Molecular Mechanism Responsible for Fibronectin-controlled Alterations in Matrix Stiffness in Advanced Chronic Liver Fibrogenesis

Iwasaki, Ayumi, Sakai, Keiko ORCID: 0000-0002-7375-5450, Moriya, Kei, Sasaki, Takako, Keene, Douglas R, Akhtar, Riaz ORCID: 0000-0002-7963-6874, Miyazono, Takayoshi, Yasumura, Satoshi, Watanabe, Masatoshi, Morishita, Shin
et al (show 1 more authors) (2016) Molecular Mechanism Responsible for Fibronectin-controlled Alterations in Matrix Stiffness in Advanced Chronic Liver Fibrogenesis. The Journal of biological chemistry, 291 (1). pp. 72-88.

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Fibrosis is characterized by extracellular matrix (ECM) remodeling and stiffening. However, the functional contribution of tissue stiffening to noncancer pathogenesis remains largely unknown. Fibronectin (Fn) is an ECM glycoprotein substantially expressed during tissue repair. Here we show in advanced chronic liver fibrogenesis using a mouse model lacking Fn that, unexpectedly, Fn-null livers lead to more extensive liver cirrhosis, which is accompanied by increased liver matrix stiffness and deteriorated hepatic functions. Furthermore, Fn-null livers exhibit more myofibroblast phenotypes and accumulate highly disorganized/diffuse collagenous ECM networks composed of thinner and significantly increased number of collagen fibrils during advanced chronic liver damage. Mechanistically, mutant livers show elevated local TGF-β activity and lysyl oxidase expressions. A significant amount of active lysyl oxidase is released in Fn-null hepatic stellate cells in response to TGF-β1 through canonical and noncanonical Smad such as PI3 kinase-mediated pathways. TGF-β1-induced collagen fibril stiffness in Fn-null hepatic stellate cells is significantly higher compared with wild-type cells. Inhibition of lysyl oxidase significantly reduces collagen fibril stiffness, and treatment of Fn recovers collagen fibril stiffness to wild-type levels. Thus, our findings indicate an indispensable role for Fn in chronic liver fibrosis/cirrhosis in negatively regulating TGF-β bioavailability, which in turn modulates ECM remodeling and stiffening and consequently preserves adult organ functions. Furthermore, this regulatory mechanism by Fn could be translated for a potential therapeutic target in a broader variety of chronic fibrotic diseases.

Item Type: Article
Uncontrolled Keywords: extracellular matrix, fibronectin, liver injury, lysyl oxidase, transforming growth factor beta (TGF-B), chronic hepatic fibrogenesis, conditional knockout mouse, tissue stiffness
Depositing User: Symplectic Admin
Date Deposited: 30 Aug 2018 08:32
Last Modified: 19 Jan 2023 01:25
DOI: 10.1074/jbc.M115.691519
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