DOI: 10.1002/ame2.12506
The N-terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism
Xue Wang1
Chunyou Ning1
Xingyi Cheng1
Zhengzhong Wu1
Dongbo Wu2
Xuemei Ding1
Cunxiang Ju3
Zhihang Zhou4
Lingfeng Wan5
Wei Zhao6
Peiliang Shi7
1.GemPharmatech Chengdu Co.,Ltd.,Chengdu,China2.Center of Infectious Diseases,West China Hospital,Sichuan University,Chengdu,China3.Gempharmatech Shanghai Co.,Ltd.,Shanghai,China4.Department of Gastroenterology,the Second Affiliated Hospital of Chongqing Medical University,Chongqing,China5.Fatty Liver Disease Center of Integrated Chinese and Western Medicine,Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing,China6.School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College,Chengdu,China;Department of Clinical Biochemistry,School of Laboratory Medicine,Chengdu Medical College,Chengdu,China7.GemPharmatech Chengdu Co.,Ltd.,Chengdu,China;GemPharmatech Co.,Ltd.,Guangdong,China
摘要：Background:The emerging incidence of pathogenic liver conditions is turning into a major concern for global health.Induction of pyroptosis in hepatocytes instigates cel-lular disintegration,which in turn liberates substantial quantities of pro-inflammatory intracellular substances,thereby accelerating the advancement of liver fibrosis.Consequently,directing therapeutic efforts towards inhibiting pyroptosis could po-tentially serve as an innovative approach in managing inflammation related chronic hepatic disorders.
Methods:GSDMD-NTki/wt mice and Alb-creki/wt mice were generated using CRISPR/Cas9 technology.After crossing the two strains together,we induced conditional cell death by doxycycline to construct a mouse model of liver fibrosis.We analyzed differ-entially expressed genes by RNA sequencing and explored their biological functions.The efficacy of obeticholic acid(OCA)in the treatment of liver fibrosis was assessed.
Results:Doxycycline-treated GSDMD-NTki/wt×Alb-creki/wt mice showed severe liver damage,vacuolation of hepatocytes,increased collagen fibers,and accumulation of lipid droplets.The expression of liver fibrosis related genes was greatly increased in the doxycycline-treated mouse liver compared with untreated mouse liver.RNA-sequencing showed that upregulated differentially expressed genes were involved in inflammatory responses,cell activation,and metabolic processes.Treatment with OCA alleviated the liver fibrosis,with reduced ALT and AST levels seen in the GSDMD-NTki/wtxAlb-creki/wt mice.
Conclusions:We successfully constructed a novel mouse model for liver fibrosis.This GSDMD-NT-induced fibrosis may be mediated by abnormal lipid metabolism.Our re-sults demonstrated that we successfully constructed a mouse model of liver fibrosis,and GSDMD-NT induced fibrosis by mediating lipid metabolism.
机标关键词：fibrosisdomaingasdermininduceslipidlivermetabolismn-terminal
论文发表日期：2025-01-28
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：12( 114-125 )
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