Bile acid homeostasis controls CAR signaling pathways in mouse testis through FXRalpha.
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.
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
Emmanuelle
E
Martinot
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
Marine
M
Baptissart
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
Aurélie
A
Véga
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
Lauriane
L
Sèdes
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
Betty
B
Rouaisnel
Academic Medical Center, University of Amsterdam, Lab. Genetic Metabolic Diseases, F0-224, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.
Fred
F
Vaz
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
Jean-Paul
JP
Saru
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
Angélique
A
de Haze
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
Silvère
S
Baron
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
Françoise
F
Caira
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
Claude
C
Beaudoin
INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France.|Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France.|CNRS, UMR 6293, GReD, F-63170 Aubière, France.|Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
David H
DH
Volle
D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000235:genetics*; D000090702:Constitutive Androstane Receptor; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012098:Reproduction / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013094:Spermatozoa / Q000378:metabolism; D013737:Testis / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D000732:Androstanols; D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C000658:androstan-3-ol; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene