MiR-128-3p mediates MRP2 internalization in estrogen-induced cholestasis through targeting PDZK1

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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Main Authors: Yue Zu, Qianyan Gao, Yisheng He, Qiao Deng, Guodong Li, Xiping Li, Tianze Shang, Xinwei Cheng, Chenglong Zhu, Jianqiao Wang, Dong Liu, Chengliang Zhang
Format: Article
Language:English
Published: Compuscript Ltd 2025-02-01
Series:Acta Materia Medica
Subjects:
mir-128-3p
estrogen-induced cholestasis
mrp2
pdzk1
localization
Online Access:https://www.scienceopen.com/hosted-document?doi=10.15212/AMM-2024-0053
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Summary: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.
ISSN:2737-7946

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