Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
Biochem Biophys Res Commun. 2012 Sep 28;426(3):404-8. doi: 10.1016/j.bbrc.2012.08.104. Epub 2012 Aug 30.
Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these cells by siRNA. We newly found that FAT1 suppression in activated HSCs caused a downregulation of NFκB activity. This transcription factor is critical for apoptosis resistance of HSCs, and consequently, we detected a higher apoptosis rate in FAT1 suppressed HSCs compared to control cells. Our findings suggest FAT1 as new therapeutic target for the prevention and treatment of hepatic fibrosis in chronic liver disease.
肝纤维化可以被认为是肝脏细胞损伤后愈合的过程。肝星状细胞（HSCs）的激活是肝纤维化的关键事件，因为激活的 HSCs 是细胞外基质沉积增加的细胞来源，肝纤维化的逆转伴随着激活的 HSCs 通过凋亡被清除。非典型钙黏蛋白 FAT1 已被证明调节多种生物学功能，如细胞增殖和平面细胞极性，并且还影响伤口愈合。在这里，我们发现不同的慢性肝损伤小鼠模型和不同肝病患者的肝硬化肝脏中 FAT1 表达增加。非酒精性脂肪性肝炎患者的肝组织中 FAT1 表达也明显增强，并与胶原 alpha I(1)表达相关。免疫组化显示正常和肝硬化肝组织中肝细胞的染色强度没有显著差异，但肝硬化纤维化隔中的肌成纤维细胞样细胞表现出明显的免疫信号。此外，FAT1 mRNA 和蛋白表达在原代人源和鼠源 HSCs 的体外激活过程中显著增加。综上所述，这些数据表明激活的 HSCs 是疾病肝脏中增强的 FAT1 表达的细胞来源。为了深入了解 FAT1 在激活的 HSCs 中的功能作用，我们通过 siRNA 抑制这些细胞中的 FAT1。我们新发现，激活的 HSCs 中 FAT1 的抑制导致 NFκB 活性的下调。这种转录因子对 HSCs 的凋亡抵抗至关重要，因此，我们在 FAT1 抑制的 HSCs 中检测到比对照细胞更高的凋亡率。我们的研究结果表明 FAT1 是慢性肝病中预防和治疗肝纤维化的新治疗靶点。
