Direct effects of thyroid hormones on hepatic lipid metabolism

Key Points

  • Thyroid hormones regulate hepatic lipid metabolism in a cell autonomous manner

  • Thyroid hormone receptors (THRα and THRβ) differentially regulate hepatic lipid metabolism

  • Thyroid hormone induces the expression of genes that encode proteins involved in hepatic lipogenesis

  • Thyroid hormone couples autophagy to mitochondrial fat oxidation to induce ketogenesis

  • Thyroid hormone induces reverse cholesterol transport

  • Thyroid hormone analogues and/or mimetics offer therapeutic alternatives for treatment of lipid-associated hepatic pathologies

Abstract

It has been known for a long time that thyroid hormones have prominent effects on hepatic fatty acid and cholesterol synthesis and metabolism. Indeed, hypothyroidism has been associated with increased serum levels of triglycerides and cholesterol as well as non-alcoholic fatty liver disease (NAFLD). Advances in areas such as cell imaging, autophagy and metabolomics have generated a more detailed and comprehensive picture of thyroid-hormone-mediated regulation of hepatic lipid metabolism at the molecular level. In this Review, we describe and summarize the key features of direct thyroid hormone regulation of lipogenesis, fatty acid β-oxidation, cholesterol synthesis and the reverse cholesterol transport pathway in normal and altered thyroid hormone states. Thyroid hormone mediates these effects at the transcriptional and post-translational levels and via autophagy. Given these potentially beneficial effects on lipid metabolism, it is possible that thyroid hormone analogues and/or mimetics might be useful for the treatment of metabolic diseases involving the liver, such as hypercholesterolaemia and NAFLD.

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Figure 1: Thyroid hormone effects on hepatic lipid metabolism.
Figure 2: Thyroid hormone regulation of cholesterol biosynthesis and clearance.

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Acknowledgements

The authors thank their funding agencies, the Singapore Ministry of Health, Ministry of Education and Ministry of Trade, the National Medical Research Council, Singapore, and the Singapore Agency for Science, Technology and Research, for grants NMRC/CSA/0054/2013 (P.M.Y.), NMRC/BNIG/2025/2014 (R.A.S.), IA/I/16/2/502691-Wellcome Trust/DBT India Alliance Intermediate Fellowship (R.A.S.) and NMRC/OFYIRG/0002/2016 (B.K.S.).

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R.A.S. and P.M.Y. contributed equally to researching data for the article, discussing the content and writing the manuscript. R.A.S., B.K.S. and P.M.Y. contributed equally to reviewing and/or editing the manuscript before submission.

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Correspondence to Rohit A. Sinha or Paul M. Yen.

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Sinha, R., Singh, B. & Yen, P. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol 14, 259–269 (2018). https://doi.org/10.1038/nrendo.2018.10

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