Dibutyltin Compounds Effects on PPARγ/RXRα Activity, Adipogenesis, and Inflammation in Mammalians Cells.
Dibutyltin Compounds Effects on PPARγ/RXRα Activity, Adipogenesis, and Inflammation in Mammalians Cells.
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DOI：
10.3389/fphar.2017.00507
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发表时间：
2017
影响因子：
5.6
通讯作者：
Neves FAR
中科院分区：
文献类型：
--
作者：
Milton FA;Lacerda MG;Sinoti SBP;Mesquita PG;Prakasan D;Coelho MS;de Lima CL;Martini AG;Pazzine GT;Borin MF;Amato AA;Neves FAR
有机锡是一组锡原子与一个或多个有机基团共价键合的化合物。研究最多的有机锡是三丁基氯化锡，它是一种环境污染物和内分泌干扰物。研究表明，三丁基锡可与PPARγ/RXRα结合，并能诱导不同哺乳动物细胞的成脂作用。然而，对其他有机锡化合物的研究很少，例如二丁基锡。本研究的目的是研究二乙酸二丁基锡、二氯化物、二月桂酸酯和马来酸对核内PPARγ和RXRα受体转录活性的影响，以及对脂肪形成和炎症的影响。与三丁基锡类似，在HeLa细胞的报告基因分析中，我们观察到二乙酸二丁基锡、二氯化物、二月桂酸酯和马来酸是PPARγ的部分激动剂。与RXRα的完全激动剂氯化三丁基锡不同，二丁基锡和二月桂酸酯是部分RXRα激动剂。此外，C285S突变的引入，破坏了三丁基锡与PPARγ的结合，取消了二丁基锡的激动剂活性。在3T3-L1前脂肪细胞中，二丁基锡均能诱导成脂，但作用不如罗格列酮和氯化三丁基锡明显。成脂标志物FABP4、ADIPOQ和GLUT4的表达证实了这种成脂作用。在PPARγ拮抗剂T0070907存在的情况下，用二丁基锡处理3T3-L1细胞，可以减少脂肪积累，这表明成脂作用是通过PPARγ发生的。此外，二丁基锡、二月桂酸酯和马来酸可抑制3T3-L1细胞中促炎基因的表达，如Vcam1、Dcn、Fn1、S100A8和Lgals9。此外，在RAW 264.7巨噬细胞中，三丁基锡氯化物和二月桂酸二丁基锡减少了脂多糖刺激的肿瘤坏死因子α的表达。我们的研究结果表明，二乙酸二丁基锡、二氯化物、二月桂酸酯和马来酸酯是PPARγ部分激动剂，二氯化二丁基锡和二月桂酸酯也是部分α激动剂。此外，二丁基锡以PPARγ依赖的方式诱导脂肪生成，并抑制3T3-L1和RAW 264.7细胞中的炎症基因。虽然二丁基锡显示出部分PPARγ/RXRα激动剂作用，但基于细胞的结果转化为体内对炎症和胰岛素抵抗的作用尚不完全清楚。然而，需要进一步的研究来解决它们在不同生命阶段的影响，并阐明有机化合物在全身环境中的作用。
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.
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影响因子：
4.6
作者：
Harada S;Hiromori Y;Nakamura S;Kawahara K;Fukakusa S;Maruno T;Noda M;Uchiyama S;Fukui K;Nishikawa J;Nagase H;Kobayashi Y;Yoshida T;Ohkubo T;Nakanishi T
通讯作者：
Nakanishi T
2型糖尿病和慢性肾脏疾病的患者的血清乳糖素-9水平升高。
影响因子：
2.3
作者：
Kurose Y;Wada J;Kanzaki M;Teshigawara S;Nakatsuka A;Murakami K;Inoue K;Terami T;Katayama A;Watanabe M;Higuchi C;Eguchi J;Miyatake N;Makino H
通讯作者：
Makino H
影响因子：
16.6
作者：
Hughes, Travis S.;Giri, Pankaj Kumar;de Vera, Ian Mitchelle S.;Marciano, David P.;Kuruvilla, Dana S.;Shin, Youseung;Blayo, Anne-Laure;Kamenecka, Theodore M.;Burris, Thomas P.;Griffin, Patrick R.;Kojetin, Douglas J.
通讯作者：
Kojetin, Douglas J.
影响因子：
8.7
作者：
Gipperth, Lena
通讯作者：
Gipperth, Lena
影响因子：
5.1
作者：
Hiromori, Youhei;Nishikawa, Jun-ichi;Nakanishi, Tsuyoshi
通讯作者：
Nakanishi, Tsuyoshi