Gentiopicroside ameliorates LKB1/AMPK-dependent alcoholic hepatosteatosis via P2x7R-NLRP3 inflammasome  

作　　者：Xia LI Yu ZHANG Kai-li XIA Min JIANG Ben-wen CUI Yan-ling WU Ji-xing NAN Li-hua LIAN 

机构地区：[1]Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China

出　　处：《中国药理学与毒理学杂志》2018年第4期265-266,共2页Chinese Journal of Pharmacology and Toxicology

基　　金：supported by National Natural Science Foundation of China(81560597;81260664;81360658;81660689)

摘　　要：OBJECTIVE 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 attributed to the bitterness of gentian root extract.METHODS An in vivo model was established by intragastrically treating mice with ethanol,and an in vitro model was created by treating HepG2 cells with ethanol or treating RAW 264.7 macrophages and murine bone marrow-derived macrophages(BMDMs) with lipopolysaccharides(LPS) plus adenosine triphos.phate(ATP).RESULTS In alcoholic hepatosteatotic mice model,GPS decreased serum aminotrans.ferase and triglyceride accumulation.GPS regulated sterol regulatory element-binding protein-1(Srebp1),peroxisome proliferators-actived receptors α(PPARα) and acetyl CoA carboxylase(ACC) expression via elevating liver kinase B1(LKB1)/AMP-activated Kinase(AMPK).Suppression of nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),caspase-1 and expression by GPS resulted in the inhibition of interleukin-1β(IL-1β) production.In ethanol-exposed HepG2 cells,GPS reduced lipo.genesis and promoted lipid oxidation via P2x7R-NLRP3 inflammasome activation.P2x7R silencing enhanced AMPK activity,and reduced Srebp1 expression in ethanol-treated hepatocytes.GPS down.regulated P2x7R-mediated inflammatory response to extracellular ATP in LPS-primed RAW 264.7 macro.phages and BMDMs.Additionally,P2x7R deficiency attenuated IL-1β cleavage in RAW 264.7 macro.phages,and GPS further suppressed IL-1β cleavage.CONCLUSION 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.OBJECTIVE 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 attributed to the bitterness of gentian root extract.METHODS An in vivo model was established by intragastrically treating mice with ethanol,and an in vitro model was created by treating HepG2 cells with ethanol or treating RAW 264.7 macrophages and murine bone marrow-derived macrophages（BMDMs） with lipopolysaccharides（LPS） plus adenosine triphos.phate（ATP）.RESULTS In alcoholic hepatosteatotic mice model,GPS decreased serum aminotrans.ferase and triglyceride accumulation.GPS regulated sterol regulatory element-binding protein-1（Srebp1）,peroxisome proliferators-actived receptors α（PPARα） and acetyl CoA carboxylase（ACC） expression via elevating liver kinase B1（LKB1）/AMP-activated Kinase（AMPK）.Suppression of nucleotide-binding oligomerization domain-like receptor protein 3（NLRP3）,caspase-1 and expression by GPS resulted in the inhibition of interleukin-1β（IL-1β） production.In ethanol-exposed HepG2 cells,GPS reduced lipo.genesis and promoted lipid oxidation via P2x7R-NLRP3 inflammasome activation.P2x7R silencing enhanced AMPK activity,and reduced Srebp1 expression in ethanol-treated hepatocytes.GPS down.regulated P2x7R-mediated inflammatory response to extracellular ATP in LPS-primed RAW 264.7 macro.phages and BMDMs.Additionally,P2x7R deficiency attenuated IL-1β cleavage in RAW 264.7 macro.phages,and GPS further suppressed IL-1β cleavage.CONCLUSION 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.

关 键 词：炎症 酒精肝 治疗方法 临床分析 

分 类 号：R364.5[医药卫生—病理学] R575[医药卫生—基础医学]