Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling
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
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
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Research Article Cell biology Hepatology

Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling

Abstract

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.

Authors

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

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Figure 6

Male and female FAKfl/fl mice were treated with AAV8-TBG-Cre (AAV-Cre) or AAV8-TBG-Null (AAV-Null) and then given 0.1% DDC diet to induce liver fibrosis.

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Male and female FAKfl/fl mice were treated with AAV8-TBG-Cre (AAV-Cre) o...
(A) Weight changes were not significantly different between male AAV-Null (n = 7) and AAV-Cre (n = 7) mice. Percentage weight loss in female mice was significantly different between AAV-Null (n = 5) and AAV-Cre (n = 5) at days 7, 14, and 21 by Student’s 2-tailed t test (*P < 0.05, **P < 0.01). Linear regression analysis showed that elevations of the AAV-Null and AAV-Cre female weight loss lines were significantly different (P < 0.0001). Data represent mean ± SEM. (B) Serum liver function tests for AAV-Null (male n = 4, female n = 5) and AAV-Cre mice (male n = 4, female n = 5). Data show individual data points and mean ± SEM. (C) Representative liver histology. Scale bar: 100 μm. (D) Liver hydroxyproline content of AAV-Null male (M; n = 4) and female (F; n = 5) compared with AAV-Cre male (n = 4) and female (n = 5) mice. (E) mRNA expression of various collagen species as determined by qRT-PCR in AAV-Null (M, n = 4; F, n = 5) and AAV-Cre (M, n = 4; F, n = 5) mice. For all collagen genes, 2-way ANOVA showed no significant interaction between AAV genotype and sex, whereas genotype contributed significantly to the overall variation (P < 0.05). For B and E, *P < 0.05 and **P < 0.01 by Student’s 2-tailed t test. Box plots show individual data points, median, interquartile range, and range.