NCoR1 regulates thyroid hormone receptor isoform-dependent adipogenesis.

Area of Science:

• Molecular Endocrinology
• Cellular Biology
• Metabolic Regulation

Background:

• Thyroid hormone receptors (TRα1 and TRβ1) have distinct roles in regulating adipogenesis.
• The nuclear receptor corepressor 1 (NCoR1) is implicated in thyroid hormone signaling.
• Understanding NCoR1's role is crucial for elucidating TR isoform-dependent adipogenesis.

Purpose of the Study:

• To investigate the role of NCoR1 in TR isoform-specific regulation of adipogenesis.
• To determine how NCoR1 protein levels and interactions with TR isoforms influence adipogenesis.
• To explore the mechanism linking aberrant TR-NCoR1 interactions to lipid disorders.

Main Methods:

• Utilized 3T3-L1 cells, including those stably expressing mutated TRα1 (L1-α1PV) and TRβ1 (L1-β1PV).
• Assessed NCoR1 protein levels, adipogenesis extent, and gene expression (C/ebpα).
• Employed siRNA knockdown of NCoR1 and investigated protein-protein interactions (NCoR1, mSiah2, TR isoforms).

Main Results:

• T(3)-stimulated adipogenesis correlated with decreased NCoR1 protein levels.
• Mutated TRα1 (L1-α1PV) showed stronger inhibition of adipogenesis with higher NCoR1 levels compared to mutated TRβ1 (L1-β1PV).
• NCoR1 knockdown promoted adipogenesis and rescued inhibition in mutant cell lines.
• mSiah2 ubiquitin ligase mediated NCoR1 degradation; NCoR1 interacted differentially with TRα1PV and TRβ1PV.
• TRα1PV-NCoR1 complex showed stronger recruitment to the C/ebpα promoter than TRβ1PV-NCoR1.

Conclusions:

• NCoR1 is essential for TR isoform-dependent adipogenesis regulation.
• Differential interaction between NCoR1 and TR isoforms dictates adipogenesis outcomes.
• Aberrant NCoR1-TR interactions may contribute to lipid metabolism disorders in hypothyroidism.