Bile acid-FXRα pathways regulate male sexual maturation in mice

Oncotarget. 2016 Apr 12;7(15):19468-82. doi: 10.18632/oncotarget.7153.


The bile acid receptor Farnesol-X-Receptor alpha (FRXα) is a member of the nuclear receptor superfamily. FRXα is expressed in the interstitial compartment of the adult testes, which contain the Leydig cells. In adult, short term treatment (12 hours) with FRXα agonist inhibits the expression of steroidogenic genes via the induction of the Small heterodimer partner (SHP). However the consequences of FRXα activation on testicular pathophysiology have never been evaluated. We demonstrate here that mice fed a diet supplemented with bile acid during pubertal age show increased incidence of infertility. This is associated with altered differentiation and increase apoptosis of germ cells due to lower testosterone levels. At the molecular level, next to the repression of basal steroidogenesis via the induction expression of Shp and Dax-1, two repressors of steroidogenesis, the main action of the BA-FRXα signaling is through lowering the Leydig cell sensitivity to the hypothalamo-pituitary axis, the main regulator of testicular endocrine function. In conclusion, BA-FRXα signaling is a critical actor during sexual maturation.

Keywords: bile acid; germ cell apoptosis; hypothalamo-pituitary axis; nuclear receptors; testicular steroidogenesis.

MeSH terms

  • Animals
  • Bile Acids and Salts / administration & dosage
  • Bile Acids and Salts / pharmacology*
  • Cell Line
  • Cholic Acid / administration & dosage
  • Cholic Acid / pharmacology
  • Fertility / drug effects
  • Isoxazoles / pharmacology
  • Leydig Cells / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • RNA Interference
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Sexual Maturation / drug effects*
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Testis / cytology
  • Testis / metabolism
  • Testosterone / metabolism


  • Bile Acids and Salts
  • Isoxazoles
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • Testosterone
  • Cholic Acid
  • GW 4064