A Renewed Focus on the Association Between Thyroid Hormones and Lipid Metabolism

Abstract

Thyroid dysfunction, manifesting as either overt or subclinical hypothyroidism, negatively affects lipid metabolism: this leads to hypercholesterolemia which progressively increases the risk for cardiovascular disease and, potentially, mortality. Hypercholesterolemia in hypothyroidism is mainly due to a reduction in low-density lipoprotein (LDL) receptor activity, this accompanied by concomitant diminishing control by triiodothyronine (T3) of sterol regulatory element-binding protein 2 (SREBP-2), which modulates cholesterol biosynthesis by regulating rate-limit degrading enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) activity. Recently, 3,5-diiodothyronine (T2), a natural thyroid hormone derivative, was found to repress the transcription factor carbohydrate-response element-binding protein (ChREBP) and also to be involved in lipid catabolism and lipogenesis, though via a different pathway than that of T3. While thyroid hormone could therapeutically reverse the dyslipidemic profile commonly occurring in hypothyroidism, it should be borne in mind that the potency of the effects may be age-and sex-dependent. Thyroid hormone administration possibly also sustains and enhances the efficacy of hypolipidemic drugs, such as statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9), in patients with dyslipidemia and hypothyroidism.

Keywords: LDL; TSH; cholesterol; hypothyroidism; thyroxine; triglyceride.

Figure 1

Thyroid hormone (TH) increases the synthesis of cholesterol and bile acids (BA) flow, resulting in depletion of hepatic cholesterol and enhancement of cholesterol uptake from the circulation to the liver. By contrast, in hypothyroidism, diminution of TH results in slowing of BA flow, marked diminution in the rate of cholesterol secretion into the bile, increase of intrahepatic cholesterol despite the decrease in cholesterol biosynthesis, and decrease of hepatic uptake of cholesterol from the circulation.

Figure 2

Long-term overt hypothyroidism, as well as subclinical hypothyroidism to a lesser degree, when left untreated cause dyslipidemia and arterial hypertension (diastolic), as well as inflammation characterized by oxidative stress and generation of reactive oxygen species, which may induce endothelial dysfunction, thereby promoting atherosclerosis.