Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling
Autor: | Miya C Yoshida, Vivian X. Zhou, Tristan K Bond, Won-Tak Choi, Yun Weng, Tyler J Lieberthal, Tammy T. Chang, Manuel Armas-Phan, Maya Lopez-Ichikawa |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Liver Cirrhosis Integrins Signal transduction Oral and gastrointestinal Liver disease Mice 0302 clinical medicine Fibrosis Cell Movement 2.1 Biological and endogenous factors Aetiology Liver injury Mice Knockout biology Chemistry Liver Disease General Medicine Smoothened Receptor Hedgehog signaling pathway Extracellular Matrix Liver 030220 oncology & carcinogenesis Medicine biological phenomena cell phenomena and immunity Research Article Cell biology Indian hedgehog Knockout Chronic Liver Disease and Cirrhosis Focal adhesion 03 medical and health sciences Rare Diseases medicine Animals Humans Hedgehog Proteins Hedgehog Cell Proliferation Hepatology Epithelial Cells Cell Biology medicine.disease biology.organism_classification 030104 developmental biology Focal Adhesion Kinase 1 Cancer research Hepatocytes Smoothened Digestive Diseases |
Zdroj: | JCI insight, vol 5, iss 20 JCI Insight, Vol 5, Iss 20 (2020) JCI Insight |
Popis: | Focal adhesion kinase (FAK) is an important mediator of extracellular matrix–integrin mechano-signal transduction that regulates cell motility, survival, and proliferation. As such, FAK is being investigated as a potential therapeutic target for malignant and fibrotic diseases, and numerous clinical trials of FAK inhibitors are underway. The function of FAK in nonmalignant, nonmotile epithelial cells is not well understood. We previously showed that hepatocytes demonstrated activated FAK near stiff collagen tracts in fibrotic livers. In this study, we examined the role of liver epithelial FAK by inducing fibrotic liver disease in mice with liver epithelial FAK deficiency. We found that mice that lacked FAK in liver epithelial cells developed more severe liver injury and worse fibrosis as compared with controls. Increased fibrosis in liver epithelial FAK-deficient mice was linked to the activation of several profibrotic pathways, including the hedgehog/smoothened pathway. FAK-deficient hepatocytes produced increased Indian hedgehog in a manner dependent on matrix stiffness. Furthermore, expression of the hedgehog receptor, smoothened, was increased in macrophages and biliary cells of hepatocyte-specific FAK-deficient fibrotic livers. These results indicate that liver epithelial FAK has important regulatory roles in the response to liver injury and progression of fibrosis. Liver epithelial-specific FAK-deficient mice develop worse liver injury and fibrosis compared to controls, indicating that FAK has a regulatory role. |
Databáze: | OpenAIRE |
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