Endocrine Abstracts

Background: Bile acids (BAs) are end-products of cholesterol catabolism, which act as signalling molecules to regulate glucose, lipid and energy metabolism. BAs activate several receptors including the ligand sensitive transcription factor Farnesoid X receptor (FXR) and the membrane G-protein coupled receptor, TGR5. Besides the organs physiologically in contact with BAs, like the gut and liver, BA-receptors are also expressed in cholesterol-rich steroidogenic tissues, such as the testes, ovaries and adrenal glands where they regulate steroidogenesis and affect fertility. Currently there is no definitive evidence that BAs exist as potential endogenous ligands in these tissues. Here we undertake a comparative analysis of BA-receptors, transporters and enzymes with ratios of BA species all necessary for functional BA pathways in steroidogenic tissues.

Methods: Steroidogenic tissues (testicular, ovarian and adrenal) and liver (control) from 12-week-old C57BL/6 mice were used to study BAs in parallel with gene expression studies. Untargeted ultra-performance liquid chromatography tandem mass-spectrometry (UPLC/MS) characterised the ratios of key BA species. Relative expression of BA-activated receptors, transporters and enzymes was assessed using quantitative RT-PCR (RT-qPCR).

Results: UPLC/MS demonstrated the presence of physiologically relevant concentrations of BA species in testes, ovaries and adrenal glands. Taurocholic (TCA) and cholic acid (CA) were found in all steroidogenic tissues. Interestingly, Deoxycholic acid (DCA), which can be cytotoxic, was found in reproductive tissues. RT-qPCR confirmed Fxr expression, which can be activated by CA and DCA to a lesser degree and Tgr5 which is activated by conjugated BAs. Furthermore, BA transporters (Mrp3, Mrp4, Bsep) and enzymes, including the rate-limiting enzyme of BA synthesis Cyp7a1, were expressed.

Conclusion: Here we systematically compare BAs in steroidogenic tissues and confirm expression of BA sensors and homeostasis genes, indicating that BAs may act as ligands in these tissues. Functional activation of BA pathways in steroidogenic tissue is the subject of future work.