Bile acids alter male fertility through G-protein-coupled bile acid receptor 1 signaling pathways in mice

Hepatology. 2014 Sep;60(3):1054-65. doi: 10.1002/hep.27204.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholic Acid / administration & dosage
  • Cholic Acid / metabolism*
  • Fertility*
  • Infertility, Male / metabolism*
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Spermatozoa / drug effects
  • Testis / drug effects*
  • Testosterone / blood


  • Gpbar1 protein, mouse
  • Receptors, G-Protein-Coupled
  • Testosterone
  • Insulin-Like Growth Factor I
  • Cholic Acid