Thyroid hormones influence the function of many organs and mediate their diverse actions through two types of thyroid hormone receptors, TR␣ and TR␤. 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 TR␤-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

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... han 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 ␣ and ␤ and the sarcoplasmic reticulum adenosine triphosphatase (Serca2). Additional dose-response studies in hypercholesteremic rats confirmed the preferential effect of GC-1 on TR␤-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 vs. the heart probably also contributes to its marked lipid-lowering effect vs. 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. (Endocrinology