JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis

• Published in: Clinical and molecular hepatology Vol. 30; no. 2; pp. 206 - 224
• Main Authors: Xie, Li, Chen, Hui, Zhang, Li, Ma, Yue, Zhou, Yuan, Yang, Yong-Yu, Liu, Chang, Wang, Yu-Li, Yan, Ya-Jun, Ding, Jia, Teng, Xiao, Yang, Qiang, Liu, Xiu-Ping, Wu, Jian
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Association for the Study of the Liver 01.04.2024; The Korean Association for the Study of the Liver; 대한간학회
• Subjects: Animals; Bile ducts; Carcinoma, Hepatocellular - pathology; Cardiovascular disease; Cholangitis; cholestasis; Cholestasis - complications; Fibroblasts; Gallbladder diseases; Genomes; Growth factors; hepatic stellate cells; Hepatic Stellate Cells - metabolism; hippo-yap signaling; Human subjects; Humans; jcad; Kinases; Liver - pathology; Liver cancer; Liver cirrhosis; Liver Cirrhosis - etiology; Liver Cirrhosis - metabolism; Liver diseases; Liver Neoplasms - pathology; Liver transplants; Mice; Mice, Knockout; Normal distribution; Original; Patients; Phosphorylation; primary biliary cholangitis; Proteins; Statistical analysis; 내과학; United States > US; China; Primary biliary cholangitis; Hepatic stellate cells; Hippo-YAP signaling; Cholestasis; JCAD
• ISSN: 2287-2728; 2287-285X; 2287-285X
• DOI: 10.3350/cmh.2023.0506

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.