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Hepatitis C virus infection reduces hepatocellular polarity in a vascular endothelial growth factor-dependent manner.

Mee, Christopher J and Farquhar, Michelle J and Harris, Helen J and Hu, Ke and Ramma, Wenda and Ahmed, Asif and Maurel, Patrick and Bicknell, Roy and Balfe, Peter and McKeating, Jane A (2010) Hepatitis C virus infection reduces hepatocellular polarity in a vascular endothelial growth factor-dependent manner. Gastroenterology, 138 (3). pp. 1134-42. ISSN 1528-0012

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Identification Number/DOI: http://dx.doi.org/10.1053/j.gastro.2009.11.047

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection leads to progressive liver disease, frequently culminating in fibrosis and hepatocellular carcinoma. The mechanisms underlying liver injury in chronic hepatitis C are poorly understood. This study evaluated the role of vascular endothelial growth factor (VEGF) in hepatocyte polarity and HCV infection. METHODS: We used polarized hepatoma cell lines and the recently described infectious HCV Japanese fulminant hepatitis (JFH)-1 cell culture system to study the role of VEGF in regulating hepatoma permeability and HCV infection. RESULTS: VEGF negatively regulates hepatocellular tight junction integrity and cell polarity by a novel VEGF receptor 2-dependent pathway. VEGF reduced hepatoma tight junction integrity, induced a re-organization of occludin, and promoted HCV entry. Conversely, inhibition of hepatoma expressed VEGF with the receptor kinase inhibitor sorafenib or with neutralizing anti-VEGF antibodies promoted polarization and inhibited HCV entry, showing an autocrine pathway. HCV infection of primary hepatocytes or hepatoma cell lines promoted VEGF expression and reduced their polarity. Importantly, treatment of HCV-infected cells with VEGF inhibitors restored their ability to polarize, showing a VEGF-dependent pathway. CONCLUSIONS: Hepatic polarity is critical to normal liver physiology. HCV infection promotes VEGF expression that depolarizes hepatoma cells, promoting viral transmission and lymphocyte migration into the parenchyma that may promote hepatocyte injury.

Type of Work:Article
Date:2010 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Immunity and Infection
Subjects:R Medicine (General)
QR355 Virology
QR180 Immunology
QR Microbiology
Institution:University of Birmingham
Copyright Holders:the AGA Institute
ID Code:465
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