👤 Charlotte L Bevan

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. Show less

The Hairy/Enhancer-of-split-related with YRPW-like motif (HEY) family of proteins are transcriptional repressors and downstream effectors of Notch signaling. We previously reported that HEY1 and HEY2 selectively repress androgen receptor (AR) signaling in mammalian cell lines and have shown that in human tissue HEY1 is excluded from the nuclei in prostate cancer but not benign prostatic hyperplasia. We have now characterized a third member of this family, HEYL, which is a more potent repressor of AR activity. HEYL interacted with and repressed AR activation function-1 domain and competitively inhibited SRC1e activation of AR transcriptional activity. Using a cell line inducibly expressing exogenous HEYL, we showed that HEYL represses endogenous AR-regulated genes and reduces androgen-dependent prostate cancer cell growth. Using a trans-repression assay, we identified both trichostatin-sensitive and -insensitive domains within HEYL; however, analysis of endogenous AR target genes suggested that HEYL represses AR activity through histone deacetylase I/II-independent mechanisms. Immunohistochemical analyses of tissue indicated that, in a fashion similar to that previously reported for HEY1, HEYL is excluded from the nuclei in prostate cancer but not adjacent benign tissue. This suggests that nuclear exclusion of HEY proteins may be an important step in the progression of prostate cancer. Show less