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
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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Duntas, L. H. Thyroid disease and lipids. Thyroid 12, 287–293 (2002).
Krotkiewski, M. Thyroid hormones and treatment of obesity. Int. J. Obes. Relat. Metab. Disord. 24, S116–S119 (2000).
Singh, B. K. et al. Hepatic FOXO1 target genes are co-regulated by thyroid hormone via RICTOR protein deacetylation and MTORC2-AKT protein inhibition. J. Biol. Chem. 291, 198–214 (2016).
Singh, B. K. et al. FoxO1 deacetylation regulates thyroid hormone-induced transcription of key hepatic gluconeogenic genes. J. Biol. Chem. 288, 30365–30372 (2013).
Martinez-Sanchez, N. et al. Hypothalamic effects of thyroid hormones on metabolism. Best practice and research. Clin. Endocrinol. Metabolism 28, 703–712 (2014).
Martinez-Sanchez, N. et al. Hypothalamic AMPK-ER stress-JNK1 axis mediates the central actions of thyroid hormones on energy balance. Cell. Metab. 26, 212–229 (2017).
Yen, P. M. & Sinha, R. Cellular action of thyroid hormone. Endotext https://www.ncbi.nlm.nih.gov/pubmed/25905423 (updated 12 Feb 2000).
Lazar, M. A. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr. Rev. 14, 184–193 (1993).
Chamba, A. et al. Expression and function of thyroid hormone receptor variants in normal and chronically diseased human liver. J. Clin. Endocrinol. Metab. 81, 360–367 (1996).
Baumann, C. T., Maruvada, P., Hager, G. L. & Yen, P. M. Nuclear cytoplasmic shuttling by thyroid hormone receptors. multiple protein interactions are required for nuclear retention. J. Biol. Chem. 276, 11237–11245 (2001).
Davis, P. J., Goglia, F. & Leonard, J. L. Nongenomic actions of thyroid hormone. Nat. Rev. Endocrinol. 12, 111–121 (2016).
Mullur, R., Liu, Y. Y. & Brent, G. A. Thyroid hormone regulation of metabolism. Physiol. Rev. 94, 355–382 (2014).
Flamant, F. et al. Thyroid hormone signaling pathways: time for a more precise nomenclature. Endocrinology 158, 2052–2057 (2017).
Furuya, F., Hanover, J. A. & Cheng, S. Y. Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone β receptor. Proc. Natl Acad. Sci. USA 103, 1780–1785 (2006).
Lin, H. Y. et al. Identification and functions of the plasma membrane receptor for thyroid hormone analogues. Discov. Med. 11, 337–347 (2011).
Araki, O., Ying, H., Zhu, X. G., Willingham, M. C. & Cheng, S. Y. Distinct dysregulation of lipid metabolism by unliganded thyroid hormone receptor isoforms. Mol. Endocrinol. 23, 308–315 (2009)This is an important work highlighting the distinct effects of unliganded THRs on lipid metabolism.
Cable, E. E. et al. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology 49, 407–417 (2009).This article presents an interesting study showing the efficacy of liver-targeted thyroid hormone agonist in reducing NAFLD in rodent models.
Erion, M. D. et al. Targeting thyroid hormone receptor-β agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc. Natl Acad. Sci. USA 104, 15490–15495 (2007).
Jornayvaz, F. R. et al. Thyroid hormone receptor-α gene knockout mice are protected from diet-induced hepatic insulin resistance. Endocrinology 153, 583–591 (2012).
Liu, Y. Y. et al. A mutant thyroid hormone receptor α antagonizes peroxisome proliferator-activated receptor α signaling in vivo and impairs fatty acid oxidation. Endocrinology 148, 1206–1217 (2007).
Shimizu, H. et al. NCoR1 and SMRT play unique roles in thyroid hormone action in vivo. Mol. Cell. Biol. 35, 555–565 (2015).
Fonseca, T. L. et al. Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity. Proc. Natl Acad. Sci. USA 112, 14018–14023 (2015).
Meyer zu Schwabedissen, H. E. et al. Hepatic organic anion transporting polypeptide transporter and thyroid hormone receptor interplay determines cholesterol and glucose homeostasis. Hepatology 54, 644–654 (2011).
Mashek, D. G. Hepatic fatty acid trafficking: multiple forks in the road. Adv. Nutr. 4, 697–710 (2013).
Klieverik, L. P. et al. Thyroid hormone effects on whole-body energy homeostasis and tissue-specific fatty acid uptake in vivo. Endocrinology 150, 5639–5648 (2009).
Santana-Farre, R. et al. Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood. PLOS ONE 7, e37386 (2012).
Nakagawa, S., Kawashima, Y., Hirose, A. & Kozuka, H. Regulation of hepatic level of fatty-acid-binding protein by hormones and clofibric acid in the rat. Biochem. J. 297, 581–584 (1994).
Czech, M. P., Tencerova, M., Pedersen, D. J. & Aouadi, M. Insulin signalling mechanisms for triacylglycerol storage. Diabetologia 56, 949–964 (2013).
Campbell, M. C., Anderson, G. W. & Mariash, C. N. Human spot 14 glucose and thyroid hormone response: characterization and thyroid hormone response element identification. Endocrinology 144, 5242–5248 (2003).
Desvergne, B., Petty, K. J. & Nikodem, V. M. Functional characterization and receptor binding studies of the malic enzyme thyroid hormone response element. J. Biol. Chem. 266, 1008–1013 (1991).
Zhang, Y., Yin, L. & Hillgartner, F. B. Thyroid hormone stimulates acetyl-coA carboxylase-α transcription in hepatocytes by modulating the composition of nuclear receptor complexes bound to a thyroid hormone response element. J. Biol. Chem. 276, 974–983 (2001).
Radenne, A. et al. Hepatic regulation of fatty acid synthase by insulin and T3: evidence for T3 genomic and nongenomic actions. Am. J. Physiol. Endocrinol. Metab. 295, E884–E894 (2008).
Wang, Y., Viscarra, J., Kim, S. J. & Sul, H. S. Transcriptional regulation of hepatic lipogenesis. Nat. Rev. Mol. Cell Biol. 16, 678–689 (2015).
Hashimoto, K., Matsumoto, S., Yamada, M., Satoh, T. & Mori, M. Liver X receptor-α gene expression is positively regulated by thyroid hormone. Endocrinology 148, 4667–4675 (2007).
Hashimoto, K. et al. Carbohydrate response element binding protein gene expression is positively regulated by thyroid hormone. Endocrinology 150, 3417–3424 (2009).
Hashimoto, K. et al. Mouse sterol response element binding protein-1c gene expression is negatively regulated by thyroid hormone. Endocrinology 147, 4292–4302 (2006).
Gnoni, G. V. et al. 3,5,3′triiodo-L-thyronine induces SREBP-1 expression by non-genomic actions in human HEP G2 cells. J. Cell. Physiol. 227, 2388–2397 (2012).
Yao, X. et al. Regulation of fatty acid composition and lipid storage by thyroid hormone in mouse liver. Cell Biosci. 4, 38 (2014).
Hashimoto, K. et al. Human stearoyl-CoA desaturase 1 (SCD-1) gene expression is negatively regulated by thyroid hormone without direct binding of thyroid hormone receptor to the gene promoter. Endocrinology 154, 537–549 (2013).
Dang, A. Q., Faas, F. H. & Carter, W. J. Influence of hypo- and hyperthyroidism on rat liver glycerophospholipid metabolism. Lipids 20, 897–902 (1985).
Davidson, N. O., Powell, L. M., Wallis, S. C. & Scott, J. Thyroid hormone modulates the introduction of a stop codon in rat liver apolipoprotein B messenger RNA. J. Biol. Chem. 263, 13482–13485 (1988).
Abrams, J. J., Grundy, S. M. & Ginsberg, H. Metabolism of plasma triglycerides in hypothyroidism and hyperthyroidism in man. J. Lipid Res. 22, 307–322 (1981).
Babenko, N. A. Long- and short-term effects of thyroxine on sphingolipid metabolism in rat liver. Med. Sci. Monit. 11, BR131–BR138 (2005).
Iannucci, L. F. et al. Metabolomic analysis shows differential hepatic effects of T2 and T3 in rats after short-term feeding with high fat diet. Sci. Rep. 7, 2023 (2017).
Bucki, R., Gorska, M., Zendzian-Piotrowska, M. & Gorski, J. Effect of triiodothyronine on the content of phospholipids in the rat liver nuclei. J. Physiol. Pharmacol. 51, 535–540 (2000).
Oppenheimer, J. H., Schwartz, H. L., Lane, J. T. & Thompson, M. P. Functional relationship of thyroid hormone-induced lipogenesis, lipolysis, and thermogenesis in the rat. J. Clin. Invest. 87, 125–132 (1991).
Quiroga, A. D. & Lehner, R. Liver triacylglycerol lipases. Biochim. Biophys. Acta 1821, 762–769 (2012).
Kihara, S., Wolle, J., Ehnholm, C., Chan, L. & Oka, K. Regulation of hepatic triglyceride lipase by thyroid hormone in HepG2 cells. J. Lipid Res. 34, 961–970 (1993).
Brenta, G. et al. Atherogenic lipoproteins in subclinical hypothyroidism and their relationship with hepatic lipase activity: response to replacement treatment with levothyroxine. Thyroid 26, 365–372 (2016).
Grasselli, E. et al. Triglyceride mobilization from lipid droplets sustains the anti-steatotic action of iodothyronines in cultured rat hepatocytes. Front. Physiol. 6, 418 (2015).
Sanchez, L. M., Chirino, A. J. & Bjorkman, P. Crystal structure of human ZAG, a fat-depleting factor related to MHC molecules. Science 283, 1914–1919 (1999).
Simo, R. et al. Thyroid hormone upregulates zinc-α2-glycoprotein production in the liver but not in adipose tissue. PLOS ONE 9, e85753 (2014).
Reiner, Z. et al. Lysosomal acid lipase deficiency — an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis 235, 21–30 (2014).
Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).
Cingolani, F. & Czaja, M. J. Regulation and functions of autophagic lipolysis. Trends Endocrinol. Metab. 27, 696–705 (2016).
Sinha, R. A. et al. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J. Clin. Invest. 122, 2428–2438 (2012).This study describes the role of autophagy in thyroid-hormone-induced ketogenesis.
Tseng, Y. H. et al. Chromosome 19 open reading frame 80 is upregulated by thyroid hormone and modulates autophagy and lipid metabolism. Autophagy 10, 20–31 (2014).
Settembre, C. & Ballabio, A. Lysosome: regulator of lipid degradation pathways. Trends Cell Biol. 24, 743–750 (2014).
Liu, H. Y. et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J. Biol. Chem. 284, 31484–31492 (2009).
Takeda, T. et al. Regulation of rat hepatic peroxisomal enoyl-CoA hydratase-3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme by thyroid hormone. Biochem. Biophys. Res. Commun. 185, 211–216 (1992).
Just, W. W., Hartl, F. U. & Schimassek, H. Rat liver peroxisomes. I. New peroxisome population induced by thyroid hormones in the liver of male rats. Eur. J. Cell Biol. 26, 249–254 (1982).
Just, W. W. & Hartl, F. U. Rat liver peroxisomes, II. Stimulation of peroxisomal fatty-acid β-oxidation by thyroid hormones. Hoppe Seylers Z. Physiol. Chem. 364, 1541–1547 (1983).
Iossa, S. et al. Effect of long-term high-fat feeding on energy balance and liver oxidative activity in rats. Br. J. Nutr. 84, 377–385 (2000).
Goudonnet, H. et al. Differential action of thyroid hormones and chemically related compounds on the activity of UDP-glucuronosyltransferases and cytochrome P-450 isozymes in rat liver. Biochim. Biophys. Acta 1035, 12–19 (1990).
Goglia, F., Liverini, G., Lanni, A., Iossa, S. & Barletta, A. Effects of 3,5,3′-triiodothyronine (T3) on rat liver peroxisomal compartment during cold exposure. Exp. Biol. 48, 135–140 (1989).
Fringes, B. & Reith, A. Time course of peroxisome biogenesis during adaptation to mild hyperthyroidism in rat liver: a morphometric/stereologic study by electron microscopy. Lab Invest. 47, 19–26 (1982).
Cioffi, F., Lanni, A. & Goglia, F. Thyroid hormones, mitochondrial bioenergetics and lipid handling. Curr. Opin. Endocrinol. Diabetes Obes. 17, 402–407 (2010).
Weitzel, J. M. & Iwen, K. A. Coordination of mitochondrial biogenesis by thyroid hormone. Mol. Cell Endocrinol. 342, 1–7 (2011).
Wrutniak-Cabello, C., Casas, F. & Cabello, G. The direct tri-lodothyronine mitochondrial pathway: science or mythology? Thyroid 10, 965–969 (2000).
Jackson-Hayes, L. et al. A thyroid hormone response unit formed between the promoter and first intron of the carnitine palmitoyltransferase-Iα gene mediates the liver-specific induction by thyroid hormone. J. Biol. Chem. 278, 7964–7972 (2003).
Thakran, S. et al. Role of sirtuin 1 in the regulation of hepatic gene expression by thyroid hormone. J. Biol. Chem. 288, 807–818 (2013).
Adams, A. C. et al. Thyroid hormone regulates hepatic expression of fibroblast growth factor 21 in a PPARα-dependent manner. J. Biol. Chem. 285, 14078–14082 (2010).
Djouadi, F., Riveau, B., Merlet-Benichou, C. & Bastin, J. Tissue-specific regulation of medium-chain acyl-CoA dehydrogenase gene by thyroid hormones in the developing rat. Biochem. J. 324, 289–294 (1997).
Holness, M. J., Bulmer, K., Smith, N. D. & Sugden, M. C. Investigation of potential mechanisms regulating protein expression of hepatic pyruvate dehydrogenase kinase isoforms 2 and 4 by fatty acids and thyroid hormone. Biochem. J. 369, 687–695 (2003).
Jekabsons, M. B., Gregoire, F. M., Schonfeld-Warden, N. A., Warden, C. H. & Horwitz, B. A. T(3) stimulates resting metabolism and UCP-2 and UCP-3 mRNA but not nonphosphorylating mitochondrial respiration in mice. Am. J. Physiol. 277, E380–E389 (1999).
Sinha, R. A. et al. Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS–AMPK–ULK1 signaling. Autophagy 11, 1341–1357 (2015).
Lesmana, R. et al. Thyroid hormone stimulation of autophagy is essential for mitochondrial biogenesis and activity in skeletal muscle. Endocrinology 157, 23–38 (2016).
Ness, G. C. Thyroid hormone. Basis for its hypocholesterolemic effect. J. Fla. Med. Assoc. 78, 383–385 (1991).
Ness, G. C., Pendleton, L. C., Li, Y. C. & Chiang, J. Y. Effect of thyroid hormone on hepatic cholesterol 7α hydroxylase, LDL receptor, HMG-CoA reductase, farnesyl pyrophosphate synthetase and apolipoprotein A-I mRNA levels in hypophysectomized rats. Biochem. Biophys. Res. Commun. 172, 1150–1156 (1990).
Mooradian, A. D., Wong, N. C. & Shah, G. N. Age-related changes in the responsiveness of apolipoprotein A1 to thyroid hormone. Am. J. Physiol. 271, R1602–R1607 (1996).
Lopez, D., Abisambra Socarras, J. F., Bedi, M. & Ness, G. C. Activation of the hepatic LDL receptor promoter by thyroid hormone. Biochim. Biophys. Acta 1771, 1216–1225 (2007).
Lagrost, L. Regulation of cholesteryl ester transfer protein (CETP) activity: review of in vitro and in vivo studies. Biochim. Biophys. Acta 1215, 209–236 (1994).
Shin, D. J. & Osborne, T. F. Thyroid hormone regulation and cholesterol metabolism are connected through sterol regulatory element-binding protein-2 (SREBP-2). J. Biol. Chem. 278, 34114–34118 (2003).This study describes the role of SREBP2 in thyroid-hormone-regulated cholesterol metabolism.
Moon, J. H. et al. Decreased expression of hepatic low-density lipoprotein receptor-related protein 1 in hypothyroidism: a novel mechanism of atherogenic dyslipidemia in hypothyroidism. Thyroid 23, 1057–1065 (2013).
Ness, G. C. & Lopez, D. Transcriptional regulation of rat hepatic low-density lipoprotein receptor and cholesterol 7α hydroxylase by thyroid hormone. Arch. Biochem. Biophys. 323, 404–408 (1995).
Goldberg, I. J. et al. Thyroid hormone reduces cholesterol via a non-LDL receptor-mediated pathway. Endocrinology 153, 5143–5149 (2012).
Bonde, Y., Plosch, T., Kuipers, F., Angelin, B. & Rudling, M. Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex. Hepatology 56, 1828–1837 (2012).
Bonde, Y. et al. Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans. J. Lipid Res. 55, 2408–2415 (2014).This study describes the effect of thyroid hormone on human proprotein convertase subtilisin/kexin type 9 (PCSK9).
Yap, C. S., Sinha, R. A., Ota, S., Katsuki, M. & Yen, P. M. Thyroid hormone negatively regulates CDX2 and SOAT2 mRNA expression via induction of miRNA-181d in hepatic cells. Biochem. Biophys. Res. Commun. 440, 635–639 (2013).This study highlights the potential role of miRNA in thyroid-hormone-regulated cholesterol metabolism.
Grasselli, E. et al. Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells. J. Endocrinol. 210, 59–69 (2011).
Cordeiro, A., Souza, L. L., Einicker-Lamas, M. & Pazos-Moura, C. C. Non-classic thyroid hormone signalling involved in hepatic lipid metabolism. J. Endocrinol. 216, R47–R57 (2013).
Cao, X., Kambe, F., Moeller, L. C., Refetoff, S. & Seo, H. Thyroid hormone induces rapid activation of Akt/protein kinase B-mammalian target of rapamycin-p70S6K cascade through phosphatidylinositol 3-kinase in human fibroblasts. Mol. Endocrinol. 19, 102–112 (2005).
Swierczynski, J. et al. Triiodothyronine-induced accumulations of malic enzyme, fatty acid synthase, acetyl-coenzyme A carboxylase, and their mRNAs are blocked by protein kinase inhibitors. Transcription is the affected step. J. Biol. Chem. 266, 17459–17466 (1991).
Yamauchi, M. et al. Thyroid hormone activates adenosine 5′-monophosphate-activated protein kinase via intracellular calcium mobilization and activation of calcium/calmodulin-dependent protein kinase kinase-β. Mol. Endocrinol. 22, 893–903 (2008).
Nakamura, H., Rue, P. A. & DeGroot, L. J. Thyroid hormone increases type I adenosine 3′, 5′-monophosphate-dependent protein kinase and casein kinase activities in rat liver cytosol: analysis of protein kinases by polyacrylamide disc gel electrophoresis. Endocrinology 112, 1427–1433 (1983).
Coppola, M. et al. Thyroid hormone analogues and derivatives: actions in fatty liver. World J. Hepatol. 6, 114–129 (2014).
Lanni, A. et al. 3,5-Diiodo-L-thyronine powerfully reduces adiposity in rats by increasing the burning of fats. FASEB J. 19, 1552–1554 (2005).
Grasselli, E. et al. Direct effects of iodothyronines on excess fat storage in rat hepatocytes. J. Hepatol. 54, 1230–1236 (2011).This article describes the role of 3,5-diiodothyronine in reducing hepatic fat.
Cavallo, A. et al. 3,5-Diiodo-L-thyronine administration to hypothyroid rats rapidly enhances fatty acid oxidation rate and bioenergetic parameters in liver cells. PLOS ONE 8, e52328 (2013).
Grasselli, E. et al. 3,5-Diiodo-L-thyronine modifies the lipid droplet composition in a model of hepatosteatosis. Cell Physiol. Biochem. 33, 344–356 (2014).
Vergani, L. Lipid lowering effects of iodothyronines: in vivo and in vitro studies on rat liver. World J. Hepatol. 6, 169–177 (2014).
Gnocchi, D., Massimi, M., Alisi, A., Incerpi, S. & Bruscalupi, G. Effect of fructose and 3,5-diiodothyronine (3,5-T(2)) on lipid accumulation and insulin signalling in non-alcoholic fatty liver disease (NAFLD)-like rat primary hepatocytes. Horm. Metab. Res. 46, 333–340 (2014).
Coppola, M., Cioffi, F., Moreno, M., Goglia, F. & Silvestri, E. 3,5-Diiodo-L-thyronine: a possible pharmacological agent? Curr. Drug Deliv. 13, 330–338 (2016).
de Lange, P. et al. Nonthyrotoxic prevention of diet-induced insulin resistance by 3,5-diiodo-L-thyronine in rats. Diabetes 60, 2730–2739 (2011).
Yan, F. et al. Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity. J. Hepatol. 61, 1358–1364 (2014).This study describes a direct action of TSH in regulating hepatic lipid metabolism.
Song, Y. et al. Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF-4α/CYP7A1 axis. J. Hepatol. 62, 1171–1179 (2015).
Zhang, X. et al. Thyroid-stimulating hormone decreases HMG-CoA reductase phosphorylation via AMP-activated protein kinase in the liver. J. Lipid Res. 56, 963–971 (2015).
Cappola, A. R. & Ladenson, P. W. Hypothyroidism and atherosclerosis. J. Clin. Endocrinol. Metab. 88, 2438–2444 (2003).
Tzotzas, T., Krassas, G. E., Konstantinidis, T. & Bougoulia, M. Changes in lipoprotein(a) levels in overt and subclinical hypothyroidism before and during treatment. Thyroid 10, 803–808 (2000).
Sherman, S. I. et al. Augmented hepatic and skeletal thyromimetic effects of tiratricol in comparison with levothyroxine. J. Clin. Endocrinol. Metab. 82, 2153–2158 (1997).
[No authors listed.] The coronary drug project. Findings leading to further modifications of its protocol with respect to dextrothyroxine. The coronary drug project research group. JAMA 220, 996–1008 (1972).
Galioni, E. F. et al. Long-term effect of dried thyroid on serum-lipoprotein and serum-cholesterol levels. Lancet 272, 120–123 (1957).
Baxter, J. D. & Webb, P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat. Rev. Drug Discov. 8, 308–320 (2009).
Elbers, L. P., Kastelein, J. J. & Sjouke, B. Thyroid hormone mimetics: the past, current status and future challenges. Curr. Atheroscler Rep. 18, 14 (2016).
Underwood, A. H. et al. A thyromimetic that decreases plasma cholesterol levels without increasing cardiac activity. Nature 324, 425–429 (1986).
Tancevski, I. et al. The liver-selective thyromimetic T-0681 influences reverse cholesterol transport and atherosclerosis development in mice. PLOS ONE 5, e8722 (2010).
Taylor, A. H., Stephan, Z. F., Steele, R. E. & Wong, N. C. Beneficial effects of a novel thyromimetic on lipoprotein metabolism. Mol. Pharmacol. 52, 542–547 (1997).
Goldman, S. et al. DITPA (3,5-Diiodothyropropionic Acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study. Circulation 119, 3093–3100 (2009).
Johansson, L. et al. Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice. Proc. Natl Acad. Sci. USA 102, 10297–10302 (2005).
Tancevski, I., Demetz, E. & Eller, P. Sobetirome: a selective thyromimetic for the treatment of dyslipidemia. Recent Pat. Cardiovasc. Drug Discov. 6, 16–19 (2011).
Kannisto, K. et al. The thyroid receptor β modulator GC-1 reduces atherosclerosis in ApoE deficient mice. Atherosclerosis 237, 544–554 (2014).
Grover, G. J., Mellstrom, K. & Malm, J. Development of the thyroid hormone receptor β-subtype agonist KB-141: a strategy for body weight reduction and lipid lowering with minimal cardiac side effects. Cardiovasc. Drug Rev. 23, 133–148 (2005).
Ladenson, P. W. et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N. Engl. J. Med. 362, 906–916 (2010).This study describes the use of a thyroid hormone analogue in treating dyslipidaemia in humans.
Kelly, M. J. et al. Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a highly selective thyroid hormone receptor β agonist in clinical trials for the treatment of dyslipidemia. J. Med. Chem. 57, 3912–3923 (2014).
Ito, B. R. et al. Thyroid hormone β receptor activation has additive cholesterol lowering activity in combination with atorvastatin in rabbits, dogs and monkeys. Br. J. Pharmacol. 156, 454–465 (2009).
Myers, C . Metabasis therapeutics announces the publication of pre-clinical findings on MB07811, its product candidate. FierceBiotech https://www.fiercebiotech.com/biotech/metabasis-therapeutics-announces-publication-of-pre-clinical-findings-on-mb07811-its (2009).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT00879112 (2018).
Trost, S. U. et al. The thyroid hormone receptor-β-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology 141, 3057–3064 (2000).
Bryzgalova, G. et al. Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor β subtype selective agonist KB-141. J. Steroid Biochem. Mol. Biol. 111, 262–267 (2008).
Ahmed, M. Non-alcoholic fatty liver disease in 2015. World J. Hepatol. 7, 1450–1459 (2015).
Adams, L. A., Anstee, Q. M., Tilg, H. & Targher, G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 66, 1138–1153 (2017).
Caligiuri, A., Gentilini, A. & Marra, F. Molecular pathogenesis of NASH. Int. J. Mol. Sci. 17, 1575 (2016).
Pais, R. et al. NAFLD and liver transplantation: current burden and expected challenges. J. Hepatol. 65, 1245–1257 (2016).
Eshraghian, A. & Hamidian Jahromi, A. Non-alcoholic fatty liver disease and thyroid dysfunction: a systematic review. World J. Gastroenterol. 20, 8102–8109 (2014).
Ludwig, U. et al. Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years. BMC Endocr. Disord. 15, 41 (2015).
Xu, C., Xu, L., Yu, C., Miao, M. & Li, Y. Association between thyroid function and nonalcoholic fatty liver disease in euthyroid elderly Chinese. Clin. Endocrinol. 75, 240–246 (2011).
Chung, G. E. et al. Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. J. Hepatol. 57, 150–156 (2012).
Bano, A. et al. Thyroid function and the risk of nonalcoholic fatty liver disease: The Rotterdam Study. J. Clin. Endocrinol. Metab. 101, 3204–3211 (2016).
Torun, E., Ozgen, I. T., Gokce, S., Aydin, S. & Cesur, Y. Thyroid hormone levels in obese children and adolescents with non-alcoholic fatty liver disease. J. Clin. Res. Pediatr. Endocrinol. 6, 34–39 (2014).
Gokmen, F. Y. et al. FT3/FT4 ratio predicts non-alcoholic fatty liver disease independent of metabolic parameters in patients with euthyroidism and hypothyroidism. Clin. (Sao Paulo) 71, 221–225 (2016).
Tao, Y., Gu, H., Wu, J. & Sui, J. Thyroid function is associated with non-alcoholic fatty liver disease in euthyroid subjects. Endocr. Res. 40, 74–78 (2015).
Sinha, R. A. & Yen, P. M. Thyroid hormone-mediated autophagy and mitochondrial turnover in NAFLD. Cell Biosci. 6, 46 (2016).
Sinha, R. A., Singh, B. K. & Yen, P. M. Thyroid hormone regulation of hepatic lipid and carbohydrate metabolism. Trends Endocrinol. Metab. 25, 538–545 (2014).
Pihlajamaki, J. et al. Thyroid hormone-related regulation of gene expression in human fatty liver. J. Clin. Endocrinol. Metab. 94, 3521–3529 (2009).This paper presents an interesting study describing defective hepatic thyroid hormone signalling in human NAFLD.
Li, Q. L., Yamamoto, N., Inoue, A. & Morisawa, S. Fatty acyl-CoAs are potent inhibitors of the nuclear thyroid hormone receptor in vitro. J. Biochem. 107, 699–702 (1990).
Bohinc, B. N. et al. Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocrinology 155, 4591–4601 (2014).
Finan, B. et al. Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. Cell 167, 843–857 (2016).This study describes a novel approach of using chemical hybridization of thyroid hormone and glucagon for the treatment of metabolic diseases.
Perra, A. et al. Thyroid hormone (T3) and TRβ agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. FASEB J. 22, 2981–2989 (2008).
Refetoff, S., Weiss, R. E. & Usala, S. J. The syndromes of resistance to thyroid hormone. Endocr. Rev. 14, 348–399 (1993).
Chng, C. L. et al. Physiological and metabolic changes during the transition from hyperthyroidism to euthyroidism in Graves' disease. Thyroid 26, 1422–1430 (2016).
Vatner, D. F. et al. Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. Am. J. Physiol. Endocrinol. Metab. 305, E89–E100 (2013).
Lammel Lindemann, J. & Webb, P. Sobetirome: the past, present and questions about the future. Expert Opin. Ther. Targets 20, 145–149 (2016).
Liangpunsakul, S. & Chalasani, N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J. Clin. Gastroenterol. 37, 340–343 (2003).
Pagadala, M. R. et al. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. Dig. Dis. Sci. 57, 528–534 (2012).
Kim, D. et al. Subclinical hypothyroidism and low-normal thyroid function are associated with nonalcoholic steatohepatitis and fibrosis. Clin. Gastroenterol. Hepatol. 16, 123–131 (2018).
Hassan, M. M. et al. Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States. Hepatology 49, 1563–1570 (2009).
Frau, C. et al. Local hypothyroidism favors the progression of preneoplastic lesions to hepatocellular carcinoma in rats. Hepatology 61, 249–259 (2015).
Chan, I. H. & Privalsky, M. L. Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs. Oncogene 25, 3576–3588 (2006).
Yen, C. C. et al. Mediation of the inhibitory effect of thyroid hormone on proliferation of hepatoma cells by transforming growth factor-β. J. Mol. Endocrinol. 36, 9–21 (2006).
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.).
The authors declare no competing financial interests.
About this article
Cite this article
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
The Thyroid Hormone Transporter Mct8 Restricts Cathepsin-Mediated Thyroglobulin Processing in Male Mice through Thyroid Auto-Regulatory Mechanisms That Encompass Autophagy
International Journal of Molecular Sciences (2021)
The combined adverse effects of cis-bifenthrin and graphene oxide on lipid homeostasis in Xenopus laevis
Journal of Hazardous Materials (2021)
Reference values and the effect of clinical parameters on thyroid hormone levels during early pregnancy
Bioscience Reports (2021)
Gestational hypothyroidism elicits more pronounced lipid dysregulation in mice than pre-pregnant hypothyroidism
Endocrine Journal (2020)
PNPLA3 polymorphism influences the association between high-normal TSH level and NASH in euthyroid adults with biopsy-proven NAFLD
Diabetes & Metabolism (2020)