Redox-dependent PPARγ/Tnpo1 complex formation enhances PPARγ nuclear localization and signaling
Redox-dependent PPARγ/Tnpo1 complex formation enhances PPARγ nuclear localization and signaling
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DOI：
10.1016/j.freeradbiomed.2020.06.005
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发表时间：
2020-08-20
影响因子：
7.4
通讯作者：
Kanai, Takanori
中科院分区：
文献类型：
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作者：
Teratani, Toshiaki;Tomita, Kengo;Kanai, Takanori
核受体过氧化物酶体增殖物激活受体（PPAR）γ与包括脂肪肝在内的各种人类疾病的发病机制有关。虽然核转位的过氧化物酶体增殖物激活物受体γ发挥重要作用的信号转导，转位机制的细节尚未阐明。在这里，我们表明，过氧化物酶体增殖物激活物受体γ 2易位到细胞核和激活信号转导通过H2 O2依赖性的形成的过氧化物酶体增殖物激活物受体γ 2和转运蛋白（Tnpo）1复合物通过氧化还原敏感的二硫键之间的半胱氨酸（Cys）176和Cys 180的前者和Cys 512的后者。使用肝细胞培养物和小鼠模型，我们表明，胞质H2 O2/Tnpo 1依赖性核转位增强的DNA结合的过氧化物酶体增殖物激活受体γ和下游信号的量，导致甘油三酯在肝细胞和肝脏中的积累。这些发现扩展了我们对PPAR γ核转位机制的理解，并表明PPAR γ和Tnpo 1复合物及其周围的氧化还原环境是治疗PPAR γ相关疾病的潜在治疗靶点。
The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma has been implicated in the pathogenesis of various human diseases including fatty liver. Although nuclear translocation of PPAR gamma plays an important role in PPAR gamma signaling, details of the translocation mechanisms have not been elucidated. Here we demonstrate that PPAR gamma 2 translocates to the nucleus and activates signal transduction through H2O2-dependent formation of a PPAR gamma 2 and transportin (Tnpo)1 complex via redox-sensitive disulfide bonds between cysteine (Cys)176 and Cys180 of the former and Cys512 of the latter. Using hepatocyte cultures and mouse models, we show that cytosolic H2O2/Tnpo1-dependent nuclear translocation enhances the amount of DNA-bound PPAR gamma and downstream signaling, leading to triglyceride accumulation in hepatocytes and liver. These findings expand our understanding of the mechanism underlying the nuclear translocation of PPAR gamma, and suggest that the PPAR gamma and Tnpo1 complex and surrounding redox environment are potential therapeutic targets in the treatment of PPAR gamma-related diseases.