(1). Distinct dysregulation of lipid metabolism by unliganded thyroid hormone receptor isoforms. In hypothyroidism TRs function as unliganded receptors. Studies of mice deficient in all TRs (TRalpha-/-TRbeta-/- mice) have shown that they exhibit a milder overall phenotype than the debilitating symptoms of severe hypothyroidism, highlighting the important role of unliganded TRs in the pathogenesis of hypothyroidism. We, therefore, used TRalpha1PV and TRbetaPV mice to ascertain whether unliganded TRs regulate lipid metabolism in an isoform-dependent manner. We showed that in contrast to TRalpha1PV mice, TRbetaPV mice exhibited no significant reduction in white adipose tissue, but had significant increases in serum free fatty acids and total triglycerides. Moreover, the liver of TRbetaPV mice was markedly increased with excess lipid accumulation, but the liver mass of TRalpha1PV mice was decreased with a paucity of lipids. These results indicate that unliganded-TRbeta and unliganded-TRalpha1 exerted distinct abnormalities in lipid metabolism. Further biochemical analyses indicate that increased lipogenic enzyme expression, activated peroxisome proliferators-activated receptor gamma (Ppargamma) signaling, and decreased fatty acid beta-oxidation activity contributed to the adipogenic steatosis and lipid accumulation in the liver of TRbetaPV mice. In contrast, the expression of lipogenic enzymes and Ppargamma was decreased in the liver of TRalpha1PV mice. These findings suggest that the regulation of genes critical for lipid metabolism by TRs in the liver is isoform-dependent. These results indicate that unliganded-TRbeta and unliganded-TRalpha1 have different effects on lipid metabolism and that both TR isoforms contribute to the pathogenesis of lipid metabolism in hypothyroidism. (2). Adipogenesis is differentially impaired by thyroid hormone receptor mutant isoforms. To dissect the molecular mechanism underlying the distinct phenotypic manifestation in white adipose tissue (WAT) between TRalpha1PV mice, but not in TRbetaPV mice, we used the 3T3-L1 cell line, which has long been utilized by investigators as a model cell line to study adipogenesis. To establish the cause-effect relationship, we stably expressed TRalpha1PV or TRbetaPV in 3T3-L1 cells and evaluated the alterations in adipogenesis as compared with parental cells that contained only the vector backbone (control cells). Clones with a similar abundance of TRalpha1PV (denoted as L1-alpha1PV cells) or TRbetaPV proteins (L1-beta1PV cells) were used to elucidate the molecular basis of the distinct phenotypic expression in adipogenesis of WAT. We found that the T3-induced adipogenesis was more severely impaired in L1-alpha1PV cells than in L1-beta1PV cells. The expression of two master regulators, Ppargamma and CCAAT enhancer binding protein alpha (C/ebpalpha), was found to be more repressed in L1-alpha1PV cells than in L1-beta1PV cells. Consistent with the gene expression patterns, the expression of several key lipogenic enzymes was more severely inhibited by TRalpha1PV than TRbetaPV. Further analysis indicated that the preferential repression of the C/ebpalpha gene by TRalpha1PV was mediated, at least in part, by more avid recruitment of TRalpha1PV to the promoter complex of the C/ebpalpha gene. That TR-mediated adipogenesis is isoform-dependent raised the possibility that isoform-specific TR ligands could be considered for therapeutic intervention of lipid abnormalities. (3). NCoR1 regulates thyroid hormone receptor isoform-dependent adipogenesis. Given that TRalpha1PV and TRbetaPV differentially affect adipogenesis in vivo, we sought to understand the role of the nuclear receptor corepressor, NCoR1, in TR isoform-dependent adipogenesis. We found that T3-stimulated adipogenesis of control 3T3-L1 cells was accompanied by progressive loss of NCoR1 protein levels. In L1-alpha1PV cells stably expressing TR alpha1PV, the T3-stimulated adipogenesis was more strongly inhibited than in L1-beta1PV cells stably expressing TRbeta1PV. The stronger inhibition of adipogenesis in L1-alpha1PV cells than that in L1-beta1PV 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 knock-down of NCoR1 promoted adipogenesis of control 3T3-L1 cells and reversed the inhibited adipogenesis of L1-alpha1PV and L1-beta1PV cells, indicating that NCoR1 plays an essential role in TR isoform-dependent adipogenesis. An ubiquitin ligase, mSiah2, that targets NCoR1 for proteasome degradation was up-regulated on Day 1 before the onset of progressive loss of NCoR1. NCoR1 was found to associate with mSiah2 and with TR, TRalpha1PV, or TRbeta1PV, but with a stronger interaction of NCoR1 with TRalpha1PV than with TRbeta1PV was detected. Furthermore, the TRalpha1PV-NCoR1 complex was more avidly recruited than TRbeta1PV-NCoR1 to the promoter of the C/ebpalpha gene, leading to more inhibition in its expression. Our studies showed for the first time that NCoR1 regulates the actions of TR isoforms in adipogenesis and that aberrant interaction of NCoR1 with TR could underlie the pathogenesis of lipid disorders in hypothyroidism. (4). Differential recruitment of nuclear co-regulators directs the isoform-dependent action of mutant thyroid hormone receptors. To elucidate the molecular mechanisms by which TR mutant isoforms mediate distinct phenotypes in TRalpha1PV mice and TRbetaPV mice, we tested the hypothesis that the distinct functions of TR mutant isoforms are directed by a subset of nuclear regulatory proteins. Tandem-affinity chromatography of HeLa nuclear extracts showed that 33 distinct nuclear proteins including NCoR1 and 6 other proteins preferentially associated with TRalpha1PV and TRbetaPV, respectively. These results indicate that recruitment of nuclear regulatory proteins by TR mutants is isoform-dependent. The involvement of NCoR1 in mediating the distinct liver phenotype of TRalpha1PV mice and TRbetaPV mice, was further explored. NCoR1 preferentially interacted with TRalpha1PV rather than with TRbetaPV. Consistent with findings in 3T3-L1 cells, NCoR1 was recruited more avidly to the thyroid hormone response element-bound TRalpha1PV than to TRbetaPV in the promoter of the C/ebpalpha gene to repress its expression in the liver of TRalpha1PV mice, but not in TRbetaPV mice. This preferential recruitment of NCoR1 by mutant isoforms could, at least in part, contribute to the distinct liver lipid phenotype of these mutant mice. The present study highlights a novel mechanism by which TR isoforms direct their selective functions via preferential recruitment of a subset of nuclear coregulatory proteins.

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