NCoR1 regulates thyroid hormone receptor isoform-dependent adipogenesis.

Abstract

We previously showed that two thyroid hormone receptor (TR) isoforms--TRα1 and TRβ1--differentially regulate thyroid hormone (triiodothyroxine, T(3))-stimulated adipogenesis in vivo. This study aims to understand the role of the nuclear receptor corepressor, NCoR1, in TR isoform-dependent adipogenesis. We found that T(3)-stimulated adipogenesis of 3T3-L1 cells was accompanied by progressive loss of NCoR1 protein levels. In 3T3-L1 cells stably expressing a mutated TRα1, PV (L1-α1PV cells), the T(3)-stimulated adipogenesis was more strongly inhibited than that in 3T3-L1 cells stably expressing an identical mutation in TRβ1 (L1-β1PV cells). The stronger inhibition of adipogenesis in L1-α1PV cells was associated with a higher NCoR1 protein level. These results indicate that the degree of loss of NCoR1 correlates with the extent of adipogenesis. siRNA knockdown of NCoR1 promoted adipogenesis of control 3T3-L1 cells and reversed the inhibited adipogenesis of L1-α1PV and L1-β1PV cells, indicating that NCoR1 plays an essential role in TR isoform-dependent adipogenesis. An ubiquitin ligase, mSiah2, that targets NCoR1 for proteasome degradation was upregulated on day 1 before the onset of progressive loss of NCoR1. NCoR1 was found to associate with mSiah2 and with TR, TRα1PV, or TRβ1PV, but a stronger interaction of NCoR1 with TRα1PV than with TRβ1PV was detected. Furthermore, TRα1PV-NCoR1 complex was more avidly recruited than TRβ1PV-NCoR1 to the promoter of the C/ebpα gene, leading to more inhibition in its expression. These results indicate that differential interaction of NCoR1 with TR isoforms accounted for the TR isoform-dependent regulation of adipogenesis and that aberrant interaction of NCoR1 with TR could underlie the pathogenesis of lipid disorders in hypothyroidism.

• Authors: Xu-Guang Zhu, Dong Wook Kim, Michael L Goodson, Martin L Privalsky, Sheue-Yann Cheng
• Journal: Journal of molecular endocrinology (J Mol Endocrinol) Vol. 46 Issue 3 Pg. 233-44 (Jun 2011) ISSN: 1479-6813 [Electronic] England
• PMID: 21389087 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• CCAAT-Enhancer-Binding Protein-alpha
• Nuclear Receptor Co-Repressor 1
• PPAR gamma
• Protein Isoforms
• RNA, Small Interfering
• Thyroid Hormone Receptors alpha
• Thyroid Hormone Receptors beta
• Triiodothyronine
• Siah2 protein, mouse
• Ubiquitin-Protein Ligases

Topics

• 3T3-L1 Cells
• Adipocytes (physiology)
• Adipogenesis (physiology)
• Animals
• CCAAT-Enhancer-Binding Protein-alpha (genetics, metabolism)
• Cell Differentiation (physiology)
• Chromatin Immunoprecipitation
• Down-Regulation
• Humans
• Mice
• Mutation
• Nuclear Receptor Co-Repressor 1 (genetics, metabolism)
• PPAR gamma (genetics, metabolism)
• Promoter Regions, Genetic
• Protein Interaction Mapping
• Protein Isoforms (genetics, metabolism)
• RNA, Small Interfering
• Thyroid Hormone Receptors alpha (genetics, metabolism)
• Thyroid Hormone Receptors beta (genetics, metabolism)
• Time Factors
• Transcriptional Activation
• Triiodothyronine (metabolism)
• Ubiquitin-Protein Ligases (metabolism)