Endocrine Abstracts

Low testosterone is associated with an increased prevalence of cardiovascular (CV) disease. Testosterone replacement improves several CV risk factors including lowering cholesterol and may protect against atherogenesis. Macrophage liver X receptor α (LXRα) stimulates cholesterol efflux which is a therapeutic target for the treatment of atherosclerosis. It was therefore proposed that the anti-atherogenic effect of testosterone may be mediated via LXRα. THP-1 macrophages were used, as they express the androgen receptor (AR) and are therefore responsive to testosterone. Cells were treated with testosterone, either alone or in combination with Flutamide (AR inhibitor) or LXR antagonist and gene expression between control and treated cells was assessed by qPCR. A fluorescent cholesterol analogue was used to observe the effect of testosterone on cholesterol efflux. Protein localisation was observed by immunofluorescence. Testosterone significantly increased the expression of LXRα and of LXRα-target genes encoding proteins involved in cholesterol efflux and metabolism, including ABCA1 (ATP-binding cassette transporter A1), APOE (apolipoprotein E), FAS (fatty acid synthase), and SREBP1c (sterol regulatory element-binding protein 1c). Blocking LXRα activity inhibited the effect of testosterone, demonstrating testosterone increases ABCA1, APOE, FAS, and SREBP1c expression by activating LXRα. Testosterone was shown to act via its AR to activate LXRα, as blocking the AR inhibited the effect of testosterone on LXRα and its downstream targets. Testosterone increased the rate of cholesterol efflux from macrophages; a high level of ABCA1 protein at the cell membrane in testosterone-treated cells suggests this may be due to an increase in intracellular cholesterol transport. We provide evidence that testosterone activates LXRα and acts through this nuclear receptor to control the expression of LXR-target genes to stimulate cholesterol efflux and metabolism.