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.
Clin Mol Hepatol. 2024 Apr;30(2):206-224. doi: 10.3350/cmh.2023.0506. Epub 2024 Jan 8.
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.
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.
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.
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.
背景/目的：包括原发性胆汁性胆管炎（PBC）在内的胆汁淤积性肝病与活跃的肝纤维化有关，后者最终会进展为肝硬化。活化的肝星状细胞（HSCs）是对胆管细胞损伤产生反应的主要纤维化效应细胞。JCAD 调节非酒精性脂肪性肝炎相关肝细胞癌（NASH-HCC）中的细胞增殖和恶性转化。然而，其在胆汁淤积性纤维化中的参与尚未得到探索。
对 PBC 患者的肝组织进行连续切片，并用免疫荧光染色。在野生型（WT）、全身性 JCAD 敲除小鼠（JCAD-KO）和 HSC 特异性 JCAD 敲除小鼠（HSC-JCAD-KO）中通过胆管结扎（BDL）诱导肝纤维化，并通过组织病理学和生化试验进行评估。从 BDL 小鼠中分离原位活化的 HSCs，用于确定 JCAD 对 HSC 活化的影响。
与 PBC 患者肝切片的染色一致，免疫荧光染色显示 JCAD 表达定位于平滑肌α-肌动蛋白（α-SMA）阳性成纤维样细胞中，并且在 WT 小鼠的 BDL 中显著上调。与 BDL 的 WT 小鼠相比，JCAD 缺乏显著改善了 BDL 诱导的肝损伤和纤维化，这通过肝羟脯氨酸含量来证明。在组织病理学上，与 WT 小鼠相比，JCAD-KO 和 HSC-JCAD-KO 小鼠的胶原沉积明显减少，如三色染色和半定量评分所示。此外，JCAD 剥夺显著减弱了 BDL 后原位 HSC 活化和纤维化基因的表达。
JCAD 缺乏有效抑制了小鼠 BDL 诱导的肝纤维化，其潜在机制主要是通过抑制 HSCs 中的 Hippo-YAP 信号活性。
