JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis
Background/Aims Cholestatic liver diseases including primary biliary cholangitis (PBC) are associated with active hepatic fibrogenesis, which ultimately progresses to cirrhosis. Activated hepatic stellate cells (HSCs) are the main fibrogenic effectors in response to cholangiocyte damage. JCAD regula...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Korean Association for the Study of the Liver
2024-04-01
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| Series: | Clinical and Molecular Hepatology |
| Subjects: | |
| Online Access: | http://e-cmh.org/upload/pdf/cmh-2023-0506.pdf |
| _version_ | 1797208833583480832 |
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| author | Li Xie Hui Chen Li Zhang Yue Ma Yuan Zhou Yong-Yu Yang Chang Liu Yu-Li Wang Ya-Jun Yan Jia Ding Xiao Teng Qiang Yang Xiu-Ping Liu Jian Wu |
| author_facet | Li Xie Hui Chen Li Zhang Yue Ma Yuan Zhou Yong-Yu Yang Chang Liu Yu-Li Wang Ya-Jun Yan Jia Ding Xiao Teng Qiang Yang Xiu-Ping Liu Jian Wu |
| author_sort | Li Xie |
| collection | DOAJ |
| description | Background/Aims Cholestatic liver diseases including primary biliary cholangitis (PBC) are associated with active hepatic fibrogenesis, which ultimately progresses to cirrhosis. Activated hepatic stellate cells (HSCs) are the main fibrogenic effectors in response to cholangiocyte damage. JCAD regulates cell proliferation and malignant transformation in nonalcoholic steatoheaptitis-associated hepatocellular carcinoma (NASH-HCC). However, its participation in cholestatic fibrosis has not been explored yet. Methods Serial sections of liver tissue of PBC patients were stained with immunofluorescence. Hepatic fibrosis was induced by bile duct ligation (BDL) in wild-type (WT), global JCAD knockout mice (JCAD-KO) and HSC-specific JCAD knockout mice (HSC-JCAD-KO), and evaluated by histopathology and biochemical tests. In situ-activated HSCs isolated from BDL mice were used to determine effects of JCAD on HSC activation. Results In consistence with staining of liver sections from PBC patients, immunofluorescent staining revealed that JCAD expression was identified in smooth muscle α-actin (α-SMA)-positive fibroblast-like cells and was significantly up-regulated in WT mice with BDL. JCAD deficiency remarkably ameliorated BDL-induced hepatic injury and fibrosis, as documented by liver hydroxyproline content, when compared to WT mice with BDL. Histopathologically, collagen deposition was dramatically reduced in both JCAD-KO and HSC-JCAD-KO mice compared to WT mice, as visualized by Trichrome staining and semi-quantitative scores. Moreover, JCAD deprivation significantly attenuated in situ HSC activation and reduced expression of fibrotic genes after BDL. Conclusions JCAD deficiency effectively suppressed hepatic fibrosis induced by BDL in mice, and the underlying mechanisms are largely through suppressed Hippo-YAP signaling activity in HSCs. |
| first_indexed | 2024-04-24T09:45:05Z |
| format | Article |
| id | doaj.art-105246d534294e329a2787001f048cec |
| institution | Directory Open Access Journal |
| issn | 2287-2728 2287-285X |
| language | English |
| last_indexed | 2024-04-24T09:45:05Z |
| publishDate | 2024-04-01 |
| publisher | Korean Association for the Study of the Liver |
| record_format | Article |
| series | Clinical and Molecular Hepatology |
| spelling | doaj.art-105246d534294e329a2787001f048cec2024-04-15T02:11:08ZengKorean Association for the Study of the LiverClinical and Molecular Hepatology2287-27282287-285X2024-04-0130220622410.3350/cmh.2023.05061877JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosisLi Xie0Hui Chen1Li Zhang2Yue Ma3Yuan Zhou4Yong-Yu Yang5Chang Liu6Yu-Li Wang7Ya-Jun Yan8Jia Ding9Xiao Teng10Qiang Yang11Xiu-Ping Liu12Jian Wu13 Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China Department of Pathology, Shanghai Fifth People’s Hospital, School of Basic Medical Sciences, Fudan University, Shanghai, China Department of Gastroenterology, Jing’an District Central Hospital, Fudan University, Shanghai, China HistoIndex Pte Ltd, Singapore, Singapore Hangzhou Choutu Technology Co., Ltd., Hangzhou, China Department of Pathology, Shanghai Fifth People’s Hospital, School of Basic Medical Sciences, Fudan University, Shanghai, China Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, ChinaBackground/Aims Cholestatic liver diseases including primary biliary cholangitis (PBC) are associated with active hepatic fibrogenesis, which ultimately progresses to cirrhosis. Activated hepatic stellate cells (HSCs) are the main fibrogenic effectors in response to cholangiocyte damage. JCAD regulates cell proliferation and malignant transformation in nonalcoholic steatoheaptitis-associated hepatocellular carcinoma (NASH-HCC). However, its participation in cholestatic fibrosis has not been explored yet. Methods Serial sections of liver tissue of PBC patients were stained with immunofluorescence. Hepatic fibrosis was induced by bile duct ligation (BDL) in wild-type (WT), global JCAD knockout mice (JCAD-KO) and HSC-specific JCAD knockout mice (HSC-JCAD-KO), and evaluated by histopathology and biochemical tests. In situ-activated HSCs isolated from BDL mice were used to determine effects of JCAD on HSC activation. Results In consistence with staining of liver sections from PBC patients, immunofluorescent staining revealed that JCAD expression was identified in smooth muscle α-actin (α-SMA)-positive fibroblast-like cells and was significantly up-regulated in WT mice with BDL. JCAD deficiency remarkably ameliorated BDL-induced hepatic injury and fibrosis, as documented by liver hydroxyproline content, when compared to WT mice with BDL. Histopathologically, collagen deposition was dramatically reduced in both JCAD-KO and HSC-JCAD-KO mice compared to WT mice, as visualized by Trichrome staining and semi-quantitative scores. Moreover, JCAD deprivation significantly attenuated in situ HSC activation and reduced expression of fibrotic genes after BDL. Conclusions JCAD deficiency effectively suppressed hepatic fibrosis induced by BDL in mice, and the underlying mechanisms are largely through suppressed Hippo-YAP signaling activity in HSCs.http://e-cmh.org/upload/pdf/cmh-2023-0506.pdfprimary biliary cholangitischolestasishepatic stellate cellsjcadhippo-yap signaling |
| spellingShingle | Li Xie Hui Chen Li Zhang Yue Ma Yuan Zhou Yong-Yu Yang Chang Liu Yu-Li Wang Ya-Jun Yan Jia Ding Xiao Teng Qiang Yang Xiu-Ping Liu Jian Wu JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis Clinical and Molecular Hepatology primary biliary cholangitis cholestasis hepatic stellate cells jcad hippo-yap signaling |
| title | JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis |
| title_full | JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis |
| title_fullStr | JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis |
| title_full_unstemmed | JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis |
| title_short | JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis |
| title_sort | jcad deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis |
| topic | primary biliary cholangitis cholestasis hepatic stellate cells jcad hippo-yap signaling |
| url | http://e-cmh.org/upload/pdf/cmh-2023-0506.pdf |
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