The inhibition of YAP Signaling Prevents Chronic Biliary Fibrosis in the Abcb4-/- Model by Modulation of Hepatic Stellate Cell and Bile Duct Epithelium Cell Pathophysiology

作者：Liangtao Ye, Andreas Ziesch, Julia Schneider, Andrea Ofner, Hanno Nieß, Gerald Denk, Simon Hohenester, Doris Mayr, Ujjwal Mukund Mahajan, Stefan Munker, Najib Ben Khaled, Ralf Wimmer, Alexander L. Gerbes, Julia Mayerle, Yulong He, Andreas Geier, Enrico N. De Toni, Changhua Zhang, Florian P. Reiter · 发表于：Aging and Disease · 年份：2024 · DOI：10.14336/ad.2023.0602 · 被引用次数：8 · 研究领域：Liver physiology and pathology、Liver Disease Diagnosis and Treatment、Liver Diseases and Immunity

Primary sclerosing cholangitis (PSC) represents a chronic liver disease characterized by poor prognosis and lacking causal treatment options. Yes-associated protein (YAP) functions as a critical mediator of fibrogenesis; however, its therapeutic potential in chronic biliary diseases such as PSC remains unestablished. The objective of this study is to elucidate the possible significance of YAP inhibition in biliary fibrosis by examining the pathophysiology of hepatic stellate cells (HSC) and biliary epithelial cells (BEC). Human liver tissue samples from PSC patients were analyzed to assess the expression of YAP/connective tissue growth factor (CTGF) relative to non-fibrotic control samples. The pathophysiological relevance of YAP/CTGF in HSC and BEC was investigated in primary human HSC (phHSC), LX-2, H69, and TFK-1 cell lines through siRNA or pharmacological inhibition utilizing verteporfin (VP) and metformin (MF). The Abcb4 -/- mouse model was employed to evaluate the protective effects of pharmacological YAP inhibition. Hanging droplet and 3D matrigel culture techniques were utilized to investigate YAP expression and activation status of phHSC under various physical conditions. YAP/CTGF upregulation was observed in PSC patients. Silencing YAP/CTGF led to inhibition of phHSC activation and reduced contractility of LX-2 cells, as well as suppression of epithelial-mesenchymal transition (EMT) in H69 cells and proliferation of TFK-1 cells. Pharmacological inhibition of YAP mi...