...] Read more.
Perinatal exposure to endocrine disrupting chemicals (EDCs) has been shown to affect male reproductive functions. However, the effects on male reproduction of exposure to EDC mixtures at doses relevant to humans have not been fully characterized. In previous studies, we found that in utero exposure to mixtures of the plasticizer di(2-ethylhexyl) phthalate (DEHP) and the soy-based phytoestrogen genistein (Gen) induced abnormal testis development in rats. In the present study, we investigated the molecular basis of these effects in adult testes from the offspring of pregnant SD rats gavaged with corn oil or Gen + DEHP mixtures at 0.1 or 10 mg/kg/day. Testicular transcriptomes were determined by microarray and RNA-seq analyses. A protein analysis was performed on paraffin and frozen testis sections, mainly by immunofluorescence. The transcription factor forkhead box protein 3 (FOXA3), a key regulator of Leydig cell function, was identified as the most significantly downregulated gene in testes from rats exposed in utero to Gen + DEHP mixtures. FOXA3 protein levels were decreased in testicular interstitium at a dose previously found to reduce testosterone levels, suggesting a primary effect of fetal exposure to Gen + DEHP on adult Leydig cells, rather than on spermatids and Sertoli cells, also expressing FOXA3. Thus, FOXA3 downregulation in adult testes following fetal exposure to Gen + DEHP may contribute to adverse male reproductive outcomes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

12 pages, 10305 KiB  
Article
DHCR24, a Key Enzyme of Cholesterol Synthesis, Serves as a Marker Gene of the Mouse Adrenal Gland Inner Cortex
by Huifei Sophia Zheng, Yuan Kang, Qiongxia Lyu, Kristina Junghans, Courtney Cleary, Olivia Reid, Greer Cauthen, Karly Laprocina and Chen-Che Jeff Huang
Int. J. Mol. Sci. 2023, 24(2), 933; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24020933 - 04 Jan 2023
Cited by 2 | Viewed by 1977
Abstract
Steroid hormones are synthesized through enzymatic reactions using cholesterol as the substrate. In steroidogenic cells, the required cholesterol for steroidogenesis can be obtained from blood circulation or synthesized de novo from acetate. One of the key enzymes that control cholesterol synthesis is 24-dehydrocholesterol [...] Read more.
Steroid hormones are synthesized through enzymatic reactions using cholesterol as the substrate. In steroidogenic cells, the required cholesterol for steroidogenesis can be obtained from blood circulation or synthesized de novo from acetate. One of the key enzymes that control cholesterol synthesis is 24-dehydrocholesterol reductase (encoded by DHCR24). In humans and rats, DHCR24 is highly expressed in the adrenal gland, especially in the zona fasciculata. We recently reported that DHCR24 was expressed in the mouse adrenal gland’s inner cortex and also found that thyroid hormone treatment significantly upregulated the expression of Dhcr24 in the mouse adrenal gland. In the present study, we showed the cellular expression of DHCR24 in mouse adrenal glands in early postnatal stages. We found that the expression pattern of DHCR24 was similar to the X-zone marker gene 20αHSD in most developmental stages. This finding indicates that most steroidogenic adrenocortical cells in the mouse adrenal gland do not synthesize cholesterol locally. Unlike the 20αHSD-positive X-zone regresses during pregnancy, some DHCR24-positive cells remain present in parous females. Conditional knockout mice showed that the removal of Dhcr24 in steroidogenic cells did not affect the overall development of the adrenal gland or the secretion of corticosterone under acute stress. Whether DHCR24 plays a role in conditions where a continuous high amount of corticosterone production is needed requires further investigation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

18 pages, 2411 KiB  
Article
Development of Human Adrenocortical Adenoma (HAA1) Cell Line from Zona Reticularis
by Hans K. Ghayee, Yiling Xu, Heather Hatch, Richard Brockway, Asha S. Multani, Tongjun Gu, Wendy B. Bollag, Adina Turcu, William E. Rainey, Juilee Rege, Kazutaka Nanba, Vikash J. Bhagwandin, Fiemu Nwariaku, Victor Stastny, Adi F. Gazdar, Jerry W. Shay, Richard J. Auchus and Sergei G. Tevosian
Int. J. Mol. Sci. 2023, 24(1), 584; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010584 - 29 Dec 2022
Cited by 1 | Viewed by 1528
Abstract
The human adrenal cortex is composed of distinct zones that are the main source of steroid hormone production. The mechanism of adrenocortical cell differentiation into several functionally organized populations with distinctive identities remains poorly understood. Human adrenal disease has been difficult to study, [...] Read more.
The human adrenal cortex is composed of distinct zones that are the main source of steroid hormone production. The mechanism of adrenocortical cell differentiation into several functionally organized populations with distinctive identities remains poorly understood. Human adrenal disease has been difficult to study, in part due to the absence of cultured cell lines that faithfully represent adrenal cell precursors in the early stages of transformation. Here, Human Adrenocortical Adenoma (HAA1) cell line derived from a patient’s macronodular adrenocortical hyperplasia and was treated with histone deacetylase inhibitors (HDACis) and gene expression was examined. We describe a patient-derived HAA1 cell line derived from the zona reticularis, the innermost zone of the adrenal cortex. The HAA1 cell line is unique in its ability to exit a latent state and respond with steroidogenic gene expression upon treatment with histone deacetylase inhibitors. The gene expression pattern of differentiated HAA1 cells partially recreates the roster of genes in the adrenal layer that they have been derived from. Gene ontology analysis of whole genome RNA-seq corroborated increased expression of steroidogenic genes upon HDAC inhibition. Surprisingly, HDACi treatment induced broad activation of the Tumor Necrosis Factor (TNF) alpha pathway. This novel cell line we developed will hopefully be instrumental in understanding the molecular and biochemical mechanisms controlling adrenocortical differentiation and steroidogenesis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

9 pages, 1566 KiB  
Article
Inclusion of 11-Oxygenated Androgens in a Clinical Routine LC-MS/MS Setup for Steroid Hormone Profiling
by Robert Zeidler, Ronald Biemann, Uta Ceglarek, Jürgen Kratzsch, Berend Isermann and Alexander Gaudl
Int. J. Mol. Sci. 2023, 24(1), 539; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010539 - 29 Dec 2022
Cited by 1 | Viewed by 1827
Abstract
11-Oxygenated androgens (11-OAs) are being discussed as potential biomarkers in diagnosis and therapy control of disorders with androgen excess such as congenital adrenal hyperplasia and polycystic ovary syndrome. However, quantification of 11-OAs by liquid chromatography-tandem mass spectrometry (LC-MS/MS) still relies on extensive sample [...] Read more.
11-Oxygenated androgens (11-OAs) are being discussed as potential biomarkers in diagnosis and therapy control of disorders with androgen excess such as congenital adrenal hyperplasia and polycystic ovary syndrome. However, quantification of 11-OAs by liquid chromatography-tandem mass spectrometry (LC-MS/MS) still relies on extensive sample preparation including liquid–liquid extraction, derivatization and partial long runtimes, which is unsuitable for high-throughput analysis under routine laboratory settings. For the first time, an established online-solid-phase extraction-LC-MS/MS (online-SPE-LC-MS/MS) method for the quantitation of seven serum steroids in daily routine use was extended and validated to include 11-ketoandrostenedione, 11-ketotestosterone, 11β-hydroxyandrostenedione and 11β-hydroxytestosterone. Combining a simple protein precipitation step with fast chromatographic separation and ammonium fluoride-modified ionization resulted in a high-throughput method (6.6 min run time) featuring lower limits of quantification well below endogenous ranges (63–320 pmol/L) with recoveries between 85% and 117% (CVs ≤ 15%). Furthermore, the ability of this method to distinguish between adrenal and gonadal androgens was shown by comparing 11-OAs in patients with hyperandrogenemia to healthy controls. Due to the single shot multiplex design of the method, potential clinically relevant ratios of 11-OAs and corresponding androgens were readily available. The fully validated method covering endogenous concentration levels is ready to investigate the diagnostic values of 11-OAs in prospective studies and clinical applications. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

16 pages, 8454 KiB  
Article
Intronic Enhancer Is Essential for Nr5a1 Expression in the Pituitary Gonadotrope and for Postnatal Development of Male Reproductive Organs in a Mouse Model
by Yuichi Shima, Kanako Miyabayashi, Takami Mori, Koji Ono, Mizuki Kajimoto, Hae Lim Cho, Hitomi Tsuchida, Yoshihisa Uenoyama, Hiroko Tsukamura, Kentaro Suzuki, Man Ho Choi and Kazunori Toida
Int. J. Mol. Sci. 2023, 24(1), 192; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010192 - 22 Dec 2022
Cited by 1 | Viewed by 1762
Abstract
Nuclear receptor subfamily 5 group A member 1 (NR5A1) is expressed in the pituitary gonadotrope and regulates their differentiation. Although several regulatory regions were implicated in Nr5a1 gene expression in the pituitary gland, none of these regions have been verified using mouse models. [...] Read more.
Nuclear receptor subfamily 5 group A member 1 (NR5A1) is expressed in the pituitary gonadotrope and regulates their differentiation. Although several regulatory regions were implicated in Nr5a1 gene expression in the pituitary gland, none of these regions have been verified using mouse models. Furthermore, the molecular functions of NR5A1 in the pituitary gonadotrope have not been fully elucidated. In the present study, we generated mice lacking the pituitary enhancer located in the 6th intron of the Nr5a1 gene. These mice showed pituitary gland-specific disappearance of NR5A1, confirming the functional importance of the enhancer. Enhancer-deleted male mice demonstrated no defects at fetal stages. Meanwhile, androgen production decreased markedly in adult, and postnatal development of reproductive organs, such as the seminal vesicle, prostate, and penis was severely impaired. We further performed transcriptomic analyses of the whole pituitary gland of the enhancer-deleted mice and controls, as well as gonadotropes isolated from Ad4BP-BAC-EGFP mice. These analyses identified several genes showing gonadotrope-specific, NR5A1-dependent expressions, such as Spp1, Tgfbr3l, Grem1, and Nr0b2. These factors are thought to function downstream of NR5A1 and play important roles in reproductive organ development through regulation of pituitary gonadotrope functions. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

13 pages, 3067 KiB  
Article
Lhb−/−Lhr−/− Double Mutant Mice Phenocopy Lhb−/− or Lhr−/− Single Mutants and Display Defects in Leydig Cells and Steroidogenesis
by Zhenghui Liu, Mark Larsen, Zhenmin Lei, C. V. Rao and T. Rajendra Kumar
Int. J. Mol. Sci. 2022, 23(24), 15725; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415725 - 11 Dec 2022
Cited by 2 | Viewed by 1368
Abstract
In the mouse, two distinct populations of Leydig cells arise during testis development. Fetal Leydig cells arise from a stem cell population and produce T required for masculinization. It is debated whether they persist in the adult testis. A second adult Leydig stem [...] Read more.
In the mouse, two distinct populations of Leydig cells arise during testis development. Fetal Leydig cells arise from a stem cell population and produce T required for masculinization. It is debated whether they persist in the adult testis. A second adult Leydig stem cell population gives rise to progenitor-immature-mature adult type Leydig cells that produce T in response to LH to maintain spermatogenesis. In testis of adult null male mice lacking either only LH (Lhb−/−) or LHR (Lhr−/−), mature Leydig cells are absent but fetal Leydig cells persist. Thus, it is not clear whether other ligands signal via LHRs in Lhb null mice or LH signals via other receptors in the absence of LHR in Lhr null mice. Moreover, it is not clear whether truncated LHR isoforms generated from the same Lhr gene promoter encode functionally relevant LH receptors. To determine the in vivo roles of LH-LHR signaling pathway in the Leydig cell lineage, we generated double null mutant mice lacking both LH Ligand and all forms of LHR. Phenotypic analysis indicated testis morpho-histological characteristics are identical among double null and single mutants which all showed poorly developed interstitium with a reduction in Leydig cell number and absence of late stage spermatids. Gene expression analyses confirmed that the majority of the T biosynthesis pathway enzyme-encoding mRNAs expressed in Leydig cells were all suppressed. Expression of thrombospondin-2, a fetal Leydig cell marker gene was upregulated in single and double null mutants indicating that fetal Leydig cells originate and develop independent of LH-LHR signaling pathway in vivo. Serum and intratesticular T levels were similarly suppressed in single and double mutants. Consequently, expression of AR-regulated genes in Sertoli and germ cells were similarly affected in single and double mutants without any evidence of any additive effect in the combined absence of both LH and LHR. Our studies unequivocally provide genetic evidence that in the mouse testis, fetal Leydig cells do not require LH-LHR signaling pathway and a one-to-one LH ligand-LHR signaling pathway exists in vivo to regulate adult Leydig cell lineage and spermatogenesis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

14 pages, 3421 KiB  
Article
Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis
by Hélène Holota, Angélique De Haze, Emmanuelle Martinot, Melusine Monrose, Jean-Paul Saru, Françoise Caira, Claude Beaudoin and David H. Volle
Int. J. Mol. Sci. 2022, 23(23), 15398; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315398 - 06 Dec 2022
Cited by 1 | Viewed by 1359
Abstract
Understanding the regulation of the testicular endocrine function leading to testosterone production is a major objective as the alteration of endocrine function is associated with the development of many diseases such as infertility. In the last decades, it has been demonstrated that several [...] Read more.
Understanding the regulation of the testicular endocrine function leading to testosterone production is a major objective as the alteration of endocrine function is associated with the development of many diseases such as infertility. In the last decades, it has been demonstrated that several endogenous molecules regulate the steroidogenic pathway. Among them, bile acids have recently emerged as local regulators of testicular physiology and particularly endocrine function. Bile acids act through the nuclear receptor FXRα (Farnesoid-X-receptor alpha; NR1H4) and the G-protein-coupled bile acid receptor (GPBAR-1; TGR5). While FXRα has been demonstrated to regulate testosterone synthesis within Leydig cells, no data are available regarding TGR5. Here, we investigated the potential role of TGR5 within Leydig cells using cell culture approaches combined with pharmacological exposure to the TGR5 agonist INT-777. The data show that activation of TGR5 results in a decrease in testosterone levels. TGR5 acts through the PKA pathway to regulate steroidogenesis. In addition, our data show that TGR5 activation leads to an increase in cholesterol ester levels. This suggests that altered lipid homeostasis may be a mechanism explaining the TGR5-induced decrease in testosterone levels. In conclusion, the present work highlights the impact of the TGR5 signaling pathway on testosterone production and reinforces the links between bile acid signaling pathways and the testicular endocrine function. The testicular bile acid pathways need to be further explored to increase our knowledge of pathologies associated with impaired testicular endocrine function, such as fertility disorders. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

17 pages, 4180 KiB  
Article
A 35-bp Conserved Region Is Crucial for Insl3 Promoter Activity in Mouse MA-10 Leydig Cells
by Xavier C. Giner, Kenley Joule Pierre, Nicholas M. Robert and Jacques J. Tremblay
Int. J. Mol. Sci. 2022, 23(23), 15060; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315060 - 01 Dec 2022
Cited by 1 | Viewed by 1665
Abstract
The peptide hormone insulin-like 3 (INSL3) is produced almost exclusively by Leydig cells of the male gonad. INSL3 has several functions such as fetal testis descent and bone metabolism in adults. Insl3 gene expression in Leydig cells is not hormonally regulated but rather [...] Read more.
The peptide hormone insulin-like 3 (INSL3) is produced almost exclusively by Leydig cells of the male gonad. INSL3 has several functions such as fetal testis descent and bone metabolism in adults. Insl3 gene expression in Leydig cells is not hormonally regulated but rather is constitutively expressed. The regulatory region of the Insl3 gene has been described in various species; moreover, functional studies have revealed that the Insl3 promoter is regulated by various transcription factors that include the nuclear receptors AR, NUR77, COUP-TFII, LRH1, and SF1, as well as the Krüppel-like factor KLF6. However, these transcription factors are also found in several tissues that do not express Insl3, indicating that other, yet unidentified factors, must be involved to drive Insl3 expression specifically in Leydig cells. Through a fine functional promoter analysis, we have identified a 35-bp region that is responsible for conferring 70% of the activity of the mouse Insl3 promoter in Leydig cells. All tri- and dinucleotide mutations introduced dramatically reduced Insl3 promoter activity, indicating that the entire 35-bp sequence is required. Nuclear proteins from MA-10 Leydig cells bound specifically to the 35-bp region. The 35-bp sequence contains GC- and GA-rich motifs as well as potential binding elements for members of the CREB, C/EBP, AP1, AP2, and NF-κB families. The Insl3 promoter was indeed activated 2-fold by NF-κB p50 but not by other transcription factors tested. These results help to further define the regulation of Insl3 gene transcription in Leydig cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

18 pages, 2344 KiB  
Article
A Novel Model Using AAV9-Cre to Knockout Adult Leydig Cell Gene Expression Reveals a Physiological Role of Glucocorticoid Receptor Signalling in Leydig Cell Function
by Anne-Louise Gannon, Annalucia L. Darbey, Grace Chensee, Ben M. Lawrence, Liza O’Donnell, Joanna Kelso, Natalie Reed, Shanmathi Parameswaran, Sarah Smith, Lee B. Smith and Diane Rebourcet
Int. J. Mol. Sci. 2022, 23(23), 15015; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315015 - 30 Nov 2022
Cited by 2 | Viewed by 1649
Abstract
Glucocorticoids are steroids involved in key physiological processes such as development, metabolism, inflammatory and stress responses and are mostly used exogenously as medications to treat various inflammation-based conditions. They act via the glucocorticoid receptor (GR) expressed in most cells. Exogenous glucocorticoids can negatively [...] Read more.
Glucocorticoids are steroids involved in key physiological processes such as development, metabolism, inflammatory and stress responses and are mostly used exogenously as medications to treat various inflammation-based conditions. They act via the glucocorticoid receptor (GR) expressed in most cells. Exogenous glucocorticoids can negatively impact the function of the Leydig cells in the testis, leading to decreased androgen production. However, endogenous glucocorticoids are produced by the adrenal and within the testis, but whether their action on GR in Leydig cells regulates steroidogenesis is unknown. This study aimed to define the role of endogenous GR signalling in adult Leydig cells. We developed and compared two models; an inducible Cre transgene driven by expression of the Cyp17a1 steroidogenic gene (Cyp17-iCre) that depletes GR during development and a viral vector-driven Cre (AAV9-Cre) to deplete GR in adulthood. The delivery of AAV9-Cre ablated GR in adult mouse Leydig cells depleted Leydig cell GR more efficiently than the Cyp17-iCre model. Importantly, adult depletion of GR in Leydig cells caused reduced expression of luteinising hormone receptor (Lhcgr) and of steroidogenic enzymes required for normal androgen production. These findings reveal that Leydig cell GR signalling plays a physiological role in the testis and highlight that a normal balance of glucocorticoid activity in the testis is important for steroidogenesis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

15 pages, 2718 KiB  
Article
FSH Regulates YAP-TEAD Transcriptional Activity in Bovine Granulosa Cells to Allow the Future Dominant Follicle to Exert Its Augmented Estrogenic Capacity
by Leonardo Guedes de Andrade, Valério Marques Portela, Esdras Corrêa Dos Santos, Karine de Vargas Aires, Rogério Ferreira, Daniele Missio, Zigomar da Silva, Júlia Koch, Alfredo Quites Antoniazzi, Paulo Bayard Dias Gonçalves and Gustavo Zamberlam
Int. J. Mol. Sci. 2022, 23(22), 14160; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214160 - 16 Nov 2022
Cited by 1 | Viewed by 1520
Abstract
The molecular mechanisms that drive the granulosa cells’ (GC) differentiation into a more estrogenic phenotype during follicular divergence and establishment of follicle dominance have not been completely elucidated. The main Hippo signaling effector, YAP, has, however, emerged as a potential key player to [...] Read more.
The molecular mechanisms that drive the granulosa cells’ (GC) differentiation into a more estrogenic phenotype during follicular divergence and establishment of follicle dominance have not been completely elucidated. The main Hippo signaling effector, YAP, has, however, emerged as a potential key player to explain such complex processes. Studies using rat and bovine GC demonstrate that, in conditions where the expression of the classic YAP-TEAD target gene tissue growth factor (CTGF) is augmented, CYP19A1 expression and activity and, consequently, estradiol (E2) secretion are reduced. These findings led us to hypothesize that, during ovarian follicular divergence in cattle, FSH downregulates YAP-TEAD-dependent transcriptional activity in GC to allow the future dominant follicle to exert its augmented estrogenic capacity. To address this, we performed a series of experiments employing distinct bovine models. Our in vitro and ex vivo experiments indicated that indeed FSH downregulates, in a concentration-dependent manner, mRNA levels not only for CTGF but also for the other classic YAP-TEAD transcriptional target genes ANKRD1 and CYR61 by a mechanism that involves increased YAP phosphorylation. To better elucidate the functional importance of such FSH-induced YAP activity regulation, we then cultured GC in the presence of verteporfin (VP) or peptide 17 (P17), two pharmacological inhibitors known to interfere with YAP binding to TEADs. The results showed that both VP and P17 increased CYP19A1 basal mRNA levels in a concentration-dependent manner. Most interestingly, by using GC samples obtained in vivo from dominant vs. subordinate follicles, we found that mRNA levels for CTGF, CYR61, and ANKRD1 are higher in subordinate follicles following the follicular divergence. Taken together, our novel results demonstrate that YAP transcriptional activity is regulated in bovine granulosa cells to allow the increased estrogenic capacity of the selected dominant follicle. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

19 pages, 4232 KiB  
Article
Targeted Disruption of Lats1 and Lats2 in Mice Impairs Testis Development and Alters Somatic Cell Fate
by Nour Abou Nader, Amélie Ménard, Adrien Levasseur, Guillaume St-Jean, Derek Boerboom, Gustavo Zamberlam and Alexandre Boyer
Int. J. Mol. Sci. 2022, 23(21), 13585; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113585 - 05 Nov 2022
Viewed by 1713
Abstract
Hippo signaling plays an essential role in the development of numerous tissues. Although it was previously shown that the transcriptional effectors of Hippo signaling Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) can fine-tune the regulation of sex differentiation genes in [...] Read more.
Hippo signaling plays an essential role in the development of numerous tissues. Although it was previously shown that the transcriptional effectors of Hippo signaling Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) can fine-tune the regulation of sex differentiation genes in the testes, the role of Hippo signaling in testis development remains largely unknown. To further explore the role of Hippo signaling in the testes, we conditionally deleted the key Hippo kinases large tumor suppressor homolog kinases 1 and -2 (Lats1 and Lats2, two kinases that antagonize YAP and TAZ transcriptional co-regulatory activity) in the somatic cells of the testes using an Nr5a1-cre strain (Lats1flox/flox;Lats2flox/flox;Nr5a1-cre). We report here that early stages of testis somatic cell differentiation were not affected in this model but progressive testis cord dysgenesis was observed starting at gestational day e14.5. Testis cord dysgenesis was further associated with the loss of polarity of the Sertoli cells and the loss of SOX9 expression but not WT1. In parallel with testis cord dysgenesis, a loss of steroidogenic gene expression associated with the appearance of myofibroblast-like cells in the interstitial space was also observed in mutant animals. Furthermore, the loss of YAP phosphorylation, the accumulation of nuclear TAZ (and YAP) in both the Sertoli and interstitial cell populations, and an increase in their transcriptional co-regulatory activity in the testes suggest that the observed phenotype could be attributed at least in part to YAP and TAZ. Taken together, our results suggest that Hippo signaling is required to maintain proper differentiation of testis somatic cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Graphical abstract

16 pages, 2877 KiB  
Article
Differential Response of Transcription Factors to Activated Kinases in Steroidogenic and Non-Steroidogenic Cells
by Kenley Joule Pierre and Jacques J. Tremblay
Int. J. Mol. Sci. 2022, 23(21), 13153; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113153 - 29 Oct 2022
Cited by 3 | Viewed by 1363
Abstract
Hormone-induced Leydig cell steroidogenesis requires rapid changes in gene expression in response to various hormones, cytokines, and growth factors. These proteins act by binding to their receptors on the surface of Leydig cells leading to activation of multiple intracellular signaling cascades, downstream of [...] Read more.
Hormone-induced Leydig cell steroidogenesis requires rapid changes in gene expression in response to various hormones, cytokines, and growth factors. These proteins act by binding to their receptors on the surface of Leydig cells leading to activation of multiple intracellular signaling cascades, downstream of which are several kinases, including protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase I (CAMKI), and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). These kinases participate in hormone-induced steroidogenesis by phosphorylating numerous proteins including transcription factors leading to increased steroidogenic gene expression. How these various kinases and transcription factors come together to appropriately induce steroidogenic gene expression in response to specific stimuli remains poorly understood. In the present work, we compared the effect of PKA, CAMKI and ERK1/2 on the transactivation potential of 15 transcription factors belonging to 5 distinct families on the activity of the Star gene promoter. We not only validated known cooperation between kinases and transcription factors, but we also identified novel cooperations that have not yet been before reported. Some transcription factors were found to respond to all three kinases, whereas others were only activated by one specific kinase. Differential responses were also observed within a family of transcription factors. The diverse response to kinases provides flexibility to ensure proper genomic response of steroidogenic cells to different stimuli. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

26 pages, 2830 KiB  
Article
Comprehensive and Quantitative Analysis of the Changes in Proteomic and Phosphoproteomic Profiles during Stimulation and Repression of Steroidogenesis in MA-10 Leydig Cells
by Zoheir B. Demmouche and Jacques J. Tremblay
Int. J. Mol. Sci. 2022, 23(21), 12846; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112846 - 25 Oct 2022
Viewed by 1378
Abstract
Leydig cells produce testosterone, a hormone essential for male sex differentiation and spermatogenesis. The pituitary hormone, LH, stimulates testosterone production in Leydig cells by increasing the intracellular cAMP levels, which leads to the activation of various kinases and transcription factors, ultimately stimulating the [...] Read more.
Leydig cells produce testosterone, a hormone essential for male sex differentiation and spermatogenesis. The pituitary hormone, LH, stimulates testosterone production in Leydig cells by increasing the intracellular cAMP levels, which leads to the activation of various kinases and transcription factors, ultimately stimulating the expression of the genes involved in steroidogenesis. The second messenger, cAMP, is subsequently degraded to AMP, and the increase in the intracellular AMP levels activates AMP-dependent protein kinase (AMPK). Activated AMPK potently represses steroidogenesis. Despite the key roles played by the various stimulatory and inhibitory kinases, the proteins phosphorylated by these kinases during steroidogenesis remain poorly characterized. In the present study, we have used a quantitative LC-MS/MS approach, using total and phosphopeptide-enriched proteins to identify the global changes that occur in the proteome and phosphoproteome of MA-10 Leydig cells during both the stimulatory phase (Fsk/cAMP treatment) and inhibitory phase (AICAR-mediated activation of AMPK) of steroidogenesis. The phosphorylation levels of several proteins, including some never before described in Leydig cells, were significantly altered during the stimulation and inhibition of steroidogenesis. Our data also provide new key insights into the finely tuned and dynamic processes that ensure adequate steroid hormone production. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

14 pages, 7955 KiB  
Article
MnHR4 Functions during Molting of Macrobrachium nipponense by Regulating 20E Synthesis and Mediating 20E Signaling
by Huwei Yuan, Wenyi Zhang, Hui Qiao, Shubo Jin, Sufei Jiang, Yiwei Xiong, Yongsheng Gong and Hongtuo Fu
Int. J. Mol. Sci. 2022, 23(20), 12528; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012528 - 19 Oct 2022
Cited by 2 | Viewed by 1280
Abstract
HR4, a member of the nuclear receptor family, has been extensively studied in insect molting and development, but reports on crustaceans are still lacking. In the current study, the MnHR4 gene was identified in Macrobrachium nipponense. To further improve the molting [...] Read more.
HR4, a member of the nuclear receptor family, has been extensively studied in insect molting and development, but reports on crustaceans are still lacking. In the current study, the MnHR4 gene was identified in Macrobrachium nipponense. To further improve the molting molecular mechanism of M. nipponense, this study investigated whether MnHR4 functions during the molting process of M. nipponense. The domain, phylogenetic relationship and 3D structure of MnHR4 were analyzed by bioinformatics. Quantitative real-time PCR (qRT-PCR) analysis showed that MnHR4 was highly expressed in the ovary. In different embryo stages, the highest mRNA expression was observed in the cleavage stage (CS). At different individual stages, the mRNA expression of MnHR4 reached its peak on the fifteenth day after hatching (L15). The in vivo injection of 20-hydroxyecdysone (20E) can effectively promote the expression of the MnHR4 gene, and the silencing of the MnHR4 gene increased the content of 20E in M. nipponense. The regulatory role of MnHR4 in 20E synthesis and 20E signaling was further investigated by RNAi. Finally, the function of the MnHR4 gene in the molting process of M. nipponense was studied by counting the molting frequency. After knocking down MnHR4, the molting frequency of M. nipponense decreased significantly. It was proved that MnHR4 plays a pivotal role in the molting process of M. nipponense. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

16 pages, 8651 KiB  
Article
A Short Promoter Region Containing Conserved Regulatory Motifs Is Required for Steroidogenic Acute Regulatory Protein (Star) Gene Expression in the Mouse Testis
by Marie France Bouchard, Julia Picard, Jacques J. Tremblay and Robert S. Viger
Int. J. Mol. Sci. 2022, 23(19), 12009; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231912009 - 09 Oct 2022
Viewed by 1884
Abstract
In the testis, Leydig cells produce steroid hormones that are needed to masculinize typical genetic males during fetal development and to initiate and maintain spermatogenesis at puberty and adulthood, respectively. Steroidogenesis is initiated by the transfer of cholesterol from the outer to the [...] Read more.
In the testis, Leydig cells produce steroid hormones that are needed to masculinize typical genetic males during fetal development and to initiate and maintain spermatogenesis at puberty and adulthood, respectively. Steroidogenesis is initiated by the transfer of cholesterol from the outer to the inner mitochondrial membrane through the action of steroidogenic acute regulatory protein (STAR). Given its importance for the steroidogenic process, the regulation of STAR gene expression has been the subject of numerous studies. These studies have involved the characterization of key promoter sequences through the identification of relevant transcription factors and the nucleotide motifs (regulatory elements) that they bind. This work has traditionally relied on in vitro studies carried out in cell cultures along with reconstructed promoter sequences. While this approach has been useful for developing models of how a gene might be transcriptionally regulated, one must ultimately validate that these modes of regulation occur in an endogenous context. We have used CRISPR/Cas9 genome editing to modify a short region of the mouse Star promoter (containing a subset of regulatory elements, including conserved CRE, C/EBP, AP1, and GATA motifs) that has been proposed to be critical for Star transcription. Analysis of the resultant mutant mice showed that this short promoter region is indeed required for maximal STAR mRNA and protein levels in the testis. Analysis also showed that both basal and hormone-activated testosterone production in mature mice was unaffected despite significant changes in Star expression. Our results therefore provide the first in vivo validation of regulatory sequences required for Star gene expression. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

Review

Jump to: Research

19 pages, 1135 KiB  
Review
Germline Mutations in Steroid Metabolizing Enzymes: A Focus on Steroid Transforming Aldo-Keto Reductases
by Andrea J. Detlefsen, Ryan D. Paulukinas and Trevor M. Penning
Int. J. Mol. Sci. 2023, 24(3), 1873; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031873 - 18 Jan 2023
Cited by 3 | Viewed by 1928
Abstract
Steroid hormones synchronize a variety of functions throughout all stages of life. Importantly, steroid hormone-transforming enzymes are ultimately responsible for the regulation of these potent signaling molecules. Germline mutations that cause dysfunction in these enzymes cause a variety of endocrine disorders. Mutations in [...] Read more.
Steroid hormones synchronize a variety of functions throughout all stages of life. Importantly, steroid hormone-transforming enzymes are ultimately responsible for the regulation of these potent signaling molecules. Germline mutations that cause dysfunction in these enzymes cause a variety of endocrine disorders. Mutations in SRD5A2, HSD17B3, and HSD3B2 genes that lead to disordered sexual development, salt wasting, and other severe disorders provide a glimpse of the impacts of mutations in steroid hormone transforming enzymes. In a departure from these established examples, this review examines disease-associated germline coding mutations in steroid-transforming members of the human aldo-keto reductase (AKR) superfamily. We consider two main categories of missense mutations: those resulting from nonsynonymous single nucleotide polymorphisms (nsSNPs) and cases resulting from familial inherited base pair substitutions. We found mutations in human AKR1C genes that disrupt androgen metabolism, which can affect male sexual development and exacerbate prostate cancer and polycystic ovary syndrome (PCOS). Others may be disease causal in the AKR1D1 gene that is responsible for bile acid deficiency. However, given the extensive roles of AKRs in steroid metabolism, we predict that with expanding publicly available data and analysis tools, there is still much to be uncovered regarding germline AKR mutations in disease. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

37 pages, 19021 KiB  
Review
Transgenic Mouse Models to Study the Development and Maintenance of the Adrenal Cortex
by Nour Abou Nader, Gustavo Zamberlam and Alexandre Boyer
Int. J. Mol. Sci. 2022, 23(22), 14388; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214388 - 19 Nov 2022
Cited by 4 | Viewed by 2600
Abstract
The cortex of the adrenal gland is organized into concentric zones that produce distinct steroid hormones essential for body homeostasis in mammals. Mechanisms leading to the development, zonation and maintenance of the adrenal cortex are complex and have been studied since the 1800s. [...] Read more.
The cortex of the adrenal gland is organized into concentric zones that produce distinct steroid hormones essential for body homeostasis in mammals. Mechanisms leading to the development, zonation and maintenance of the adrenal cortex are complex and have been studied since the 1800s. However, the advent of genetic manipulation and transgenic mouse models over the past 30 years has revolutionized our understanding of these mechanisms. This review lists and details the distinct Cre recombinase mouse strains available to study the adrenal cortex, and the remarkable progress total and conditional knockout mouse models have enabled us to make in our understanding of the molecular mechanisms regulating the development and maintenance of the adrenal cortex. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

26 pages, 2063 KiB  
Review
Basic Leucine Zipper Transcription Factors as Important Regulators of Leydig Cells’ Functions
by Luc J. Martin and Ha Tuyen Nguyen
Int. J. Mol. Sci. 2022, 23(21), 12887; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112887 - 25 Oct 2022
Cited by 5 | Viewed by 2008
Abstract
Transcription factors members of the basic leucine zipper (bZIP) class play important roles in the regulation of genes and functions in testicular Leydig cells. Many of these factors, such as cAMP responsive element binding protein 1 (CREB1) and CCAAT enhancer binding protein beta [...] Read more.
Transcription factors members of the basic leucine zipper (bZIP) class play important roles in the regulation of genes and functions in testicular Leydig cells. Many of these factors, such as cAMP responsive element binding protein 1 (CREB1) and CCAAT enhancer binding protein beta (CEBPB), are regulated by the cAMP/protein kinase A (PKA) pathway, the main signaling pathway activated following the activation of the luteinizing hormone/choriogonadotropin membrane receptor LHCGR by the - hormone LH. Others, such as X-box binding protein 1 (XBP1) and members of the cAMP responsive element binding protein 3 (CREB3)-like superfamily, are implicated in the endoplasmic reticulum stress by regulating the unfolded protein response. In this review, the influences of bZIP transcription factors, including CREB1, CEBPB and activator protein 1 (AP-1) family members, on the regulation of genes important for cell proliferation, steroidogenesis and Leydig cell communication will be covered. In addition, unresolved questions regarding the mechanisms of actions of bZIP members in gene regulation will be identified. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

14 pages, 1769 KiB  
Review
Role of STAR and SCP2/SCPx in the Transport of Cholesterol and Other Lipids
by Melanie Galano, Sathvika Venugopal and Vassilios Papadopoulos
Int. J. Mol. Sci. 2022, 23(20), 12115; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012115 - 11 Oct 2022
Cited by 8 | Viewed by 2413
Abstract
Cholesterol is a lipid molecule essential for several key cellular processes including steroidogenesis. As such, the trafficking and distribution of cholesterol is tightly regulated by various pathways that include vesicular and non-vesicular mechanisms. One non-vesicular mechanism is the binding of cholesterol to cholesterol [...] Read more.
Cholesterol is a lipid molecule essential for several key cellular processes including steroidogenesis. As such, the trafficking and distribution of cholesterol is tightly regulated by various pathways that include vesicular and non-vesicular mechanisms. One non-vesicular mechanism is the binding of cholesterol to cholesterol transport proteins, which facilitate the movement of cholesterol between cellular membranes. Classic examples of cholesterol transport proteins are the steroidogenic acute regulatory protein (STAR; STARD1), which facilitates cholesterol transport for acute steroidogenesis in mitochondria, and sterol carrier protein 2/sterol carrier protein-x (SCP2/SCPx), which are non-specific lipid transfer proteins involved in the transport and metabolism of many lipids including cholesterol between several cellular compartments. This review discusses the roles of STAR and SCP2/SCPx in cholesterol transport as model cholesterol transport proteins, as well as more recent findings that support the role of these proteins in the transport and/or metabolism of other lipids. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Biosynthesis and Action)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-19
Back to TopTop