MiR-128-3p mediates MRP2 internalization in estrogen-induced cholestasis through targeting PDZK1
Estrogens have been reported to cause dysfunction in biliary transport systems, thereby inducing cholestasis. Multidrug resistance-associated protein 2 (MRP2) is a transporter responsible for independent bile flow. Emerging evidence indicates that PDZ domain containing 1 (PDZK1) regulates localizati...
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2025-02-01
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| Series: | Acta Materia Medica |
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| author | Yue Zu Qianyan Gao Yisheng He Qiao Deng Guodong Li Xiping Li Tianze Shang Xinwei Cheng Chenglong Zhu Jianqiao Wang Dong Liu Chengliang Zhang |
| author_facet | Yue Zu Qianyan Gao Yisheng He Qiao Deng Guodong Li Xiping Li Tianze Shang Xinwei Cheng Chenglong Zhu Jianqiao Wang Dong Liu Chengliang Zhang |
| author_sort | Yue Zu |
| collection | DOAJ |
| description | Estrogens have been reported to cause dysfunction in biliary transport systems, thereby inducing cholestasis. Multidrug resistance-associated protein 2 (MRP2) is a transporter responsible for independent bile flow. Emerging evidence indicates that PDZ domain containing 1 (PDZK1) regulates localization of MRP2; however, PDZK1’s role and regulatory machinery in MRP2-mediated estrogen-induced cholestasis (EIC) remain unclear. Herein, in a mouse model of EIC, we observed downregulated PDZK1 expression in the liver and enhanced intracellular domain MRP2 internalization. Notably, expression of miR-128-3p, a potential biomarker of estrogen-related cholestasis discovered by our group, was significantly elevated. We demonstrated that miR-128-3p targeted the 3’-untranslated region of PDZK1 in EIC and consequently promoted MRP2 internalization. Accordingly, miR-128-3p suppression upregulated PDZK1, thereby suppressing MRP2 internalization and significantly attenuating cholestatic liver disease. Furthermore, we observed MRP2 internalization and PDZK1 downregulation, as well as excessive miR-128-3p, in clinical samples from patients with cholestatic liver injury. Overall, our findings illustrate that miR-128-3p inhibits PDZK1 expression, thereby inhibiting the membrane localization of MRP2 in EIC. Enhancing or restoring PDZK1 expression might therefore have therapeutic potential for cholestatic liver injury. |
| format | Article |
| id | doaj-art-6e1796bb13cb46228f10979e0bb494c6 |
| institution | Kabale University |
| issn | 2737-7946 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Compuscript Ltd |
| record_format | Article |
| series | Acta Materia Medica |
| spelling | doaj-art-6e1796bb13cb46228f10979e0bb494c62025-02-10T05:44:45ZengCompuscript LtdActa Materia Medica2737-79462025-02-014115717310.15212/AMM-2024-0053MiR-128-3p mediates MRP2 internalization in estrogen-induced cholestasis through targeting PDZK1Yue Zu0Qianyan Gao1Yisheng He2Qiao Deng3Guodong Li4Xiping Li5Tianze Shang6Xinwei Cheng7Chenglong Zhu8Jianqiao Wang9Dong Liu10Chengliang Zhang11Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaCiechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong-Shenzhen, Shenzhen 518100, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaEstrogens have been reported to cause dysfunction in biliary transport systems, thereby inducing cholestasis. Multidrug resistance-associated protein 2 (MRP2) is a transporter responsible for independent bile flow. Emerging evidence indicates that PDZ domain containing 1 (PDZK1) regulates localization of MRP2; however, PDZK1’s role and regulatory machinery in MRP2-mediated estrogen-induced cholestasis (EIC) remain unclear. Herein, in a mouse model of EIC, we observed downregulated PDZK1 expression in the liver and enhanced intracellular domain MRP2 internalization. Notably, expression of miR-128-3p, a potential biomarker of estrogen-related cholestasis discovered by our group, was significantly elevated. We demonstrated that miR-128-3p targeted the 3’-untranslated region of PDZK1 in EIC and consequently promoted MRP2 internalization. Accordingly, miR-128-3p suppression upregulated PDZK1, thereby suppressing MRP2 internalization and significantly attenuating cholestatic liver disease. Furthermore, we observed MRP2 internalization and PDZK1 downregulation, as well as excessive miR-128-3p, in clinical samples from patients with cholestatic liver injury. Overall, our findings illustrate that miR-128-3p inhibits PDZK1 expression, thereby inhibiting the membrane localization of MRP2 in EIC. Enhancing or restoring PDZK1 expression might therefore have therapeutic potential for cholestatic liver injury.https://www.scienceopen.com/hosted-document?doi=10.15212/AMM-2024-0053mir-128-3pestrogen-induced cholestasismrp2pdzk1localization |
| spellingShingle | Yue Zu Qianyan Gao Yisheng He Qiao Deng Guodong Li Xiping Li Tianze Shang Xinwei Cheng Chenglong Zhu Jianqiao Wang Dong Liu Chengliang Zhang MiR-128-3p mediates MRP2 internalization in estrogen-induced cholestasis through targeting PDZK1 Acta Materia Medica mir-128-3p estrogen-induced cholestasis mrp2 pdzk1 localization |
| title | MiR-128-3p mediates MRP2 internalization in estrogen-induced cholestasis through targeting PDZK1 |
| title_full | MiR-128-3p mediates MRP2 internalization in estrogen-induced cholestasis through targeting PDZK1 |
| title_fullStr | MiR-128-3p mediates MRP2 internalization in estrogen-induced cholestasis through targeting PDZK1 |
| title_full_unstemmed | MiR-128-3p mediates MRP2 internalization in estrogen-induced cholestasis through targeting PDZK1 |
| title_short | MiR-128-3p mediates MRP2 internalization in estrogen-induced cholestasis through targeting PDZK1 |
| title_sort | mir 128 3p mediates mrp2 internalization in estrogen induced cholestasis through targeting pdzk1 |
| topic | mir-128-3p estrogen-induced cholestasis mrp2 pdzk1 localization |
| url | https://www.scienceopen.com/hosted-document?doi=10.15212/AMM-2024-0053 |
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