NCoR1 regulates thyroid hormone receptor isoform-dependent adipogenesis

Xu guang Zhu, Dong Wook Kim, Michael L. Goodson, Martin L. Privalsky, Sheue Yann Cheng

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

We previously showed that two thyroid hormone receptor (TR) isoforms - TRα1 and TRβ1 - differentially regulate thyroid hormone (triiodothyroxine, T3)-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 T3-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 T3-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.

Original languageEnglish (US)
Pages (from-to)233-244
Number of pages12
JournalJournal of Molecular Endocrinology
Volume46
Issue number3
DOIs
StatePublished - Jun 2011

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology

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  • Cite this

    Zhu, X. G., Kim, D. W., Goodson, M. L., Privalsky, M. L., & Cheng, S. Y. (2011). NCoR1 regulates thyroid hormone receptor isoform-dependent adipogenesis. Journal of Molecular Endocrinology, 46(3), 233-244. https://doi.org/10.1530/JME-10-0163