Anticholestatic mechanisms of ursodeoxycholic acid in lipopolysaccharide-induced cholestasis

RAZORI, MV; MAIDAGAN, PM; CIRIACI, N; ANDERMATTEN, RB; BAROSSO IR; MARTÍN, PL; BASIGLIO, CL; SANCHEZ POZZI EJ; RUIZ ML; ROMA, MG

BIOCHEMICAL PHARMACOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2019 vol. 168 p. 48 - 56

0006-2952

Lipopolysaccharide (LPS) from Gram (-) bacteria induces inflammatory cholestasis by impairing the expression/localization of transporters involved in bile formation (e.g., Bsep, Mrp2). Therapeutic options for this disease arelacking. Ursodeoxycholic acid (UDCA) is the first choice therapy in cholestasis, but its anticholestatic efficacy inthis hepatopathy remains to be evaluated. To asses it, male Wistar rats received UDCA for 5 days (25 mg/Kg/day,i.p.) with or without LPS, administered at 8 a.m. of the last 2 days (4 mg/Kg/day, i.p.), plus half of this dose at8 p.m. of the last day. Then, plasma alkaline phosphatase (ALP), bile flow, basal and taurocholate-stimulated bileacid output, total glutathione output, and total/plasma membrane liver protein expression of Bsep and Mrp2 byconfocal microscopy were assessed. mRNA levels of both transporters were assessed by Real-Time PCR. Plasmapro-inflammatory cytokines (IL-6 and TNF-α) were measured by ELISA. Our results showed that UDCA attenuatedLPS-induced ALP plasma release and the impairment in the excretion of the Bsep substrate, taurocholate.This was associated with an improved Bsep expression at both mRNA and protein levels, and by an improvedlocalization of Bsep in plasma membrane. UDCA failed to reduce the increase in plasma pro-inflammatory cytokinesinduced by LPS and Mrp2 expression/function. In conclusion, UDCA protects the hepatocyte against thedamaging effect of bile acids accumulated by the LPS-induced secretory failure. This involved an enhancedsynthesis of Bsep and an improved membrane stability of the newly synthesized transporters.