Characterising the role of metabolic nuclear receptors: Farnesoid X receptor (FXR) and Liver X Receptor (LXR) in male fertility

Abstract

Both Farnesoid X receptors (FXR) and Liver X receptors (LXRs) are metabolic nuclear receptors which regulate bile acid and cholesterol homeostasis. A number of other biological functions are being increasingly described for these receptors in glucose metabolism, cardiorespiratory and renal disease, neurodegeneration, endocrine roles and in fertility. Until now there was little information about their likely roles in human male fertility. Both FXRα and LXR α/b act as transcription factors crucial for lipid homeostasis it is possible that their function or dysfunction may explain some cases of infertility. With a more overweight/obese population and rising prevalence of male fertility defects; identifying mechanisms and potential molecular targets is important. Form the work undertaken, I have shown that conjugated and unconjugated bile acids are present in the mouse and human testis with a specific BA signature and can potentially signal via BA receptors (FXR, TGR5, VDR, PXR) also characterised in the testis. Extensive studies undertaken in this project show that FXRα does not have a critical role in fertility, but BA may signal via other BA receptors such as TGR5 in the testis which is intriguing and required future studies. For LXRs in the testis, a comprehensive assessment of LXR signalling has been undertaken using multiple approaches including in vitro, ex vivo and in vivo models with consistent findings with regard to cholesterol efflux and lipogenic regulation. Additionally I have confirmed that in human testis LXR pathways are functional and there may be an association of defective LXR signalling in subfertility. Furthermore, using transcriptomic studies, novel LXR targets (notably LIPG, GSTM1, ALDH1L1) have been identified and with the use of a human testicular explant model are proven to relevant clinically and directly regulated by LXRs. Furthermore, an extensive assessment Lxrab- /- DKO mice using multi-omic integrated approaches has revealed potentially new roles for LXRs in glycolipid, sphingolipid balance and on phospholipase signalling which provides valuable new insights and sets the scene for future research. Finally, using a diet induced obesity model to study the effects of high fat on the testis, I uncovered a compensatory alteration in LXR signalling and deregulation of key proteins involved in maintaining the blood testis barrier, as well as crucial components for Androgen receptor signalling and lipid metabolism genes were altered testis in response to obesity. Together the work has brought new insights into the potential mechanisms between male infertility and lipid disorders and/or obesity in humans.