title: NCoR1 and SMRT play unique roles in thyroid hormone action in vivo.
abstract: NCoR1 (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors; NCoR2) are well-recognized coregulators of nuclear receptor (NR) action. However, their unique roles in the regulation of thyroid hormone (TH) signaling in specific cell types have not been determined. To accomplish this we generated mice that lacked function of either NCoR1, SMRT, or both in the liver only and additionally a global SMRT knockout model. Despite both corepressors being present in the liver, deletion of SMRT in either euthyroid or hypothyroid animals had little effect on TH signaling. In contrast, disruption of NCoR1 action confirmed that NCoR1 is the principal mediator of TH sensitivity in vivo. Similarly, global disruption of SMRT, unlike the global disruption of NCoR1, did not affect TH levels. While SMRT played little role in TH-regulated pathways, when disrupted in combination with NCoR1, it greatly accentuated the synthesis and storage of hepatic lipid. Taken together, these data demonstrate that corepressor specificity exists in vivo and that NCoR1 is the principal regulator of TH action. However, both corepressors collaborate to control hepatic lipid content, which likely reflects their cooperative activity in regulating the action of multiple NRs including the TH receptor (TR).
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston Massachusetts, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston Massachusetts, USA.
authors.forename: Inna
authors.initials: I
authors.lastname: Astapova
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston Massachusetts, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Laboratory Medicine and Core Facility Genomics, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.affiliation: Section of Endocrinology, University of Chicago, Chicago, Illinois, USA roncohen@medicine.bsd.uchicago.edu thollenb@bidmc.harvard.edu.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Cohen
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston Massachusetts, USA roncohen@medicine.bsd.uchicago.edu thollenb@bidmc.harvard.edu.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
mesh_terms: D000818:Animals; D008055:Lipids / Q000096:biosynthesis; D051379:Mice; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013963:Thyroid Hormones / Q000378:metabolism*
chemical_list: D008055:Lipids; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones