Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2020-10-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.141217 |
| _version_ | 1828919461787205632 |
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| author | Yun Weng Tyler J. Lieberthal Vivian X. Zhou Maya Lopez-Ichikawa Manuel Armas-Phan Tristan K. Bond Miya C. Yoshida Won-Tak Choi Tammy T. Chang |
| author_facet | Yun Weng Tyler J. Lieberthal Vivian X. Zhou Maya Lopez-Ichikawa Manuel Armas-Phan Tristan K. Bond Miya C. Yoshida Won-Tak Choi Tammy T. Chang |
| author_sort | Yun Weng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T21:28:30Z |
| format | Article |
| id | doaj.art-0bff35d1afa14287b8227e909f2a2ad1 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-13T21:28:30Z |
| publishDate | 2020-10-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-0bff35d1afa14287b8227e909f2a2ad12022-12-21T23:30:53ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-10-01520Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signalingYun WengTyler J. LieberthalVivian X. ZhouMaya Lopez-IchikawaManuel Armas-PhanTristan K. BondMiya C. YoshidaWon-Tak ChoiTammy T. ChangFocal 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.https://doi.org/10.1172/jci.insight.141217Cell biologyHepatology |
| spellingShingle | Yun Weng Tyler J. Lieberthal Vivian X. Zhou Maya Lopez-Ichikawa Manuel Armas-Phan Tristan K. Bond Miya C. Yoshida Won-Tak Choi Tammy T. Chang Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling JCI Insight Cell biology Hepatology |
| title | Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling |
| title_full | Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling |
| title_fullStr | Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling |
| title_full_unstemmed | Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling |
| title_short | Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling |
| title_sort | liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling |
| topic | Cell biology Hepatology |
| url | https://doi.org/10.1172/jci.insight.141217 |
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