Thyroid hormone and the Liver

Abstract

It is known that thyroid hormone can regulate hepatic metabolic pathways including cholesterol, de novo lipogenesis, fatty acid oxidation, lipophagy, and carbohydrate metabolism. Thyroid hormone action is mediated by the thyroid hormone receptor (THR) isoforms and their coregulators, and THRβ is the main isoform expressed in the liver. Dysregulation of thyroid hormone levels, as seen in hypothyroidism, has been associated with dyslipidemia and metabolic dysfunction-associated fatty liver disease. Given the beneficial effects of thyroid hormone in liver metabolism and the advances illuminating the use of thyroid hormone analogs such as resmetirom as therapeutic agents in the treatment of metabolic dysfunction-associated fatty liver disease, this review aims to further explore the relationship between TH, the liver, and metabolic dysfunction-associated fatty liver disease. Herein, we summarize the current clinical therapies and highlight future areas of research.

FIGURE 1

Overview of TH action in the liver. TH enters the cell through transporters on the cell membrane. The nuclear THR forms a heterodimer with the RXR receptor at TRE sequences on DNA. In the presence of T3, coactivators are recruited to facilitate gene expression that regulates gluconeogenesis, de novo lipogenesis, fatty acid oxidation, cholesterol metabolism, and lipophagy. Abbreviations: RXR, retinoid X receptor; T3, 3,5,3′-triiodothyronine; TH, thyroid hormone; THR, thyroid hormone receptor; TRE, thyroid hormone response element.

FIGURE 2

Key enzymes of glucose metabolism (gluconeogenesis, green arrows), DNL (blue arrows), and FAO (orange arrows) are activated by TH (in red). Glycolysis is a metabolic pathway that converts glucose into pyruvate. Gluconeogenesis is the metabolic process that synthesizes glucose from non-carbohydrate precursors. TH regulates key enzymes involved in these pathways, including G6PC and PEPCK. PEPCK is the rate-limiting step of gluconeogenesis and catalyzes the reaction of oxaloacetate to PEP. DNL is the process by which glucose or other carbohydrates are converted to fatty acids for triglyceride synthesis. Key enzymes activated by TH in this process include ACC, which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA in the first step of DNL. Downstream of this reaction, FASN catalyzes the formation of palmitate, a long-chain fatty acid. Conversely, FAO is the process by which long-chain fatty acids are oxidized for energy during energy-deficient states. TH acts on CPT1, the rate-limiting enzyme of FAO. Additional enzymes regulated by TH critical for FAO include PDK4 and UCP2. Abbreviations: ACC, acetyl-CoA carboxylase; CPT1, carnitine palmitoyltransferase 1; DNL, de novo lipogenesis; FAO, fatty acid oxidation; FASN, fatty acid synthetase; PDK4, pyruvate dehydrogenase kinase 4; PEP, phosphoenolpyruvate; PEPCK, phosphoenolpyruvate carboxykinase 1; TH, thyroid hormone; UCP2, uncoupling protein 2.

FIGURE 3

TH and cholesterol metabolism. Key areas of TH on cholesterol metabolism are in red. (A) TH acts to increase transcription of the LDL-R, which increases LDL-R–mediated endocytosis and lowers serum cholesterol. (B) HMG-CoA reductase catalyzes the rate-limiting step in cholesterol synthesis and is activated, ultimately increasing cholesterol synthesis. (C) Cholesterol is broken down into bile acids for excretion. CYP7A1 is the rate-limiting enzyme of this process that catalyzes the conversion of cholesterol to 7-alpha-hydroxy cholesterol, and its activity is increased by TH. Abbreviation: LDL-R, low-density lipoprotein receptor.