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T-Cell Death Associated Gene 51 Is a Novel Negative Regulator of PPAR? That Inhibits PPAR?RXR? Heterodimer Formation in Adipogenesis.

ABSTRACT: The nuclear receptor peroxisome proliferator-activated receptor ? (PPAR?) is the master transcriptional regulator in adipogenesis. PPAR? forms a heterodimer with another nuclear receptor, retinoid X receptor (RXR), to form an active transcriptional complex, and their transcriptional activity is tightly regulated by the association with either coactivators or corepressors. In this study, we identified T-cell death-associated gene 51 (TDAG51) as a novel corepressor of PPAR?-mediated transcriptional regulation. We showed that TDAG51 expression is abundantly maintained in the early stage of adipogenic differentiation. Forced expression of TDAG51 inhibited adipocyte differentiation in 3T3-L1 cells. We found that TDAG51 physically interacts with PPAR? in a ligand-independent manner. In deletion mutant analyses, large portions of the TDAG51 domains, including the pleckstrin homology-like, glutamine repeat and proline-glutamine repeat domains but not the proline-histidine repeat domain, are involved in the interaction with the region between residues 140 and 506, including the DNA binding domain, hinge, ligand binding domain and activation function-2 domain, in PPAR?. The heterodimer formation of PPAR?-RXR? was competitively inhibited in a ligand-independent manner by TDAG51 binding to PPAR?. Thus, our data suggest that TDAG51, which could determine adipogenic cell fate, acts as a novel negative regulator of PPAR? by blocking RXR? recruitment to the PPAR?-RXR? heterodimer complex in adipogenesis.

SUBMITTER: Kim S

PROVIDER: S-EPMC7854182 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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T-Cell Death Associated Gene 51 Is a Novel Negative Regulator of PPARγ That Inhibits PPARγ-RXRα Heterodimer Formation in Adipogenesis

Kim Sumi S Lee Nari N Park Eui-Soon ES Yun Hyeongseok H Ha Tae-Uk TU Jeon Hyoeun H Yu Jiyeon J Choi Seunga S Shin Bongjin B Yu Jungeun J Rhee Sang Dal SD Choi Yongwon Y Rho Jaerang J

Molecules and cells 20210101 1

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the master transcriptional regulator in adipogenesis. PPARγ forms a heterodimer with another nuclear receptor, retinoid X receptor (RXR), to form an active transcriptional complex, and their transcriptional activity is tightly regulated by the association with either coactivators or corepressors. In this study, we identified T-cell death-associated gene 51 (TDAG51) as a novel corepressor of PPARγ-mediated transcriptiona ...[more]

PMID: 33335079

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Project description:Organotins are a group of chemical compounds that have a tin atom covalently bound to one or more organic groups. The best-studied organotin is tributyltin chloride, which is an environmental pollutant and an endocrine disruptor. Tributyltin chloride has been shown to bind to PPARγ/RXRα and induces adipogenesis in different mammalian cells. However, there are few studies with other organotin compounds, such as dibutyltins. The aim of this study was to investigate the effect of dibutyltins diacetate, dichloride, dilaurate, and maleate on the transcriptional activity of the nuclear PPARγ and RXRα receptors, and on adipogenesis and inflammation. Analogous to tributyltin chloride, in reporter gene assay using HeLa cells, we observed that dibutyltins diacetate, dichloride, dilaurate, and maleate are partial agonists of PPARγ. Unlike tributyltin chloride, which is a full agonist of RXRα, dibutyltins dichloride and dilaurate are partial RXRα agonists. Additionally, the introduction of the C285S mutation, which disrupts tributyltin chloride binding to PPARγ, abrogated the dibutyltin agonistic activity. In 3T3-L1 preadipocytes, all dibutyltin induced adipogenesis, although the effect was less pronounced than that of rosiglitazone and tributyltin chloride. This adipogenic effect was confirmed by the expression of adipogenic markers Fabp4, Adipoq, and Glut4. Exposure of 3T3-L1 cells with dibutyltin in the presence of T0070907, a specific PPARγ antagonist, reduced fat accumulation, suggesting that adipogenic effect occurs through PPARγ. Furthermore, dibutyltins dichloride, dilaurate, and maleate inhibited the expression of proinflammatory genes in 3T3-L1 cells, such as Vcam1, Dcn, Fn1, S100a8, and Lgals9. Additionally, in RAW 264.7 macrophages, tributyltin chloride and dibutyltin dilaurate reduced LPS-stimulated TNFα expression. Our findings indicate that dibutyltins diacetate, dichloride, dilaurate, and maleate are PPARγ partial agonists and that dibutyltins dichloride and dilaurate are also partial RXRα agonists. Furthermore, dibutyltins induce adipogenesis in a PPARγ-dependent manner and repress inflammatory genes in 3T3-L1 and RAW 264.7 cells. Although dibutyltins display some partial PPARγ/RXRα agonistic effects, the translation of cell-based results assays into in vivo effects on inflammation and insulin resistance is not entirely known. Nevertheless, further studies are necessary to address their effects in different periods of life and to elucidate the actions of organostanic compounds in whole-body context.

Dataset Information

T-Cell Death Associated Gene 51 Is a Novel Negative Regulator of PPAR? That Inhibits PPAR?RXR? Heterodimer Formation in Adipogenesis.

Publications

T-Cell Death Associated Gene 51 Is a Novel Negative Regulator of PPARγ That Inhibits PPARγ-RXRα Heterodimer Formation in Adipogenesis

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