TY - JOUR
T1 - Redox-dependent PPARγ/Tnpo1 complex formation enhances PPARγ nuclear localization and signaling
AU - Teratani, Toshiaki
AU - Tomita, Kengo
AU - Toma-Fukai, Sachiko
AU - Nakamura, Yutaro
AU - Itoh, Toshimasa
AU - Shimizu, Hikaru
AU - Shiraishi, Yasunaga
AU - Sugihara, Nao
AU - Higashiyama, Masaaki
AU - Shimizu, Takahiko
AU - Inoue, Ikuo
AU - Takenaka, Yasuhiro
AU - Hokari, Ryota
AU - Adachi, Takeshi
AU - Shimizu, Toshiyuki
AU - Miura, Soichiro
AU - Kanai, Takanori
N1 - Funding Information:
This study was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to K.T.).
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/8/20
Y1 - 2020/8/20
N2 - The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ has been implicated in the pathogenesis of various human diseases including fatty liver. Although nuclear translocation of PPARγ plays an important role in PPARγ signaling, details of the translocation mechanisms have not been elucidated. Here we demonstrate that PPARγ2 translocates to the nucleus and activates signal transduction through H2O2-dependent formation of a PPARγ2 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 PPARγ and downstream signaling, leading to triglyceride accumulation in hepatocytes and liver. These findings expand our understanding of the mechanism underlying the nuclear translocation of PPARγ, and suggest that the PPARγ and Tnpo1 complex and surrounding redox environment are potential therapeutic targets in the treatment of PPARγ-related diseases.
AB - The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ has been implicated in the pathogenesis of various human diseases including fatty liver. Although nuclear translocation of PPARγ plays an important role in PPARγ signaling, details of the translocation mechanisms have not been elucidated. Here we demonstrate that PPARγ2 translocates to the nucleus and activates signal transduction through H2O2-dependent formation of a PPARγ2 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 PPARγ and downstream signaling, leading to triglyceride accumulation in hepatocytes and liver. These findings expand our understanding of the mechanism underlying the nuclear translocation of PPARγ, and suggest that the PPARγ and Tnpo1 complex and surrounding redox environment are potential therapeutic targets in the treatment of PPARγ-related diseases.
KW - Fatty liver
KW - Hydrogen peroxide
KW - Nuclear translocation
KW - Peroxisome proliferator-activated receptor γ
KW - Redox
KW - Superoxide dismutase
KW - Transportin
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U2 - 10.1016/j.freeradbiomed.2020.06.005
DO - 10.1016/j.freeradbiomed.2020.06.005
M3 - Article
C2 - 32553752
AN - SCOPUS:85086655278
SN - 0891-5849
VL - 156
SP - 45
EP - 56
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -
