3 years ago

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

Ji-Xing Nan, Li-Hua Lian, Yan-Ling Wu, Quan Jin, Kai-Li Xia, Yu Zhang, Shun-Zong Song, Xia Li, Ben-Wen Cui, Min Jiang
Background and purpose 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 the main active secoiridoid glycoside from Gentiana manshurica Kitagawa. Experimental approach In vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administrated 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. Key results In both the acute and chronic alcohol-induced mouse hepatosteatosis models, GPS decreased serum aminotransferases and triglyceride accumulation. Upregulated SREBP1, downregulated PPARα and phosphorylated ACC caused by acute and chronic alcohol feeding were modulated by GPS application through the elevation of LKB1/AMPK. Suppression of P2x7R-NLRP3 activation by GPS led to the inhibition of IL-1β production. In ethanol-exposed HepG2 cells, GPS reduced lipogenesis and promoted lipid oxidation via P2x7R-NLRP3 inflammasome activation. Genetic or pharmacological blockade of P2x7R enhanced AMPK activity and reduced SREBP1 expression in ethanol-treated HepG2 cells. GPS downregulated the P2x7R-mediated inflammatory response in LPS/ATP-stimulated RAW 264.7 macrophages and BMDMs. IL-1β from macrophages accelerated the lipid accumulation in hepatocytes. Depleting macrophages by clodronate liposomes ameliorated alcoholic hepatosteatosis, and it was further alleviated by GPS. Conclusions and implications Activation of LKB1/AMPK signaling by GPS might be mediated by the P2x7R-NLRP3 inflammasome, suggesting a therapeutic utility of P2x7R blockade in alcoholic hepatosteatosis treatment.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14145

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