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Amitriptyline inhibits NLRP3 inflammasome activation via the asm/ce pathway in a cell model of NAFLD

BIOceLL 2024年第5期48卷 759-769页

作者： QIN LIU CHUNYAN NIU QIANG ZHANG SHIQIN SUN YUE CHEN YONGQIANG SHI Shengli Clinical Medical College Fujian Medical UniversityFuzhou350001China Department of Gastroenterology Nanjing Lishui People’s HospitalZhongda Hospital Lishui BranchSoutheast UniversityNanjing211200China Department of Gastroenterology Yancheng Third People’s Hospital(The Yancheng School of Clinical Medicine of Nanjing Medical University)Yancheng224000China Administrative Department of Teaching and Scientific Research Nanjing Lishui People’s HospitalZhongda Hospital Lishui BranchSoutheast UniversityNanjing211200China

Background:Nonalcoholic fatty liver disease(NAFLD)is a global health concern with the acid sphingomyelinase(asm)/ceramide(ce)pathway and the NOD-like receptor family,pyrin domain-containing protein 3(NLRP3)inflammasome identified as pivotal players in lipid disorders and inflammation.This study explores the interaction mechanism between the asm/ce pathway and NLRP3 in NAFLD cell models,aiming to understand the impact of amitriptyline(Ami),an asm inhibitor,on lipid deposition and hepatocyte injury by regulating the asm/ce-NLRP3 pathway.Methods:HepG2 and HL-7702 cells were exposed to free fatty acids(FFAs)to establish the NAFLD model.The cells were divided into 5 groups:control group,model group,Ami group,tumor necrosis factoralpha(TNF-α)group,and Ami+TNF-αgroup.Intracellular lipid droplets were visualized using Oil Red O staining,and Western blot analysis quantified asm,NLRP3,and caspase 1 protein expression.Enzyme linked immunosorbent assay(ELISA)was measured ce and asm levels,while qRT-PCR assessed mRNA expression.The apoptotic rate was evaluated by flow cytometry(FCM).Results:Following FFAs incubation,significant increases in asm and ce levels were observed in HepG2 and HL-7702 cells,accompanied by elevated expression of NLRP3,and caspase 1,and IL-1β.TNF-αtreatment further amplified these indicators.Ami demonstrated a reduction in lipid deposition,suppressed asm/ce pathway activation,downregulated NLRP3 and caspase 1 expression,and improved apoptosis.Additionally,MCC950,a selective inhibitor of the NLRP3,mitigated NLRP3,caspase 1,and IL-1βexpression,alleviating lipid deposition and apoptosis in the NAFLD cell model.Conclusion:The asm/ce-NLRP3 pathway in NAFLD cells promotes hepatocyte steatosis,inflammation,and cell damage.Ami emerges as a promising therapeutic agent by inhibiting the asm/ce-NLRP3 pathway,underscoring its potential as a key target for NAFLD treatment.

关键词： Nonalcoholic fatty liver disease Hepatocyte Amitriptyline asm/ce pathway NLRP3 Nonalcoholic steatohepatitis

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