BACKGROUND Cholelithiasis is a prevalent biliary tract disorder primarily characterized by gallbladder or biliary stone formation.Although succinylation has been exten-sively studied as a protein post-translational mo...BACKGROUND Cholelithiasis is a prevalent biliary tract disorder primarily characterized by gallbladder or biliary stone formation.Although succinylation has been exten-sively studied as a protein post-translational modification,its role in cholelithiasis remains unexplored.AIM To investigate the functional role of succinylation in cholelithiasis and determine its underlying molecular mechanisms.METHODS A murine cholelithiasis model was established through high-fat diet feeding,followed by isolation of mouse gallbladder mucosal epithelial cells(GMECs)for in vitro analysis.Gallbladder tissues and serum samples were collected for subsequent analysis.Inflammatory cytokine production was quantified using enzyme-linked immunosorbent assay.Pyroptosis was analyzed by flow cytometry,while succinylation-and pyroptosis-related protein expression was detected via western blot.RESULTS Our findings demonstrated that lysine acetyltransferase 2A(KAT2A)-mediated succinylation regulated gallstone formation.KAT2A overexpression inhibited the pyroptosis,inflammatory responses,and promoted the activation of the adenosine monophosphate-activated protein kinase(AMPK)/silent information regulator 1(SIRT1)sig-naling pathway in GMECs.Mechanistically,AMPK exhibited succinylation at lysine 170(K170).Notably,AMPK inhibition significantly increased pyroptosis rates,inflammatory responses,and pyroptosis-related protein ex-pression in GMECs.Furthermore,in vivo experiments revealed that KAT2A overexpression suppressed both inflammation and gallstone formation.CONCLUSION KAT2A-mediated succinylation of AMPK inhibited cholelithiasis progression by modulating the AMPK/SIRT1 signaling pathway,offering potential therapeutic strategies for this condition.展开更多
基金Supported by National Natural Science Foundation of China,No.82000579 and No.81870205Natural Science Foundation of Shandong Province,No.ZR2021QH061 and No.ZR2021QH186.
文摘BACKGROUND Cholelithiasis is a prevalent biliary tract disorder primarily characterized by gallbladder or biliary stone formation.Although succinylation has been exten-sively studied as a protein post-translational modification,its role in cholelithiasis remains unexplored.AIM To investigate the functional role of succinylation in cholelithiasis and determine its underlying molecular mechanisms.METHODS A murine cholelithiasis model was established through high-fat diet feeding,followed by isolation of mouse gallbladder mucosal epithelial cells(GMECs)for in vitro analysis.Gallbladder tissues and serum samples were collected for subsequent analysis.Inflammatory cytokine production was quantified using enzyme-linked immunosorbent assay.Pyroptosis was analyzed by flow cytometry,while succinylation-and pyroptosis-related protein expression was detected via western blot.RESULTS Our findings demonstrated that lysine acetyltransferase 2A(KAT2A)-mediated succinylation regulated gallstone formation.KAT2A overexpression inhibited the pyroptosis,inflammatory responses,and promoted the activation of the adenosine monophosphate-activated protein kinase(AMPK)/silent information regulator 1(SIRT1)sig-naling pathway in GMECs.Mechanistically,AMPK exhibited succinylation at lysine 170(K170).Notably,AMPK inhibition significantly increased pyroptosis rates,inflammatory responses,and pyroptosis-related protein ex-pression in GMECs.Furthermore,in vivo experiments revealed that KAT2A overexpression suppressed both inflammation and gallstone formation.CONCLUSION KAT2A-mediated succinylation of AMPK inhibited cholelithiasis progression by modulating the AMPK/SIRT1 signaling pathway,offering potential therapeutic strategies for this condition.
