Cross-talk between the Androgen Receptor and the Liver X Receptor

Abstract

High cholesterol levels are associated with prostate cancer development. Androgens promote cholesterol accumulation by activating the sterol-regulatory element-binding protein isoform 2 (SREBP-2) transcription factor. However, SREBP-2 is in balance with the liver X receptor (LXR; NR1H2/NR1H3), a transcription factor that prevents cholesterol accumulation. Here, we show that LXR activity is down-regulated by the androgen receptor (AR; NR3C4). In turn, this reduces LXR target gene expression. This antagonism on LXR is also exerted by other steroid hormone receptors, including the estrogen, glucocorticoid, and progesterone receptors. This suggests a generalizable mechanism, but the AR does not affect LXR mRNA levels, protein degradation, or DNA binding. We also found that the AR does not require protein synthesis to influence LXR, suggesting a direct antagonism. However, the AR does not directly bind LXR. The AR N-terminal domain (involved in transactivation), but not its DNA-binding domain, is required to suppress LXR activity, suggesting coactivator competition. Overall, this androgen-mediated antagonism of LXR complements SREBP-2 activation, providing a more complete picture as to how androgens increase cellular cholesterol levels in a prostate cancer setting. Given the cross-talk between other steroid hormone receptors and LXR, hormonal regulation of cholesterol via LXR may occur in a variety of cellular contexts.

Controlling Cholesterol Synthesis beyond 3-Hydroxy-3-methylglutaryl-CoA Reductase (HMGCR)

“…34). Growth factors involving signaling via the androgen receptor or Akt can also up-regulate cholesterogenic genes, but this occurs indirectly, through activation of SREBP-2 (35,36).…”

Liver X receptor activation downregulates organic anion transporter 1 (OAT1) in the renal proximal tubule

“…Since it has been reported that LXR activation decreased intracellular cholesterol levels (13,40), it was possible that changes in hOAT1 activity might be secondary to changes in cellular cholesterol levels. This notion came from the study of Dias and Ribeiro (5), who reported that cholesterol regulated gene expression of OCT1 (SLC22A1) and Na ϩ -bile acid cotransporter NTCP (SLC10A1) in HepG2 cells (5).…”

LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity

“…There is recognized physiologic interplay between the LXR and ER ligand/receptor systems. LXR activation influences the synthesis and metabolism of estrogen (22,23), estrogen causes attenuated expression of LXRα and its target genes in white adipose tissue (24), and estrogen also antagonizes LXR transcriptional activity in breast cancer cells (25). However, direct functional partnership between LXR and ER has not been previously observed in any biological context.…”