LKB1/AMPK-Mediated Regulation by Gentiopicroside Ameliorates P2x7R-Dependent Alcoholic Hepatosteatosis

[Speaker] Li-Hua Lian:1
[Co-author] Yu Zhang:1, Xia Li:1, Ben-Wen Cui:1, Xin Han:1, Yan-Ling Wu:1, Ji-Xing Nan:1
1:Yanbian Univerisity, China

Regulating P2x7R-NLRP3 inflammasome activation might be a potential therapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process would be modulated by gentiopicroside (GPS), which is main active secoiridoid glycoside from Gentiana manshurica Kitagawa. In vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administrated with ethanol or using chronic plus binge ethanol feeding of Lieber-DeCarli liquid diet to male C57BL/6 mice. In vitro models were created by treating HepG2 cells with ethanol or stimulating RAW 264.7 macrophages and murine bone marrow-derived macrophages (BMDMs) with LPS plus ATP. Both of acute and chronic alcohol-induced mice hepatosteatosis model, GPS decreased serum aminotransferases and triglyceride accumulation. Upregulated SREBP1 and downregulated PPARalpha and phosphorated ACC caused by acute and chronic alcohol feeding was modulated by GPS application through elevating LKB1/AMPK. Suppression of P2x7R-NLRP3 activation by GPS led to inhibition of IL-1beta production. In ethanol-exposed HepG2 cells, GPS reduced lipogenesis and promoted lipid oxidation via P2x7R-NLRP3 inflammasome activation. Genetical or pharmacological blockade of P2x7R enhanced AMPK activity, and reduced SREBP1 expression in ethanol-treated HepG2 cells. GPS downregulated P2x7R-mediated inflammatory response LPS plus ATP stimulated RAW 264.7 macrophages and BMDMs. IL-1beta from macrophages accelerate lipid accumulation of hepatocytes. Depleting macrophages by clodronate liposomes ameliorated alcoholic hepatosteatosis, and further alleviated by GPS. Activation of LKB1-AMPK signaling by GPS might be mediated by P2x7R-NLRP3 inflammasome, suggesting a therapeutic utility of P2x7R blockade in alcoholic hepatosteatosis treatment.
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