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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| Format: | Article |
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/15398 |
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| author | Hélène Holota Angélique De Haze Emmanuelle Martinot Melusine Monrose Jean-Paul Saru Françoise Caira Claude Beaudoin David H. Volle |
| author_facet | Hélène Holota Angélique De Haze Emmanuelle Martinot Melusine Monrose Jean-Paul Saru Françoise Caira Claude Beaudoin David H. Volle |
| author_sort | Hélène Holota |
| collection | DOAJ |
| 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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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:44:14Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1e531b1e3e8f47bb9ef66989138646f22023-11-24T11:18:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123231539810.3390/ijms232315398Identification of the Role of TGR5 in the Regulation of Leydig Cell HomeostasisHélène Holota0Angélique De Haze1Emmanuelle Martinot2Melusine Monrose3Jean-Paul Saru4Françoise Caira5Claude Beaudoin6David H. Volle7INSERM U1103, CNRS UMR-6293, Université Clermont Auvergne, GReD Institute, Team-Volle, F-63001 Clermont-Ferrand, FranceINSERM U1103, CNRS UMR-6293, Université Clermont Auvergne, GReD Institute, Team-Volle, F-63001 Clermont-Ferrand, FranceINSERM U1103, CNRS UMR-6293, Université Clermont Auvergne, GReD Institute, Team-Volle, F-63001 Clermont-Ferrand, FranceINSERM U1103, CNRS UMR-6293, Université Clermont Auvergne, GReD Institute, Team-Volle, F-63001 Clermont-Ferrand, FranceINSERM U1103, CNRS UMR-6293, Université Clermont Auvergne, GReD Institute, Team-Volle, F-63001 Clermont-Ferrand, FranceINSERM U1103, CNRS UMR-6293, Université Clermont Auvergne, GReD Institute, Team-Volle, F-63001 Clermont-Ferrand, FranceINSERM U1103, CNRS UMR-6293, Université Clermont Auvergne, GReD Institute, Team-Volle, F-63001 Clermont-Ferrand, FranceINSERM U1103, CNRS UMR-6293, Université Clermont Auvergne, GReD Institute, Team-Volle, F-63001 Clermont-Ferrand, FranceUnderstanding 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.https://www.mdpi.com/1422-0067/23/23/15398bile acidsTGR5testosteronecholesterol esters |
| spellingShingle | Hélène Holota Angélique De Haze Emmanuelle Martinot Melusine Monrose Jean-Paul Saru Françoise Caira Claude Beaudoin David H. Volle Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis International Journal of Molecular Sciences bile acids TGR5 testosterone cholesterol esters |
| 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 | bile acids TGR5 testosterone cholesterol esters |
| url | https://www.mdpi.com/1422-0067/23/23/15398 |
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