Liver X Receptors and Male (In)fertility

Abstract

Liver X receptors (LXRs) are ligand-dependent transcription factors acting as 'cholesterol sensors' to regulate lipid homeostasis in cells. The two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), are differentially expressed, with the former expressed predominantly in metabolically active tissues and the latter more ubiquitously. Both are activated by oxidised cholesterol metabolites, endogenously produced oxysterols. LXRs have important roles in lipid metabolism and inflammation, plus a number of newly emerging roles. They are implicated in regulating lipid balance in normal male reproductive function and may provide a link between male infertility and lipid disorders and/or obesity. Studies from Lxr knockout mouse models provide compelling evidence to support this. More recently published data suggest distinct and overlapping roles of the LXR isoforms in the testis and recent evidence of a role for LXRs in human male fertility. This review summarises the current literature and explores the likely link between LXR, lipid metabolism and male fertility as part of a special issue on Liver X receptors in International Journal of Molecular Sciences.

Keywords: infertility; liver X receptors; oxysterols; steroidogenesis; testis.

Figure 1

The roles of LXRs in lipid metabolism. LXRs regulate hepatic cholesterol elimination by upregulating CYP7A1 as well as excreting cholesterol via ATP binding cassette transporters ABCG5/8 (typically in hepatobiliary system). They also facilitate reverse cholesterol transport by regulating cholesterol efflux from peripheral tissues and cells (e.g., typically macrophages, Sertoli cells of the testis) where ABCA1 and ABCG1 transport cholesterol to APO-A1-HDL and mature HDL respectively. LXRs regulate lipogenesis (usually via hepatic LXRα) with upregulation of SREBP1c, FASN and SCD-1. ChREBP is also able to activate SCD-1 but has a role in carbohydrate metabolism. Finally, LXRs regulate phospholipid remodelling through direct activation of LPCAT3, a crucial enzyme in this process which facilitates the turnover of PUFAs (shown to occur in macrophages, liver, intestine), which will affect membrane phospholipid and allows cells to become resistant to sterol mediated cellular stress. LXRs and the SREBP1 axis are also important for the activation of PLTP which facilitates the production of nascent VLDL. CE, cholesteryl esters; Tgs, triglycerides.

Figure 2

Schematic representation of seminiferous tubule and interstitium illustrating main roles of LXRs in the testis. LXRα is expressed in Leydig cells and LXRβ is expressed in Sertoli cells. Male germ cells express both isoforms. LXRβ regulates expression of genes important for lipid homeostasis processes such as (1) cholesterol efflux notably ABC transporters ABCA1, ABCG1 which reduce cellular cholesterol levels (2) fatty acid synthesis genes SREBP1c, SCD1, FASN and fatty acids. which are used by Sertoli cells but also maturing germ cells as fuel (3) LXRβ is important for maintenance of the blood testis barrier and (4) LXRβ regulates the endocrine function of Leydig cells.