A thyromimetic that decreases plasma cholesterol levels without increasing cardiac activity

Underwood, Anthony H.; Emmett, J. C.; Ellis, David; Flynn, Sheila B.; Leeson, Paul D.; Benson, G. Martin; Novelli, Riccardo; Pearce, Nigel J.; Shah, Virendra P.

doi:10.1038/324425a0

Cited by 130 publications

(77 citation statements)

References 21 publications

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“…Hypercholesterolemia is found in patients with hypothyroidism and in those with resistance to thyroid hormone (2)(3)(4). Elevated serum cholesterol levels in hypothyroidism are restored to normal levels upon treatment with thyroid hormone (2,5).…”

mentioning

confidence: 88%

Cross-talk between Thyroid Hormone Receptor and Liver X Receptor Regulatory Pathways Is Revealed in a Thyroid Hormone Resistance Mouse Model

Hashimoto

Cohen

Yamada

et al. 2006

Journal of Biological Chemistry

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Hypercholesterolemia is found in patients with hypothyroidism and resistance to thyroid hormone. In this study, we examined cholesterol metabolism in a thyroid hormone receptor ␤ (TR-␤) mutant mouse model of resistance to thyroid hormone. Whereas studies of cholesterol metabolism have been reported in TR-␤ knock-out mice, generalized expression of a non-ligand binding TR-␤ protein in this knock-in model more fully recapitulates the hypothyroid state, because the hypothyroid effect of TRs is mediated by the unliganded receptor. In the hypothyroid state, a high cholesterol diet increased serum cholesterol levels in wild-type animals (WT) but either did not change or reduced levels in mutant (MUT) mice relative to hypothyroidism alone. 7␣-Hydroxylase (CYP7A1) is the rate-limiting enzyme in cholesterol metabolism and mRNA levels were undetectable in the hypothyroid state in all animals. triiodothyronine replacement restored CYP7A1 mRNA levels in WT mice but had minimal effect in MUT mice. In contrast, a high cholesterol diet markedly induced CYP7A1 levels in MUT but not WT mice in the hypothyroid state. Elevation of CYP7A1 mRNA levels and reduced hepatic cholesterol content in MUT animals are likely because of cross-talk between TR-␤ and liver X receptor ␣ (LXR-␣), which both bind to a direct repeat ؉ 4 (DR؉4) element in the CYP7A1 promoter. In transfection studies, WT but not MUT TR-␤ antagonized induction of this promoter by LXR-␣. Electromobility shift analysis revealed that LXR/RXR heterodimers bound to the DR؉4 element in the presence of MUT but not WT TR-␤. A mechanism for cross-talk, and potential antagonism, between TR-␤ and LXR-␣ is proposed.

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mentioning

confidence: 88%

Cross-talk between Thyroid Hormone Receptor and Liver X Receptor Regulatory Pathways Is Revealed in a Thyroid Hormone Resistance Mouse Model

Hashimoto

Cohen

Yamada

et al. 2006

Journal of Biological Chemistry

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“…The effects of T 3 on cholesterol are similar in TR␣ 1 Ϫ͞Ϫ animals relative to WT. This lowering is likely due to a decrease in LDL cholesterol, because Ͼ90% of the total plasma cholesterol in these animals is the LDL form (27)(28)(29)(30)(31)(32). Thus, under these conditions, cholesterol lowering is primarily regulated by TR␤, MV O 2 by both TR␤ and -␣, and HR mostly by TR␣.…”

Section: Methodsmentioning

confidence: 99%

Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability

Grover

Mellström

Liu

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

209

182

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Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TR␤ subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TR␣ appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TR␤ activation on metabolic rate and HR with either TR␣1 ؊͞؊ mice or the selective TR␤ agonist KB-141 in mice, rats, and monkeys. 3,5,3 -triiodi-L-thyronine (T3) had a greater effect on increasing HR in WT than in TR␣ ؊͞؊ mice (ED15 values of 34 and 469 nmol͞kg͞day, respectively). T 3 increased metabolic rate [whole body oxygen consumption (MV O 2 )] in both WT and TR␣ ؊͞؊ mice, but the effect in the TR␣ 1 ؊͞؊ mice at the highest dose was half that of the WT mice. Thus, stimulation of MV O 2 is likely due to both TR␣ and -␤. T3 had equivalent potency for cholesterol reduction in WT and TR␣ ؊͞؊ mice. KB-141 increased MVO 2 with selectivities of 16.5-and 11.2-fold vs. HR in WT and TR␣ 1 ؊͞؊ mice, respectively. KB-141 also increased MV O 2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TR␤-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).O besity and atherosclerosis are important medical problems with major impact on morbidity and mortality. Current treatments for obesity have shown limited efficacy and safety; therefore, there is a need for improved therapies (1). A major risk factor for atherosclerosis is low-density lipoprotein (LDL) cholesterol. Although there are excellent treatments for elevated LDL cholesterol, therapeutic goals are commonly not met. As targets for lowering of cholesterol become more aggressive, there is a need for more modalities to meet these goals. Lipoprotein (a) [Lp(a)] is an important risk factor, elevated in many patients with premature atherosclerosis, and few therapies lower Lp(a) (2).Thyroid hormones reduce body weight, LDL cholesterol, and Lp(a); thus, exploitation of these properties may be useful for therapy (3-6). Unfortunately, endogenous thyroid hormones are nonselective and produce undesirable side effects, particularly cardiac stimulation (7,8). Development of thyromimetics devoid of cardiac effects could have therapeutic potential as antiobesity and lipid-lowering agents.Thyroid hormone receptors (TRs) are divided into two primary subtypes (TR␣ and -␤), which are the products of two genes of the superfamily of nuclear hormone receptors (4, 7). TRs mediate distinct physiologic effects due to differences in tissue abundance or receptor-specific activity (9). Studies in patients with th...

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“…Recently, the concept has been discussed that initiation of thyroxine (T 4 ) replacement therapy may precipitate angina pectoris (Gammage & Franklyn 1997), whereas increased serum triiodothyronine (T 3 ) at the time of admission to hospital is associated with a greater risk for the development of myocardial ischemia (Peters et al 2000). This underscores the importance of developing thyromimetic compounds with lipid-decreasing activity, without cardiovascular and thermogenic effects (Boyd & Oliver 1960, Underwood et al 1986, Stephan et al 1996, Ichikawa et al 2000, Trost et al 2000.…”

Section: Introductionmentioning

confidence: 99%

Uptake of triiodothyronine and triiodothyroacetic acid in neonatal rat cardiomyocytes: effects of metabolites and analogs

Verhoeven¹,

Putten²,

Hennemann³

et al. 2002

Journal of Endocrinology

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Cellular and nuclear uptake of [125 I]tri-iodothyronine (T 3 ) and [125 I]triiodothyroacetic acid (Triac) were compared in cardiomyocytes of 2-3 day old rats, and the effect of thyroid hormone analogs on cellular T 3 uptake was measured. Cells (5-10 10 5 per well) were cultured in DMEM-M199 with 5% horse serum and 5% FCS. Incubations were performed for from 15 min to 24 h at 37 C in the same medium, 0·5% BSA and [125 I]T 3 (100 pM), or [ 125 I]Triac (240 pM). Expressed as % dose, T 3 uptake was five times Triac uptake, but expressed as fmol/pM free hormone, Triac uptake was at least 30% (P<0·001) greater than T 3 uptake, whereas the relative nuclear binding of the two tracers was comparable. The 15 min uptake of [ 125

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A thyromimetic that decreases plasma cholesterol levels without increasing cardiac activity

Cited by 130 publications

References 21 publications

Cross-talk between Thyroid Hormone Receptor and Liver X Receptor Regulatory Pathways Is Revealed in a Thyroid Hormone Resistance Mouse Model

Cross-talk between Thyroid Hormone Receptor and Liver X Receptor Regulatory Pathways Is Revealed in a Thyroid Hormone Resistance Mouse Model

Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability

Uptake of triiodothyronine and triiodothyroacetic acid in neonatal rat cardiomyocytes: effects of metabolites and analogs

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