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

Int J Mol Sci. 2022 Dec 6;23(23):15398. doi: 10.3390/ijms232315398.


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.

Keywords: TGR5; bile acids; cholesterol esters; testosterone.

MeSH terms

  • Bile Acids and Salts*
  • Homeostasis
  • Humans
  • Leydig Cells* / metabolism
  • Male
  • Receptors, G-Protein-Coupled / metabolism
  • Testosterone


  • Bile Acids and Salts
  • Receptors, G-Protein-Coupled
  • Testosterone

Grants and funding

The study was funded by Inserm; CNRS; Université Clermont Auvergne; Ligue contre le cancer (comité Puy de Dôme). Laura Thirouard and Manon Garcia received support from the Fondation Recherche Médicale (FDT202001010780 and R17089CC). Volle’s team received support by the Cancer-Inserm (C20010CS) and the French government IDEX-ISITE initiative 16-IDEX-0001 (CAP 20-25).