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Publication : Hepatocyte ERBB3 and EGFR are required for maximal CCl4-induced liver fibrosis.

First Author  Scheving LA Year  2016
Journal  Am J Physiol Gastrointest Liver Physiol Volume  311
Issue  5 Pages  G807-G816
PubMed ID  27586651 Mgi Jnum  J:240432
Mgi Id  MGI:5883389 Doi  10.1152/ajpgi.00423.2015
Citation  Scheving LA, et al. (2016) Hepatocyte ERBB3 and EGFR are required for maximal CCl4-induced liver fibrosis. Am J Physiol Gastrointest Liver Physiol 311(5):G807-G816
abstractText  Epidermal growth factor receptor (EGFR) and its ligands have been implicated in liver fibrosis. However, it has not been directly shown that hepatocellular genetic ablation of either this receptor tyrosine kinase or ERBB3, its interactive signaling partner, affects hepatic fibrosis. Carbon tetrachloride (CCl4)-induced liver fibrosis in hepatocyte-specific (HS) mouse models of EGFR and ERBB3 ablation was evaluated in both single gene knockouts and an HS-EGFR-ERBB3 double knockout (DKO). Loss of hepatocellular EGFR or ERBB3 did not impact cytochrome P450-2E1 expression, the extent of centrilobular injury, or the initial regenerative response, but it did diminish liver fibrosis induced by chronic intraperitoneal administration of CCl4 The reduction of liver fibrosis correlated with reduced alpha-smooth muscle actin expression. Maximal impact to fibrogenesis occurred in the ERBB3 and EGFR-ERBB3 DKO models, suggesting that EGFR-ERBB3 heterodimeric signaling in damaged hepatocytes may play a more important role in liver fibrosis than EGFR-EGFR homodimeric signaling. Immunohistochemical analyses of phospho-EGFR and phospho-ERBB3 isoforms revealed clear staining in hepatocytes, activated stellate cells, and macrophages. Our results support a role for the hepatocellular ERBB tyrosine kinases in fibrogenesis and suggest that pharmacologic inhibition of EGFR-ERBB3 signaling may reverse or retard hepatic fibrosis.
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