Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy
Rohit Anthony Sinha, … , Mitchell A. Lazar, Paul M. Yen
Rohit Anthony Sinha, … , Mitchell A. Lazar, Paul M. Yen
Published June 11, 2012
Citation Information: J Clin Invest. 2012;122(7):2428-2438. https://doi.org/10.1172/JCI60580.
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Research Article Metabolism

Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy

Abstract

For more than a century, thyroid hormones (THs) have been known to exert powerful catabolic effects, leading to weight loss. Although much has been learned about the molecular mechanisms used by TH receptors (TRs) to regulate gene expression, little is known about the mechanisms by which THs increase oxidative metabolism. Here, we report that TH stimulation of fatty acid β-oxidation is coupled with induction of hepatic autophagy to deliver fatty acids to mitochondria in cell culture and in vivo. Furthermore, blockade of autophagy by autophagy-related 5 (ATG5) siRNA markedly decreased TH-mediated fatty acid β-oxidation in cell culture and in vivo. Consistent with this model, autophagy was altered in livers of mice expressing a mutant TR that causes resistance to the actions of TH as well as in mice with mutant nuclear receptor corepressor (NCoR). These results demonstrate that THs can regulate lipid homeostasis via autophagy and help to explain how THs increase oxidative metabolism.

Authors

Rohit Anthony Sinha, Seo-Hee You, Jin Zhou, Mobin M. Siddique, Boon-Huat Bay, Xuguang Zhu, Martin L. Privalsky, Sheue-Yann Cheng, Robert D. Stevens, Scott A. Summers, Christopher B. Newgard, Mitchell A. Lazar, Paul M. Yen

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Figure 8

T3-induced autophagy is tightly coupled with fatty acid β-oxidation in mouse liver in vivo.

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T3-induced autophagy is tightly coupled with fatty acid β-oxidation in m...
(A) Immunoblot of ATG5 and LC3-II from livers of representative mice treated with control siRNA or ATG5 siRNA in the absence or presence of T3. (B) Densitometric analyses of immunoblots of ATG5 and LC3-II in livers of mice treated with control siRNA or ATG5 siRNA in the absence or presence of T3 (n = 4–5; *P < 0.05). Note that T3 stimulation of LC3-II was blocked in the ATG5-knockdown mice. (C) Serum β-hydroxybutyrate levels from mice treated with control siRNA or ATG5 siRNA in the absence or presence of T3 (n = 4–5; *P < 0.05). Note that β-hydroxybutyrate levels in ATG5-knockdown mice treated with T3 returned to the same levels as those in mice treated with control siRNA alone. Results are expressed as mean ± SEM.