Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy

• Published in: The Journal of clinical investigation Vol. 122; no. 7; pp. 2428 - 2438
• Main Authors: Sinha, Rohit Anthony, You, Seo-Hee, Zhou, Jin, Siddique, Mobin M, Bay, Boon-Huat, Zhu, Xuguang, Privalsky, Martin L, Cheng, Sheue-Yann, Stevens, Robert D, Summers, Scott A, Newgard, Christopher B, Lazar, Mitchell A, Yen, Paul M
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2012
• Subjects: Animals; Autophagy; Autophagy-Related Protein 5; Biomedical research; Carnitine - analogs & derivatives; Carnitine - metabolism; Cell culture; Cell Line, Tumor; Energy consumption; Fatty acids; Fatty Acids - metabolism; Gene expression; Gene Expression Profiling; Gene Knockdown Techniques; Health aspects; Hepatocytes - metabolism; Hepatocytes - physiology; Hepatocytes - ultrastructure; Histone Deacetylases - metabolism; Hormones; Humans; Ketone Bodies - metabolism; Lipid Metabolism; Lipids; Liver; Liver - metabolism; Male; Metabolic Networks and Pathways - genetics; Metabolism; Metabolome; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondrial DNA; Nuclear Receptor Co-Repressor 1 - metabolism; Oligonucleotide Array Sequence Analysis; Oxidation; Oxidation-Reduction; Phagosomes - metabolism; Physiological aspects; Protein Binding; Proteins; Receptors, Thyroid Hormone - metabolism; RNA Interference; Thyroid gland; Thyroid hormones; Triiodothyronine - physiology; United States
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/jci60580

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.