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.