The thyroid hormone receptor-beta-selective agonist GC-1 differentially affects plasma lipids and cardiac activity

Thyroid hormones influence the function of many organs and mediate their diverse actions through two types of thyroid hormone receptors, TR alpha and TR beta. Little is known about effects of ligands that preferentially interact with the two different TR subtypes. In the current study the comparison of the effects of the novel synthetic TRP-selective compound GC-1 with T-3 at equimolar doses in hypothyroid mice revealed that GC-1 had better triglyceride-lowering and similar cholesterol-lowering effects than T-3. T-3, but not GC-1, increased heart rate and elevated messenger RNA levels coding for the I-f channel (HCN2), a cardiac pacemaker that was decreased in hypothyroid mice. T-3 had a larger positive inotropic effect than GC-1. T-3, but not GC-1, normalized heart and body weights and messenger RNAs of myosin heavy chain alpha and beta and the sarcoplasmic reticulum adenosine triphosphatase (Serca2). Additional dose-response studies in hypercholesteremic rats confirmed the preferential effect of GC-1 on TRP-mediated parameters by showing a much higher potency to influence cholesterol and TSH than heart rate. The preferred accumulation of GC-1 in the liver us. the heart probably also contributes to its marked lipid-lowering effect us, the absent effect on heart rate. These data indicate that GC-1 could represent a prototype for new drugs for the treatment of high lipid levels or obesity.