Beneficial Effects of a Novel Thyromimetic on Lipoprotein Metabolism

Abstract

Although L-triiodothyronine (L-T3) lowers cholesterol, this hormone is not used to treat hypercholesterolemia because of its cardiotoxic effects. Thyromimetics, such as the novel compound CGS 23425, that mimic the beneficial but lack the detrimental effects of T3, may be useful in the treatment of hypercholesterolemia. To show that CGS 23425 has no cardiotoxicity, atrial contractility and force were both measured and found to be unchanged in rats treated with up to 10 mg/kg drug. The lipid lowering actions of this drug resulted in a 44% decrease in low-density lipoprotein (LDL) cholesterol in hypercholesterolemic rats treated with 10 microg/kg of the compound. Normal rats required a higher dose of 1000 microg/kg to elicit a similar 50% reduction in LDL cholesterol. Both CGS 23425 or T3 (10 nM) increased the specific binding of 125I-labeled LDL to Hep G2 cells and increased LDL receptor number by 44 and 49%, respectively. These data indicate that CGS 23425 enhances hepatic clearance of serum LDL cholesterol. Normal and fat-fed animals treated with the drug showed a dose-dependent increase in apolipoprotein AI, a protein that promotes the efflux of cholesterol from peripheral tissues. Transient transfection of a rat apolipoprotein AI promoter-chloramphenicol acetyltransferase construct, in human hepatoma cells, showed a dose-dependent increase in chloramphenicol acetyltransferase activity with EC50 values of 2 x 10(-12) M and 10(-10) M for thyroid hormone receptors beta1 and alpha1, respectively, with maximal responses at 10(-7) M. These data indicate that CGS 23425 is a thyromimetic that increases apolipoprotein AI expression via thyroid hormone receptor. In summary, CGS 23425 ameliorates hypercholesterolemia by increasing apolipoprotein A1 and the clearance of LDL cholesterol. Therefore, a compound like CGS 23425 may be useful for the prevention and reversal of atherosclerosis.

Thyroid hormone in health and disease

“…In 1963, the first of these thyroid hormone analogues was described (Blank et al 1963) and medicinal chemistry efforts since have demonstrated that selective thyromimetics can be produced through a variety of approaches. Specifically, liverselective, cardiac-sparing thyromimetics have been investigated as potential cholesterol-lowering drugs and their use for the prevention and reversal of atherosclerosis has been advocated (Taylor et al 1997, Chiellini et al 1998. Animal studies have shown promising results (Taylor et al 1997) and selective TR activation in rats and monkeys has been shown to provide a potentially useful treatment for obesity and cholesterol reduction (Grover et al 2004).…”

“…Specifically, liverselective, cardiac-sparing thyromimetics have been investigated as potential cholesterol-lowering drugs and their use for the prevention and reversal of atherosclerosis has been advocated (Taylor et al 1997, Chiellini et al 1998. Animal studies have shown promising results (Taylor et al 1997) and selective TR activation in rats and monkeys has been shown to provide a potentially useful treatment for obesity and cholesterol reduction (Grover et al 2004). However, the widespread use of these compounds for the treatment of metabolic disorders appears a long way off.…”

Hormonal regulation of apolipoprotein AI

“…The results from these studies show the dual effects of thyroid hormone on apo AI gene activity. This information has already proven useful in the research and development of thyromimetics that may eventually prove to be useful in regulating levels of apo AI expression (Taylor et al 1997). …”

Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5

“…The two major subtypes of the thyroid hormone receptors that mediate these responses, TR␣ and TR␤, are the products of different genes and are also differentially processed to each yield two isoforms. It has been argued that modulation of heart rate and rhythm is mediated predominantly by activation of TR␣ 1 (2)(3)(4), and as a result, recent pharmaceutical research efforts have focused on developing specific TR␤ 1 agonists (5)(6)(7)(8).…”