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Actions of thyroid hormones and thyromimetics on the liver

Nature Reviews Gastroenterology & Hepatology volume 22, pages 9–22 (2025)Cite this article

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Abstract

Thyroid hormones (triiodothyronine and thyroxine) are pivotal for metabolic balance in the liver and entire body. Dysregulation of the hypothalamus–pituitary–thyroid axis can contribute to hepatic metabolic disturbances, affecting lipid metabolism, glucose regulation and protein synthesis. In addition, reductions in circulating and intrahepatic thyroid hormone concentrations increase the risk of metabolic dysfunction-associated steatotic liver disease by inducing lipotoxicity, inflammation and fibrosis. Amelioration of hepatic metabolic disease by thyroid hormones in preclinical and clinical studies has spurred the development of thyromimetics that target THRB (the predominant thyroid hormone receptor isoform in the liver) and/or the liver itself to provide more selective activation of hepatic thyroid hormone-regulated metabolic pathways while reducing thyrotoxic side effects in tissues that predominantly express THRA such as the heart and bone. Resmetirom, a liver and THRB-selective thyromimetic, recently became the first FDA-approved drug for metabolic dysfunction-associated steatohepatitis (MASH). Thus, a better understanding of the metabolic actions of thyroid hormones and thyromimetics in the liver is timely and clinically relevant. Here, we describe the roles of thyroid hormones in normal liver function and pathogenesis of MASH, as well as some potential clinical issues that might arise when treating patients with MASH with thyroid hormone supplementation or thyromimetics.

Key points

  • Hypothyroidism is associated with metabolic dysfunction-associated steatohepatitis (MASH).

  • Deiodinase 1 mRNA and protein expression and activity are downregulated as MASH progresses to cause ‘intrahepatic’ hypothyroidism.

  • Increased lipogenesis and decreased fatty acid β-oxidation cause hepatosteatosis and lipotoxicity that lead to inflammation and fibrosis in MASH.

  • Thyroid hormones increase autophagy of lipids (lipophagy), β-oxidation of fatty acids and mitochondrial turnover to reverse inflammation and fibrosis.

  • Thyroid hormones or thyromimetics are effective therapeutic agents for MASH in mouse and human studies.

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Fig. 1: A critical developmental window of Dio2 expression governs susceptibility to diet- and alcohol-induced hepatic steatosis in mice.
Fig. 2: Thyroid hormone regulation of hepatic triglycerides and cholesterol metabolism.
Fig. 3: Thyroid hormone regulation of hepatic glucose metabolism.

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Acknowledgements

This work is supported by Wellcome Trust/DBT India Alliance Fellowship (IA/I/16/2/502691) and SERB (CRG/2022/002149) awarded to R.A.S. and CSASI19may-0002 and NMRC/CIRG/1457/2016 to P.M.Y.

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  1. These authors contributed equally: Rohit A. Sinha, Eveline Bruinstroop.

Authors and Affiliations

  1. Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

    Rohit A. Sinha

  2. Department of Endocrinology and Metabolism, Amsterdam UMC, Location University of Amsterdam, Amsterdam, Netherlands

    Eveline Bruinstroop

  3. Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore

    Paul M. Yen

  4. Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA

    Paul M. Yen

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Sinha, R.A., Bruinstroop, E. & Yen, P.M. Actions of thyroid hormones and thyromimetics on the liver. Nat Rev Gastroenterol Hepatol 22, 9–22 (2025). https://doi.org/10.1038/s41575-024-00991-4

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