SUSTAINED INTERNALIZATION OF THE HEPATO-CANALICULAR TRANSPORTER MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2 (MRP2) IN CHOLESTASIS LEADS TO ITS EXACERBATED PROTEOSOMAL DEGRADATION

MEDEOT, ANABELA CAROLINA; ANDERMATTEN, ROMINA B.; SALAS, GIMENA; SCHUCK, VIRGINIA SOLEDAD; BAROSSO, ISMAEL R.; CROCENZI, FERNANDO A.; ROMA, MARCELO G

Mar del Plata

Congreso; Reunion Anual de Sociedades de Biociencias 2022; 2022

SAIC-SAI-SAFIS

Exacerbated endocytosis of canalicular carriers, including Mrp2, is a main mechanism involved in cholestasis, as has been shown with the model cholestatic agent, taurolithocholate (TLC) (Crocenzi et al. Gut 52: 1170, 2003). We hypothesized that this exacerbat- ed internalization is followed by accelerated degradation, thus ex- plaining the unchanged carrier protein expression despite increased synthesis observed in chronic cholestatic diseases. We therefore tested here whether sustained Mrp2 internalization leads to accelerated degradation, and if so, which degradation mechanism is involved. Mrp2 protein expression was quantified by Western blot in sandwich-cultured rat hepatocytes (SCRH) incubated with TLC (2.5 μM), or vehicle (DMSO) in controls (C), in the presence of cycloheximide to block “de novo” Mrp2 synthesis. TLC exposure for 12 hs induced no change in Mrp2 expression as compared to C, whereas a significant decrease was observed at 24 h (69±4%; n=7) and 48 h (66±8%; n=3); p