Endocrine Abstracts

Testosterone deficiency is associated with several cardiovascular risk factors. Testosterone replacement therapy (TRT) improves insulin sensitivity, inflammation and cholesterol. Liver X receptor (LXR) is a nuclear receptor which regulates lipid and glucose metabolism, stimulates cholesterol efflux and ApoE, and suppresses inflammation. LXR agonists cause hepatic steatosis but protect against atherosclerosis. TRT attenuates high-cholesterol diet-induced hepatic steatosis in the testicular feminised mouse (Tfm), (which exhibit non-functional androgen receptors and low circulating testosterone) independent of androgen receptor (AR) function. This study investigates the effect of testosterone on LXR and ApoE expression in the Tfm mouse model.

Tfm mice were fed a high-cholesterol diet ad libitum for 28 weeks and received either physiological TRT (intramuscular mixed testosterone esters) or placebo (saline) and were compared to wild-type littermates. Liver tissue was collected and relative concentrations of mRNA and protein were analysed by qPCR and western blotting for expression of Liver X receptor (LXR), as well as Apolipoprotein E (ApoE).

The relative expression of LXR mRNA was significantly decreased in the Tfm mouse compared to wild type littermates (WT) (Relative fold change 0.7±0.09 SEM, P=0.011) and there was a non-significant decrease in ApoE (0.82±0.1, P=0.07). Following TRT, mRNA expression increased for LXR (1.3±0.2 P=0.03) and ApoE (1.2±0.12, P=0.03) in Tfm mice compared to placebo. Western blot analysis confirmed reduced LXR (0.16±0.03 vs 0.07±0.01, P=0.05) and ApoE (3.07±0.4 vs 2.45±0.2, P=0.029) protein expression in Tfm mice compared to WT. Following TRT ApoE protein expression increased to wild-type levels (2.92±0.5 vs 3.07±0.4, P=0.89), however LXR protein expression was not significantly altered compared to Tfm placebo mice (0.05±0.0 vs 0.07±0.01, P=0.34).

This is the first study to demonstrate that testosterone deficiency is associated with decreased expression of LXR and ApoE. TRT increased ApoE and LXR mRNA expression as well as ApoE protein expression, suggesting AR-independent actions. The atheroprotective action of testosterone may in part be mediated through activation of LXR and ApoE.

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.