Thyroid Hormone and Metabolites: Central Versus Peripheral Effects

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Mini Review
11 September 2018
Metabolic Effects of the Intracellular Regulation of Thyroid Hormone: Old Players, New Concepts
Annunziata G. Cicatiello
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Monica Dentice
Metabolic effects of the intracellular regulation of thyroid hormone in different tissues. (A) Liver: Lipid homeostasis is regulated by local T3 level thereby influencing susceptibility to obesity and liver steatosis. (B) Pancreas: The balance between the deiodinases controls the development and function of β-cells by enhancing Mafa transcription factor and inducing insulin secretion. (C) Hypothalamus: Local availability of TH regulates feeding behavior and controls energy expenditure. (D) Skeletal Muscle: Increased T3 levels in skeletal muscle promote the shift from type I to type II fibers, influence regeneration and increase energy expenditure. (E) BAT: D2-mediated TH activation regulates UCP1 expression and thermogenesis, adipocyte proliferation and differentiation and body weight. (F) WAT: Local T3 metabolism regulates adipocyte proliferation/differentiation.

Thyroid hormones (THs) are key determinants of cellular metabolism and regulate a variety of pathways that are involved in the metabolism of carbohydrates, lipids and proteins in several target tissues. Notably, hyperthyroidism induces a hyper-metabolic state characterized by increased resting energy expenditure, reduced cholesterol levels, increased lipolysis and gluconeogenesis followed by weight loss, whereas hypothyroidism induces a hypo-metabolic state characterized by reduced energy expenditure, increased cholesterol levels, reduced lipolysis and gluconeogenesis followed by weight gain. Thyroid hormone is also a key regulator of mitochondria respiration and biogenesis. Besides mirroring systemic TH concentrations, the intracellular availability of TH is potently regulated in target cells by a mechanism of activation/inactivation catalyzed by three seleno-proteins: type 1 and type 2 iodothyronine deiodinase (D1 and D2) that convert the biologically inactive precursor thyroxine T4 into T3, and type 3 iodothyronine deiodinase (D3) that inactivates TH action. Thus, the pleiotropic effects of TH can fluctuate among tissues and strictly depend on the cell-autonomous action of the deiodinases. Here we review the mechanisms of TH action that mediate metabolic regulation. This review traces the critical impact of peripheral regulation of TH by the deiodinases on the pathways that regulate energy metabolism and the balance among energy intake, expenditure and storage in specific target tissues.

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110 citations
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.
Review
03 September 2018

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.

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150 citations