Objectives: Symptomatic hypogonadism is common in obese men with type-2 diabetes (T2DM) and metabolic syndrome (MetS), and is now an independent risk factor for cardiovascular disease. Testosterone replacement therapy (TRT) improves cholesterol metabolism in hypogonadal men with T2DM and/or MetS. We have previously shown that a non-functional androgen receptor (AR) and low levels of circulating testosterone in the testicular feminised (Tfm) mouse is associated with elevated cholesterol, high-fat diet-induced fatty liver and aortic fatty streak formation. TRT improved both hepatic steatosis and aortic lipid deposition although the exact mechanisms are unclear. This study investigates whether the known protective effect of testosterone in the Tfm mouse model is associated with an effect on the expression of key enzymes involved with cholesterol homeostasis in the liver.
Methods: 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 were analysed by qPCR for the expression of liver X receptor (LXR), Apolipoprotein E (ApoE), Hydroxyl-methyl-glutaryl CoA reductase (HMGCoA), hormone sensitive lipase (Lipe), ATP-binding cassette transporter A1 (ABC-A1) and peroxisome proliferator-activated receptors α (PPARα) and γ (PPARγ).
Results: Compared to XY littermates, Tfm mice had significantly lower mRNA expression of LXR (Relative fold change in mRNA Mean ± SD, 0.7±0.09 P=0.01). TRT increased the expression of LXR (1.28±0.2 vs 0.7±0.09, P=0.04) and ApoE (1.3±0.1 vs 0.9±0.1 P=0.06), and decreased Lipe (0.78±0.1 vs 1.3±0.2 P=0.02). However, TRT had no significant effect on the expression of PPARα, PPARγ, HMGCoA, and ABC-A1. Discussion: TRT has a beneficial effect on hepatic expression of LXR and ApoE as key regulators of cholesterol metabolism. Therefore, testosterone has favourable actions on cholesterol homeostasis in liver which is, in part, independent of the AR.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.