Anticholestatic mechanisms of obeticholic acid (OCA) in lipoplysacaride (LPS)-induced cholestasis in the rat

RAZORI, MV; MARTÍN, PL; BAROSSO IR; MEDEOT, AC; CIRIACI, N; ANDERMATTEN, RB; SCHUK, VS; SALAS, G; BASIGLIO CL; RUIZ ML; ROMA MG

Virtual

Congreso; Reunión Conjunta SAIC SAI AAFE NANOMED; 2021

SAIC SAI AAFE NANOMED

Sepsis-induced cholestasis is due the release of inflammatory cytokines induced by LPS from Gram (-) bacteria, which impair expression/localization of hepatocellular transporters. There is no therapy for this condition. OCA is a potent FXR agonist used to treat human inflammatory chronic cholestasis. We ascertained here its anticholestatic mechanisms in LPS-induced cholestasis.Methods: Male Wistar rats were randomized in Control, OCA (20 mg/Kg/day, i.p., 6 days), LPS (6.5 mg/Kg, i.p., last 2 days) and OCA+LPS groups. Then, we assessed serum alkaline phosphatase (ALP), a surrogate of bile salt (BS) hepatic accumulation, and taurocholate-stimulated BS output (BSO). mRNA/protein levels of Bsep and Mrp3 (apical and sinusoidal BS efflux pumps, respectively) and Ntcp (BS uptake carrier) were assessed by either or both Real time PCR and Western blot. Bsep localization was assessed by immunohistochemistry followed by confocal microscopy and image analysis. The inflammatory cytokines TNF-α and IL-1β were measured in serum by ELISA.Results: (*p