These authors contributed equally to this work.
Fibronectin is essential for survival but is dispensable for proliferation of hepatocytes in acute liver injury in mice†
Article first published online: 5 JUN 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 1, pages 311–321, July 2012
How to Cite
Moriya, K., Sakai, K., Yan, M. H. and Sakai, T. (2012), Fibronectin is essential for survival but is dispensable for proliferation of hepatocytes in acute liver injury in mice. Hepatology, 56: 311–321. doi: 10.1002/hep.25624
Potential conflict of interest: Nothing to report.
- Issue published online: 3 JUL 2012
- Article first published online: 5 JUN 2012
- Accepted manuscript online: 9 FEB 2012 12:25AM EST
- Manuscript Accepted: 18 JAN 2012
- Manuscript Received: 22 NOV 2011
- National Institutes of Health research. Grant Number: DK074538
Acute liver injury causes massive hepatocyte apoptosis and/or fatal liver damage. Fibronectin, an extracellular matrix glycoprotein, is prominently expressed during adult tissue repair. However, the extent of fibronectin dependence on hepatocyte response to acute liver damage remains to be defined. Because identification of hepatic survival factors is critical for successful therapeutic intervention in liver failure, this relationship has been investigated using a fibronectin-deficient mouse model of acute liver injury. Here, we show that lack of fibronectin induces significantly increased hepatocyte apoptosis, which is accompanied by significant down-regulation of the antiapoptotic protein, B-cell lymphoma—extra large (Bcl-xL). Furthermore, fibronectin deficiency leads to a significantly elevated production of hepatocyte growth factor in hepatic stellate cells postinjury, which, in turn, results in an earlier onset and acceleration of hepatocyte regeneration. Primary hepatocytes on fibronectin are protected from reactive oxygen species–induced cellular damage, retaining the expression of Bcl-xL, whereas those on type I collagen are not. This retained expression of Bcl-xL is inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Conclusion: We provide evidence that fibronectin-mediated matrix survival signals for hepatocytes are transduced through the PI3K/Bcl-xL-signaling axis in response to injury. This work defines fibronectin as a novel antiapoptotic factor for hepatocytes after acute liver injury, but demonstrates that fibronectin is not essential for subsequent hepatocyte proliferation. (HEPATOLOGY 2012;56:311–321)