Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy

J Clin Invest. 2012 Jul;122(7):2428-38. doi: 10.1172/JCI60580. Epub 2012 Jun 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Autophagy-Related Protein 5
  • Carnitine / analogs & derivatives
  • Carnitine / metabolism
  • Cell Line, Tumor
  • Fatty Acids / metabolism
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Hepatocytes / metabolism
  • Hepatocytes / physiology
  • Hepatocytes / ultrastructure
  • Histone Deacetylases / metabolism
  • Humans
  • Ketone Bodies / metabolism
  • Lipid Metabolism*
  • Liver / metabolism*
  • Male
  • Metabolic Networks and Pathways / genetics
  • Metabolome
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Nuclear Receptor Co-Repressor 1 / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Oxidation-Reduction
  • Phagosomes / metabolism
  • Protein Binding
  • RNA Interference
  • Receptors, Thyroid Hormone / metabolism
  • Triiodothyronine / physiology*

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Fatty Acids
  • Ketone Bodies
  • Microtubule-Associated Proteins
  • Nuclear Receptor Co-Repressor 1
  • Receptors, Thyroid Hormone
  • acylcarnitine
  • light chain 3, human
  • Triiodothyronine
  • Histone Deacetylases
  • histone deacetylase 3
  • Carnitine