Clin Mol Hepatol.
2024 Apr;30(2):206-224. 10.3350/cmh.2023.0506.
JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis
- Affiliations
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- 1Department 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
- 2Department of Pathology, Shanghai Fifth People’s Hospital, School of Basic Medical Sciences, Fudan University, Shanghai, China
- 3Department of Gastroenterology, Jing’an District Central Hospital, Fudan University, Shanghai, China
- 4HistoIndex Pte Ltd, Singapore, Singapore
- 5Hangzhou Choutu Technology Co., Ltd., Hangzhou, China
- 6Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
- 7Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
- KMID: 2554427
- DOI: http://doi.org/10.3350/cmh.2023.0506
Abstract
- 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.
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