Endocrine Abstracts

Testosterone deficiency is common in men with type 2 diabetes (T2D) and cardiovascular diseases (CVD), such as atherosclerosis. Previous studies have shown that testosterone replacement improves several cardiovascular risk factors including insulin resistance, glycaemic control, cholesterol and inflammation. The mechanisms by which testosterone mediates these effects are unknown. LXR, a nuclear receptor also regulates these cardiovascular risk factors and the atheroprotective lipoprotein APOE. LXR agonists have been shown to reduce atherosclerosis but can cause hepatic stenosis. The objective of this study is to determine whether testosterone mediates its action via LXRα. Using the human monocyte cell line THP-1, differentiated into macrophages, which we have shown express the androgen receptor, the effect of 10⁻⁸ M testosterone on the expression of LXRα and LXR- targets including APOE, IL6 and TNFα, was investigated following RNA extraction and qPCR. Cells were exposed to testosterone for 24, 48 and 72 h. LXRα gene expression was increased in macrophages following exposure to 10⁻⁸ M testosterone for 72 h. Similarly the LXR-target gene APOE, which encodes the protein apolipoprotein E, involved in binding cholesterol following its removal from the cell, was also upregulated in these cells following testosterone exposure. Conversely, the expression of two pro-inflammatory genes IL6 and TNFα, were suppressed in macrophages following exposure to 10⁻⁸ M testosterone. This is the first study to show that testosterone induces expression of LXRα and APOE in human macrophages. The results suggest testosterone activates LXR and acts through this nuclear receptor to control the expression of LXR- target genes such as APOE, IL6 and TNFα to aid cholesterol efflux and suppress inflammation in human macrophages. We therefore hypothesize that testosterone exerts its anti-diabetic and anti-atherogenic effects in part through the activation of LXR and LXR-target genes.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.