Potential conflict of interest: Nothing to report.
Bile acids alter male fertility through G-protein-coupled bile acid receptor 1 signaling pathways in mice
Article first published online: 25 AUG 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 60, Issue 3, pages 1054–1065, September 2014
How to Cite
Baptissart, M., Vega, A., Martinot, E., Pommier, A. J., Houten, S. M., Marceau, G., Haze, A. d., Baron, S., Schoonjans, K., Lobaccaro, J.-M. A. and Volle, D. H. (2014), Bile acids alter male fertility through G-protein-coupled bile acid receptor 1 signaling pathways in mice. Hepatology, 60: 1054–1065. doi: 10.1002/hep.27204
This work was funded by Inserm, CNRS, Clermont Université, Ministère de l'Enseignement Supérieur et de la Recherche (to M.B.), the Swiss National Science Foundation (to K.S.), Ligue contre le Cancer (Comité Puy de Dôme, to D.H.V.), Nouveau Chercheur Auvergne (to S.B. and no. R12087CC, to D.H.V.), and ANR Jeune Chercheur (no. 1103, to D.H.V.).
- Issue published online: 25 AUG 2014
- Article first published online: 25 AUG 2014
- Accepted manuscript online: 3 MAY 2014 10:35AM EST
- Manuscript Accepted: 1 MAY 2014
- Manuscript Received: 14 NOV 2013
Bile acids (BAs) are signaling molecules that are involved in many physiological functions, such as glucose and energy metabolism. These effects are mediated through activation of the nuclear and membrane receptors, farnesoid X receptor (FXR-α) and TGR5 (G-protein-coupled bile acid receptor 1; GPBAR1). Although both receptors are expressed within the testes, the potential effect of BAs on testis physiology and male fertility has not been explored thus far. Here, we demonstrate that mice fed a diet supplemented with cholic acid have reduced fertility subsequent to testicular defects. Initially, germ cell sloughing and rupture of the blood-testis barrier occur and are correlated with decreased protein accumulation of connexin-43 (Cx43) and N-cadherin, whereas at later stages, apoptosis of spermatids is observed. These abnormalities are associated with increased intratesticular BA levels in general and deoxycholic acid, a TGR5 agonist, in particular. We demonstrate here that Tgr5 is expressed within the germ cell lineage, where it represses Cx43 expression through regulation of the transcriptional repressor, T-box transcription factor 2 gene. Consistent with this finding, mice deficient for Tgr5 are protected against the deleterious testicular effects of BA exposure. Conclusions: These data identify the testis as a new target of BAs and emphasize TGR5 as a critical element in testicular pathophysiology. This work may open new perspectives on the potential effect of BAs on testis physiology during liver dysfunction. (Hepatology 2014;60:1054-1065)