PDZK1's role in estrogen-induced cholestasis unveiled

Announcing a new publication for Acta Materia Medica journal. 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.

The authors of this article observed, in a mouse model of EIC, 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 the authors, was significantly elevated. It was 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, MRP2 internalization and PDZK1 downregulation, as well as excessive miR-128-3p, in clinical samples from patients with cholestatic liver injury were observed.

Overall, these 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.​