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Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis

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 endoge...

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Autores principales: Holota, Hélène, De Haze, Angélique, Martinot, Emmanuelle, Monrose, Melusine, Saru, Jean-Paul, Caira, Françoise, Beaudoin, Claude, Volle, David H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9738292/
https://www.ncbi.nlm.nih.gov/pubmed/36499726
http://dx.doi.org/10.3390/ijms232315398
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author Holota, Hélène
De Haze, Angélique
Martinot, Emmanuelle
Monrose, Melusine
Saru, Jean-Paul
Caira, Françoise
Beaudoin, Claude
Volle, David H.
author_facet Holota, Hélène
De Haze, Angélique
Martinot, Emmanuelle
Monrose, Melusine
Saru, Jean-Paul
Caira, Françoise
Beaudoin, Claude
Volle, David H.
author_sort Holota, Hélène
collection PubMed
description 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.
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spelling pubmed-97382922022-12-11 Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis Holota, Hélène De Haze, Angélique Martinot, Emmanuelle Monrose, Melusine Saru, Jean-Paul Caira, Françoise Beaudoin, Claude Volle, David H. Int J Mol Sci Article 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. MDPI 2022-12-06 /pmc/articles/PMC9738292/ /pubmed/36499726 http://dx.doi.org/10.3390/ijms232315398 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Holota, Hélène
De Haze, Angélique
Martinot, Emmanuelle
Monrose, Melusine
Saru, Jean-Paul
Caira, Françoise
Beaudoin, Claude
Volle, David H.
Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis
title Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis
title_full Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis
title_fullStr Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis
title_full_unstemmed Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis
title_short Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis
title_sort identification of the role of tgr5 in the regulation of leydig cell homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9738292/
https://www.ncbi.nlm.nih.gov/pubmed/36499726
http://dx.doi.org/10.3390/ijms232315398
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