Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy.
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.
Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Rohit Anthony
RA
Sinha
Seo-Hee
SH
You
Jin
J
Zhou
Mobin M
MM
Siddique
Boon-Huat
BH
Bay
Xuguang
X
Zhu
Martin L
ML
Privalsky
Sheue-Yann
SY
Cheng
Robert D
RD
Stevens
Scott A
SA
Summers
Christopher B
CB
Newgard
Mitchell A
MA
Lazar
Paul M
PM
Yen
D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007657:Ketone Bodies / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D014284:Triiodothyronine / Q000502:physiology*; D000099186:Histone Deacetylase 3
D000071187:Autophagy-Related Protein 5; D002331:Carnitine; D005227:Fatty Acids; D006655:Histone Deacetylases; D007657:Ketone Bodies; D008869:Microtubule-Associated Proteins; D056971:Nuclear Receptor Co-Repressor 1; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D000099186:Histone Deacetylase 3; C495773:Atg5 protein, mouse; C477012:MAP1LC3A protein, human; C116917:acylcarnitine