The N‐terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism
Abstract Background The emerging incidence of pathogenic liver conditions is turning into a major concern for global health. Induction of pyroptosis in hepatocytes instigates cellular disintegration, which in turn liberates substantial quantities of pro‐inflammatory intracellular substances, thereby...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | Animal Models and Experimental Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ame2.12506 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832087824753491968 |
|---|---|
| author | Xue Wang Chunyou Ning Xingyi Cheng Zhengzhong Wu Dongbo Wu Xuemei Ding Cunxiang Ju Zhihang Zhou Lingfeng Wan Wei Zhao Peiliang Shi |
| author_facet | Xue Wang Chunyou Ning Xingyi Cheng Zhengzhong Wu Dongbo Wu Xuemei Ding Cunxiang Ju Zhihang Zhou Lingfeng Wan Wei Zhao Peiliang Shi |
| author_sort | Xue Wang |
| collection | DOAJ |
| description | Abstract Background The emerging incidence of pathogenic liver conditions is turning into a major concern for global health. Induction of pyroptosis in hepatocytes instigates cellular 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 potentially 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 differentially 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/wt × Alb‐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 results demonstrated that we successfully constructed a mouse model of liver fibrosis, and GSDMD‐NT induced fibrosis by mediating lipid metabolism. |
| format | Article |
| id | doaj-art-bd7849bf977f4232aed32842e9c49e0e |
| institution | Kabale University |
| issn | 2576-2095 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Animal Models and Experimental Medicine |
| spelling | doaj-art-bd7849bf977f4232aed32842e9c49e0e2025-02-06T03:52:55ZengWileyAnimal Models and Experimental Medicine2576-20952025-01-018111412510.1002/ame2.12506The N‐terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolismXue Wang0Chunyou Ning1Xingyi Cheng2Zhengzhong Wu3Dongbo Wu4Xuemei Ding5Cunxiang Ju6Zhihang Zhou7Lingfeng Wan8Wei Zhao9Peiliang Shi10GemPharmatech Chengdu Co., Ltd. Chengdu ChinaGemPharmatech Chengdu Co., Ltd. Chengdu ChinaGemPharmatech Chengdu Co., Ltd. Chengdu ChinaGemPharmatech Chengdu Co., Ltd. Chengdu ChinaCenter of Infectious Diseases West China Hospital, Sichuan University Chengdu ChinaGemPharmatech Chengdu Co., Ltd. Chengdu ChinaGempharmatech Shanghai Co., Ltd. Shanghai ChinaDepartment of Gastroenterology the Second Affiliated Hospital of Chongqing Medical University Chongqing ChinaFatty Liver Disease Center of Integrated Chinese and Western Medicine Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing ChinaSchool of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College Chengdu ChinaGemPharmatech Chengdu Co., Ltd. Chengdu ChinaAbstract Background The emerging incidence of pathogenic liver conditions is turning into a major concern for global health. Induction of pyroptosis in hepatocytes instigates cellular 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 potentially 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 differentially 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/wt × Alb‐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 results demonstrated that we successfully constructed a mouse model of liver fibrosis, and GSDMD‐NT induced fibrosis by mediating lipid metabolism.https://doi.org/10.1002/ame2.12506GSDMD‐NTlipid metabolismliver fibrosisNASHpyroptosis |
| spellingShingle | Xue Wang Chunyou Ning Xingyi Cheng Zhengzhong Wu Dongbo Wu Xuemei Ding Cunxiang Ju Zhihang Zhou Lingfeng Wan Wei Zhao Peiliang Shi The N‐terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism Animal Models and Experimental Medicine GSDMD‐NT lipid metabolism liver fibrosis NASH pyroptosis |
| title | The N‐terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism |
| title_full | The N‐terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism |
| title_fullStr | The N‐terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism |
| title_full_unstemmed | The N‐terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism |
| title_short | The N‐terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism |
| title_sort | n terminal domain of gasdermin d induces liver fibrosis by reprogrammed lipid metabolism |
| topic | GSDMD‐NT lipid metabolism liver fibrosis NASH pyroptosis |
| url | https://doi.org/10.1002/ame2.12506 |
| work_keys_str_mv | AT xuewang thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT chunyouning thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT xingyicheng thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT zhengzhongwu thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT dongbowu thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT xuemeiding thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT cunxiangju thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT zhihangzhou thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT lingfengwan thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT weizhao thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT peiliangshi thenterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT xuewang nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT chunyouning nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT xingyicheng nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT zhengzhongwu nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT dongbowu nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT xuemeiding nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT cunxiangju nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT zhihangzhou nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT lingfengwan nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT weizhao nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism AT peiliangshi nterminaldomainofgasdermindinducesliverfibrosisbyreprogrammedlipidmetabolism |