Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists

Abstract

Background: Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs. Summary: THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-l-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver. Conclusions: TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/thyroid axis raise the issue of monitoring liver-specific markers of TH action to assess clinical efficacy and dosing of these compounds.

Keywords: NAFLD; analogs; cholesterol; metabolites; thyroid hormone.

Fig. 1. TH and hepatic TAG metabolism.

TH regulates several processes involved in TAG anabolism, catabolism, and export. Genes and proteins positively regulated by TH are shown in bold black and those negatively regulated by TH are shown as gray color fonts. Transcription factors and other proteins are shown as running font, whereas genes are italicized. Black arrows represent processes/pathways that are upregulated (upward arrow) or downregulated (downward arrow) by TH. DNL, de novo lipogenesis; FAO, fatty acid oxidation; FFAs, free fatty acids; TAG, triacylglycerol; TH, thyroid hormone; VLDL, very-low-density lipoproteins.

Fig. 2. TH and hepatic cholesterol metabolism.

TH regulates several processes involved in hepatic cholesterol biosynthesis, export, and degradation. Genes and proteins positively regulated by TH are shown in bold black and those negatively regulated by TH are shown as gray color fonts. Transcription factors and other proteins are shown as running font, whereas genes are italicized. Black arrows represent processes/pathways that are upregulated (upward arrow) or downregulated (downward arrow) by TH. HDL, high-density lipoprotein; LDL, low-density lipoprotein.