Producción CyT
Congreso
Autoría
Razori, María V
;
MARTÍN, PAMELA LUCÍA
;
Barosso, Ismael R.
;
Medeot, Anabela
;
Ciriaci, Nadia
;
Andermatten, Romina B.
;
Schuck, Virginia
;
Salas, Gimena
;
Basiglio, Cecilia L
;
Ruiz, María Laura
;
Roma, Marcelo G
Fecha
2021
Editorial y Lugar de Edición
Gráfica Taddeo
ISSN
1669-9106
Resumen
Información suministrada por el agente en
SIGEVA
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 therapyfor 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 da...
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 therapyfor 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<0.05 vs. control; #p<0.05 vs. LPS). OCA reduced ALP (U/L) in LPS-treated rats (193 ± 18# vs. 338 ± 72*), and improved BSO (nmol/g liver) (1274 ± 152 vs. 896 ± 86). This was due to anincrease in the % of Bsep in the apical membrane (104 ± 13# vs. 52 ± 9*), a finding confirmed by image analysis of confocal images (p<0.001). OCA also halted the elevations (pg/ml) of TNF-α (266 ± 56*# vs. 860 ± 153*) and IL-1β (13 ± 2# vs. 52 ± 8*). Neither the drop in Ntcp (46 ± 11* vs. 52 ± 9*) nor the increase in Mrp3 (279 ± 29* vs. 299 ± 60*) expression induced by LPS (% of control) was affected. Conclusions: LPS impairs BSO, leading to BS accumulation (cholestasis). OCA prevented this by improving apical Bsep localization and the subsequent BSO; the adaptive BS urinary elimination afforded by the impaired uptake and the increased sinusoidal efflux of BSs was maintained. Counteraction of cytokine elevations may be crucial for OCA beneficial effects.
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Palabras Clave
OBETICHOLIC ACIDANTICHOLESTATICCHOLESTASISLIPOPLYSACARIDE (LPS)