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

Estrogens are reported to cause the dysfunction of biliary transport systems inducing cholestasis, and multidrug resistance-associated protein 2 (MRP2), is a significant transporter responsible for independent bile flow. Emerging evidence shows that the PDZ domain containing 1 (PDZK1) regulates the localization of MRP2, but whether PDZK1 is involved in the MRP2-mediated estrogen-induced cholestasis (EIC), and the regulatory machinery of PDZK1 is unclear. Our study utilized a mouse model of EIC to show that PDZK1 expression was downregulated in liver, which is consistent with increased intracellular domain MRP2 internalization. Notably, the miR-128-3p expression, one of the potential biomarkers of estrogen-related cholestasis discovered by our group, was significantly elevated. We discovered that miR-128-3p targeted the 3’-untranslated region (UTR) of PDZK1 in EIC, thereby promoting MRP2 internalization. Accordingly, miR-128-3p suppression effectively upregulated PDZK1, thereby suppressing the internalization of MRP2 and significantly attenuating cholestatic liver disease. Furthermore, the MRP2 internalization and PDZK1 downregulation, as well as excessive miR-128-3p, were also observed in clinical samples from patients with cholestatic liver injury. Overall, the study’s results illustrate that miR-128-3p inhibited PDZK1 expression, thereby inhibiting the membrane localization of MRP2 and resulting in EIC, and enhancing PDZK1 expression has therapeutic potential to treat cholestatic liver injury.