Endocrine Abstracts

Testosterone deficiency increases risk for cardiovascular disease (CVD) and type 2 diabetes. Testosterone replacement (TRT) improves insulin resistance, glycaemic control and cholesterol in hypogonadal men. Liver X receptor (LXR) is a nuclear receptor which regulates lipid and glucose metabolism. LXR agonists protect against atherosclerosis but cause hepatic steatosis. We have previously shown that TRT protects against hepatic steatosis and atherosclerosis in high-fat diet-fed testicular feminised (Tfm) mice, which exhibit non-functional androgen receptors (AR) and low circulating testosterone levels. This study investigated LXR expression and key downstream targets involved in lipid and glucose homeostasis in liver, muscle and adipose tissue of Tfm mice.

High-cholesterol diet-fed Tfm mice received either TRT or placebo and were compared to wild-type littermates. Liver, muscle, visceral adipose and subcutaneous adipose tissue mRNA and protein were analysed by qPCR and western blotting for LXR expression and downstream targets involved in lipid metabolism (acetyl coA carboxylase (ACC), fatty acid synthase (FAS), lipoprotein lipase (LPL), apolipoprotein E (ApoE), and ATP-binding cassette transporters (ABC-A1, ABC-G5)), glucose control (glucose transporter 4 (GLUT4), hexokinases (HK2, HK4), and phosphofructokinase (PFK)) and master regulators of lipid and glucose metabolism (peroxisome proliferator-activated receptors (PPARα; PPARγ) and sterol regulatory element-binding proteins (Srebp1, Srepb2)).

LXR was down-regulated in liver and subcutaneous adipose of Tfm mice compared to wild-type with TRT increasing LXR expression. LXR was not altered in muscle or visceral adipose. Downstream targets of LXR were altered in the liver (↑FAS, ↑ACC, ↓ApoE, ↓ABC-A1, ↓HK4, and ↓PFK) muscle (↓HK2, ↓GLUT4, and ↓PFK) and subcutaneous adipose (↓LPL, ↓ABC-A1, ↓ApoE, ↓HK2, ↓GLUT4, ↓Srebp-1, and ↓Srebp-2). All other targets in alternate tissues were not affected. TRT returned hepatic FAS, ACC, ApoE, ABC-A1, HK4; muscle GLUT4 and subcutaneous ApoE, HK2, Srebp-1, Srebp-2 to wild-type levels.

Testosterone may act through LXR to influence carbohydrate and lipid metabolism as a mechanism to improve insulin resistance and reducing cardiovascular risk.