Endocrine Abstracts

Low testosterone is associated with an increased prevalence of cardiovascular (CV) diseases such as atherosclerosis. Testosterone replacement improves several CV risk factors including lowering cholesterol. Liver X receptor α (LXRα) is present in various cell types such as macrophages where it stimulates cholesterol efflux and this ability means LXRα agonists are a potential therapy for atherosclerosis. It was therefore proposed that testosterone acts to reduce the features of atherosclerosis by acting through LXRα. THP-1 macrophages were used, as they express the androgen receptor (AR) and are therefore responsive to testosterone. Cells were treated with 10⁻⁸ M testosterone (24, 48 and 72 h) either alone or in combination with Flutamide (an AR inhibitor) or LXRα antagonist and gene expression between control and treated cells was assessed by qPCR. The fluorescent cholesterol analogue dehydroergosterol (DHE) was used to directly observe the effect of testosterone on cholesterol efflux. Testosterone significantly increased LXRα expression in macrophages. In addition, testosterone increased the expression of genes downstream of LXRα which encode 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, as blocking the AR inhibited the effect of testosterone on LXRα and LXR-target genes. Testosterone increased the rate of cholesterol efflux from macrophages. 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. We therefore hypothesize that testosterone exerts its anti-atherogenic effects in part through the activation of LXRα and LXR-target genes.