Liver kinase B1/AMP-activated protein kinase-mediated regulation by gentiopicroside ameliorates P2X7 receptor-dependent alcoholic hepatosteatosis.
Br J Pharmacol
; 175(9): 1451-1470, 2018 05.
Article
en En
| MEDLINE
| ID: mdl-29338075
ABSTRACT
BACKGROUND AND PURPOSE:
Regulating P2X7 receptor-mediated activation of NLRP3 inflammasomes could be a therapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process was modulated by gentiopicroside, the main active secoiridoid glycoside from Gentiana manshurica Kitagawa. EXPERIMENTALAPPROACH:
In vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administered ethanol or using chronic plus binge ethanol feeding of Lieber-DeCarli liquid diet to male C57BL/6 mice. In vitro, HepG2 cells were treated with ethanol. RAW 264.7 macrophages and murine bone marrow-derived macrophages (BMDMs) were stimulated with LPS and ATP. KEYRESULTS:
In both the acute and chronic alcohol-induced mouse hepatosteatosis models, gentiopicroside decreased serum aminotransferases and triglyceride accumulation. Up-regulated SREBP1, down-regulated PPARα and phosphorylated acetyl-CoA carboxylase caused by acute and chronic alcohol feeding were modulated by gentiopicroside, through the elevation of LKB1 and AMPK. Suppression of P2X7 receptor-NLRP3 activation by gentiopicroside inhibited IL-1ß production. In ethanol-exposed HepG2 cells, gentiopicroside reduced lipogenesis and promoted lipid oxidation via activation of P2X7 receptor-NLRP3 inflammasomes. Genetic or pharmacological blockade of P2X7 receptors enhanced AMPK activity and reduced SREBP1 expression in ethanol-treated HepG2 cells. Gentiopicroside down-regulated P2X7 receptor-mediated inflammatory responses in LPS/ATP-stimulated RAW 264.7 macrophages and BMDMs. IL-1ß from macrophages accelerated lipid accumulation in hepatocytes. Depleting macrophages by clodronate liposomes ameliorated alcoholic hepatosteatosis, and it was further alleviated by gentiopicroside. CONCLUSIONS AND IMPLICATIONS Activation of LKB1/AMPK signalling by gentiopicroside was mediated by the P2X7 receptor-NLRP3 inflammasome, suggesting the therapeutic value of blocking P2X7 receptors in the treatment of alcoholic hepatosteatosis.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Serina-Treonina Quinasas
/
Proteínas Quinasas Activadas por AMP
/
Hígado Graso Alcohólico
/
Glucósidos Iridoides
/
Receptores Purinérgicos P2X7
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Br J Pharmacol
Año:
2018
Tipo del documento:
Article
País de afiliación:
China