Demonstration of potent lipid-lowering activity by a thyromimetic agent devoid of cardiovascular and thermogenic effects

doi:10.1016/0021-9150(96)05893-5

Atherosclerosis

Volume 126, Issue 1, 27 September 1996, Pages 53-63

https://doi.org/10.1016/0021-9150(96)05893-5 Get rights and content

Abstract

A potent lipid-lowering thyromimetic (CGS 26214) devoid of cardiac and thermogenic activity was identified based on its ability to preferentially access and bind the nuclear fraction of hepatocytes over that of myocytes in culture. The difference in access achieved with CGS 26214 was at least 100-fold better for hepatocytes than for myocytes. This in vitro hepatoselectivity resulted in a compound with unprecedented in vivo lipid-lowering potency with a minimal effective dose of 1 μg/kg in rats and dogs (~25x that of L-T₃). At the same time, CGS 26214 was free of any cardiovascular effects up to the highest dose tested of 25 mg/kg and 100 μg/kg in rats and dogs, respectively.

References (35)

WB Kannel et al.
Role of lipids and lipoprotein fractions in assessing atherogenesis. The Framingham Study
Prog Lipid Res
(1981)
GC Ness et al.
Thyroid hormone rapidly induces hepatic LDL receptor mRNA levels in hypophysectomized rats
Arch Biochem Biophys
(1994)
E Morkin et al.
Biochemical and physiologic effects of thyroid hormone on cardiac performance
Prog Cardiovasc Dis
(1983)
I Klein
Thyroid hormone and the cardiovascular system
Am J Med
(1990)
P Emmelot et al.
Isolation of plasma membranes from rat and mouse livers and hepatomas
PT Kovanen et al.
Increased binding of low density lipoprotein to liver membranes from rats treated with 17α-ethinyl estradiol
J Biol Chem
(1979)
ZF Stephan et al.
Rapid fluorometric assay of LDL receptor activity by Dil-labeled LDL
J Lipid Res
(1993)
MM Bradford
Rapid and sensitive method for quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal Biochem
(1976)
JH Oppenheimer et al.
Effect of thyroid hormone analogues on the displacement of ¹²⁵I-l-triiodothyronine from hepatic and heart nuclei in vivo: possible relationship to hormonal activity
Biochem Biophys Res Commun
(1973)
DS Darling et al.
Different dimerization activities of α- and β-thyroid hormone receptor isoforms
J Biol Chem
(1993)

T Haba et al.

A case of heterozygous familial hypercholesterolemia associated with hyperthyroidism: effects of triiodothyronine on low-density lipoprotein receptor and cholesterol synthesis

Metabolism

(1983)

Lipid Research Clinics Program

The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering

J Am Med Assoc

(1984)

CB Blum et al.

Current therapy for hypercholesterolemia

J Am Med Assoc

(1989)

A Chait et al.

Regulatory role of triiodothyronine in the degradation of low density lipoprotein by cultured human skin fibroblasts

J Clin Endocrinol Metab

(1979)

UW Walton et al.

The significance of alterations in serum lipids in thyroid dysfunction. II. Alterations of the metabolism and turnover of ¹²⁵I-low density lipoprotein in hypothyroidism and thyrotoxicosis

Clin Sci

(1965)

GR Thompson et al.

Defects of receptor mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo

B Staels et al.

Alterations in thyroid status modulate apolipoprotein, hepatic triglyceride lipase and low density lipoprotein receptor in rats

Endocrinology

(1990)

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Research paperDemonstration of potent lipid-lowering activity by a thyromimetic agent devoid of cardiovascular and thermogenic effects

Abstract

Prog Lipid Res

Arch Biochem Biophys

Prog Cardiovasc Dis

Am J Med

J Biol Chem

J Lipid Res

Anal Biochem

Biochem Biophys Res Commun

J Biol Chem

Metabolism

The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering

J Am Med Assoc

Current therapy for hypercholesterolemia

J Am Med Assoc

Regulatory role of triiodothyronine in the degradation of low density lipoprotein by cultured human skin fibroblasts

J Clin Endocrinol Metab

The significance of alterations in serum lipids in thyroid dysfunction. II. Alterations of the metabolism and turnover of 125I-low density lipoprotein in hypothyroidism and thyrotoxicosis

Clin Sci

Defects of receptor mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo

Alterations in thyroid status modulate apolipoprotein, hepatic triglyceride lipase and low density lipoprotein receptor in rats

Endocrinology

Research paper
Demonstration of potent lipid-lowering activity by a thyromimetic agent devoid of cardiovascular and thermogenic effects

The significance of alterations in serum lipids in thyroid dysfunction. II. Alterations of the metabolism and turnover of ¹²⁵I-low density lipoprotein in hypothyroidism and thyrotoxicosis