Thyroid Hormone Reduces Cholesterol via a Non-LDL Receptor-Mediated Pathway

Abstract

Although studies in vitro and in hypothyroid animals show that thyroid hormone can, under some circumstances, modulate the actions of low-density lipoprotein (LDL) receptors, the mechanisms responsible for thyroid hormone's lipid-lowering effects are not completely understood. We tested whether LDL receptor (LDLR) expression was required for cholesterol reduction by treating control and LDLR-knockout mice with two forms of thyroid hormone T(3) and 3,5-diiodo-l-thyronine. High doses of both 3,5-diiodo-l-thyronine and T(3) dramatically reduced circulating total and very low-density lipoprotein/LDL cholesterol (∼70%) and were associated with reduced plasma T(4) level. The cholesterol reduction was especially evident in the LDLR-knockout mice. Circulating levels of both apolipoprotein B (apo)B48 and apoB100 were decreased. Surprisingly, this reduction was not associated with increased protein or mRNA expression of the hepatic lipoprotein receptors LDLR-related protein 1 or scavenger receptor-B1. Liver production of apoB was markedly reduced, whereas triglyceride production was increased. Thus, thyroid hormones reduce apoB lipoproteins via a non-LDLR pathway that leads to decreased liver apoB production. This suggests that drugs that operate in a similar manner could be a new therapy for patients with genetic defects in the LDLR.

3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

“…But in contrast to these beneficial effects, an undesired negative feedback inhibition of the hypothalamuspituitary-thyroid (HPT) axis accompanied by increased heart weight was observed at the dose effectively improving hepatic lipid metabolism and systemic lipid status (Jonas et al 2014). Such observations on doserelated thyromimetic actions, among others also on the pituitary and the heart, are in agreement with published results on mice and rats treated with 3,5-T 2 (Horst et al 1995, Goldberg et al 2012, Padron et al 2014.…”

“…Most of the beneficial effects of 3,5-T 2 reported on mitochondrial function, lipid mobilization, and fatty acid oxidation were observed in experimental models of obesity or chronic hypothyroidism in rodents, mainly rats , Grasselli et al 2012, Cavallo et al 2013, Silvestri et al 2010, while only scarce data exist regarding the effects of 3,5-T 2 on metabolism in euthyroid mammals on standard or on HFD in a mouse model (Goldberg et al 2012). …”

Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2?

“…To ensure an effect on resting metabolic rate, most of the studies used a daily intraperitoneal injection of 25 lg 3,5-T2 per 100 g body weight (10,12,14), and rather high doses were needed for oral administration in humans and rodents (49,50). In detail, a chronic treatment with 3,5-T2 at doses of up to 900 lg per day led to a significant weight loss in one human study (49), a 3,5-T2 dose ninefold higher than average daily thyroidal production of T4, the putative precursor of 3,5-T2, which is only a minor metabolite of T4 according to previous kinetic studies (17,18).…”

Thyroid: biological actions of ‘nonclassical’ thyroid hormones

“…These mice develop much higher levels of cholesterol and atherosclerosis. T 2 had no effect on TG levels, probably due to increased lipolysis, but led to marked reductions in liver apoB and circulating apoB48 and apoB100 (Goldberg et al 2012).…”

“…A mechanism by which T 2 reduces cholesterol in the serum (Lanni et al 2005, Antonelli et al 2011, De Lange et al 2011 was recently called into question. T 2 's LDL-lowering effects are independent of the LDL receptor (Goldberg et al 2012), as determined by feeding a western type diet to LDL receptor-deficient mice (Ldlr K/K ) and treating with T 2 . The diet was chosen because dietary absorption of cholesterol and TG drives hepatic apoB production, especially in Ldlr K/K mice.…”