Thyroid hormone analogues and derivatives: Actions in fatty liver

Abstract

Fatty liver or nonalcoholic fatty liver disease (NAFLD), a problem of increasing clinical significance and prevalence worldwide, is associated with increased risk for the development of cirrhosis and hepatocellular carcinoma. Although several therapeutic approaches can be used in the context of NAFLD, dietary and physical activities are still the most frequently used strategies. Some pharmacological agents show promising results although no conclusions can be drawn from recent clinical trials. Thyroid hormones [THs; thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3)] coordinate a diverse array of physiological events during development and lipid/energy homeostasis and have some potentially therapeutic actions which include inducing weight loss, and lowering plasma cholesterol levels and tissue adiposity. The thyroid hormones exert their physiological effects by binding to specific nuclear receptors [thyroid hormone receptors (TR)] of which the TRβ isoform is liver specific and has been considered a putative target for the treatment of dyslipidemia and fatty liver. In view of this, the aim of the review is (1) to provide an overview of the action of T3 on lipid metabolism with implications for liver steatosis and (2) to provide an update on the current knowledge concerning the administration of TRβ selective thyromimetics (GC-1 and MB07811), as well as of 3,5-diiodo-L-thyronine and its novel functional analogue TRC150094 in animal models of overweight and related disorders including primarily fatty liver.

Keywords: 3,5-diiodo-L-thyronine; Fatty liver; Lipid metabolism; Thyroid hormones; Thyromimetics.

Figure 1

Hepatic lipid partitioning and liver and systemic metabolic damages in nonalcoholic fatty liver disease (A) and a schematic representation of the anti-steatotic effect of 3,3’,5-triiodo-L-thyronine (B). A: Hepatic lipid partitioning and liver and systemic metabolic damages in nonalcoholic fatty liver disease. Chronic overnutrition/hyperlipidemic feeding causes fat retention in hepatocytes that, in turn, results in alteration of fat uptake, de novo synthesis (lipogenesis) and oxidation with a significant imbalance of lipid homeostasis. This can subsequently induce insulin-resistance, metabolic syndrome and cardiovascular diseases; B: A schematic representation of the anti-steatotic effect of T3: An update. T3-administration associated adverse effects are also highlighted (for details see the text). T3: 3,3’,5-triiodo-L-thyronine; TRs: Thyroid hormone receptor isoforms; FFA: Free fatty acid; TG: Triglyceride; L-FABP: Liver-type fatty acid-binding protein; COX2: Cyclooxygenase 2; JNK: c-Jun N-terminal kinases; STAT3: Signal transducer and activator of transcription 3.

Figure 2

Chemical structure of thyroid hormones and thyromimetics/analogues with reported anti-steatotic effects.

Figure 3

A summary of key events and molecular pathways underlying GC-1 (A) and MB07811 (B) anti-steatotic and hypolipidemic effects (for details see the text). TSH: Thyroid-stimulating hormone; T3: 3,3’,5-triiodo-L-thyronine; TRβ: Thyroid hormone receptor β isoform; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; FFA: Free fatty acid; TG: Triglyceride; T4: Thyroxine; Apo-C3: Apolipoprotein C3; mGPDH: Mitochondrial glycerol-3-phosphate dehydrogenase; CPT-1α: Carnitine palmitoyltransferase-1α.

Figure 4

A summary of key events and molecular pathways underlying T2 (A) and TRC (B) anti-steatotic and hypolipidemic effects (for details see the text). T2: 3,5-diiodo-L-thyronine; TR: Thyroid hormone receptor; COX Va: Cytochrome-c oxidase Va subunit; FFA: Free fatty acid; TG: Triglyceride; P-AMPK: Phosphorylated AMP-activated protein kinase; SIRT1: NAD⁺-dependent deacetylase sirtuin 1; PGC-1α: Peroxisome proliferator-activated receptor γ coactivator; SREBP-1c: Sterol response element binding protein-1c; CPT: Carnitine palmitoyltransferase system; OXPHOS: Oxidative phosphorylation system.