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
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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