Bile Acid Receptors Investigations – BARI

Bile acids are increasingly being appreciated as complex metabolic integrators and signaling factors rather than lipid solubilizers and simple regulators of bile-acid homeostasis only. It is therefore not surprising that a number of bile-acid-activated signaling pathways have become attractive therapeutic targets for metabolic disorders. Among all the consequences of Metabolic Syndrome, male reproductive dysfunctions have often been observed in patients. It seems thus of highly interest to analyze the potential consequences of long term treatment with bile acids (BAs). Besides, many experiments have suggested the putative impact of BAs on testicular physiology. Indeed, it has been published that bile duct ligation, increasing plasma level of BAs in rat and chicken, induced a decrease in testosterone concentration and a decrease in testicular weight, probably associated with a loss of germ cells. Even if these results clearly suggest the deleterious effects of BAs on testicular physiology in pathological conditions such as cholestasis, molecular mechanisms remained unknown so far. Moreover, both receptors for BAs, FXRa and TGR5, are expressed in the testis. Based on these data, our research project is focused on the study of the direct impact of BAs on testicular functions. Several approaches will be used: transgenic mice models for these receptors, as well as a human tissue collection.
Three paralleled tasks will be developed: 1) to define the precise role of bile acid exposure on the mouse testis physiology and functioning during adulthood or during development; 2) to decipher the molecular pathways involved in such modifications; 3) to screen the role of the BA receptors FXRa and TGR5 in human testis physiology and pathology.
The numerous deleterious effects of Metabolic Syndrome are being investigated throughout the medical and academic community, as Metabolic Syndrome potentially affects many aspects of human physiology due to its systemic nature. Our project is in line with this competitive worldwide research area, with a focus on the impact of long term exposure to BAs particularly on male reproductive functions. The short term milestone will be to increase our knowledge regarding the crosstalk between the Metabolic Syndrome and infertility. It should help to have a global view to determine the potential risks of pharmacologic modulations of BA pathways on male reproduction.
New biomarkers of male infertility risk will also be pointed out to identify potential alterations of the reproductive function linked to alterations of the BA metabolism or signalization (middle term milestone).
Altogether, this project will help in the understanding of putative links between infertilities and exposure to endocrine disruptors such as nutritional disequilibria. Hence, new field of investigations could be opened regarding the therapeutic approach of male infertility (long term milestone