INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.
Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.
Sci Rep. 2017 Feb 9;7:42182. doi: 10.1038/srep42182.
Bile acids (BAs) are molecules with endocrine activities controlling several physiological functions such as immunity, glucose homeostasis, testicular physiology and male fertility. The role of the nuclear BA receptor FXRα in the control of BA homeostasis has been well characterized. The present study shows that testis synthetize BAs. We demonstrate that mice invalidated for the gene encoding FXRα have altered BA homeostasis in both liver and testis. In the absence of FXRα, BA exposure differently alters hepatic and testicular expression of genes involved in BA synthesis. Interestingly, Fxrα-/- males fed a diet supplemented with BAs show alterations of testicular physiology and sperm production. This phenotype was correlated with the altered testicular BA homeostasis and the production of intermediate metabolites of BAs which led to the modulation of CAR signaling pathways within the testis. The role of the CAR signaling pathways within testis was validated using specific CAR agonist (TCPOBOP) and inverse agonist (androstanol) that respectively inhibited or reproduced the phenotype observed in Fxrα-/- males fed BA-diet. These data open interesting perspectives to better define how BA homeostasis contributes to physiological or pathophysiological conditions via the modulation of CAR activity.
胆汁酸（BAs）是具有内分泌活性的分子，可控制多种生理功能，如免疫、葡萄糖稳态、睾丸生理学和男性生育力。核 BA 受体 FXRα 在控制 BA 稳态中的作用已得到很好的描述。本研究表明睾丸合成 BAs。我们证明，编码 FXRα 的基因缺失的小鼠的肝脏和睾丸中的 BA 稳态发生改变。在缺乏 FXRα 的情况下，BA 暴露会以不同的方式改变肝脏和睾丸中参与 BA 合成的基因的表达。有趣的是，用 BAs 补充饮食喂养的 Fxrα-/- 雄性小鼠表现出睾丸生理学和精子生成的改变。这种表型与睾丸 BA 稳态的改变以及 BA 中间代谢产物的产生相关，这导致了睾丸内 CAR 信号通路的调节。使用特定的 CAR 激动剂（TCPOBOP）和反向激动剂（androstanol）验证了 CAR 信号通路在睾丸中的作用，它们分别抑制或再现了用 BA 饮食喂养的 Fxrα-/- 雄性中观察到的表型。这些数据为更好地定义 BA 稳态如何通过调节 CAR 活性来促进生理或病理生理状况提供了有趣的前景。
