Anticholestatic mechanisms of ursodeoxycholic acid in lipopolysaccharide-induced cholestasis.
Biochem Pharmacol
; 168: 48-56, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31202734
ABSTRACT
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 are lacking. Ursodeoxycholic acid (UDCA) is the first choice therapy in cholestasis, but its anticholestatic efficacy in this hepatopathy remains to be evaluated. To asses it, male Wistar rats received UDCA for 5â¯days (25â¯mg/Kg/day, i.p.) with or without LPS, administered at 8â¯a.m. of the last 2â¯days (4â¯mg/Kg/day, i.p.), plus half of this dose at 8â¯p.m. of the last day. Then, plasma alkaline phosphatase (ALP), bile flow, basal and taurocholate-stimulated bile acid output, total glutathione output, and total/plasma membrane liver protein expression of Bsep and Mrp2 by confocal microscopy were assessed. mRNA levels of both transporters were assessed by Real-Time PCR. Plasma pro-inflammatory cytokines (IL-6 and TNF-α) were measured by ELISA. Our results showed that UDCA attenuated LPS-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 improved localization of Bsep in plasma membrane. UDCA failed to reduce the increase in plasma pro-inflammatory cytokines induced by LPS and Mrp2 expression/function. In conclusion, UDCA protects the hepatocyte against the damaging effect of bile acids accumulated by the LPS-induced secretory failure. This involved an enhanced synthesis of Bsep and an improved membrane stability of the newly synthesized transporters.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácido Ursodesoxicólico
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Colagogos e Coleréticos
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Lipopolissacarídeos
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Colestase
Limite:
Animals
Idioma:
En
Revista:
Biochem Pharmacol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Argentina