Hepatitis C virus infection reduces hepatocellular polarity in a vascular
endothelial growth factor-dependent manner
#MMPMID19944696
Mee CJ
; Farquhar MJ
; Harris HJ
; Hu K
; Ramma W
; Ahmed A
; Maurel P
; Bicknell R
; Balfe P
; McKeating JA
Gastroenterology
2010[Mar]; 138
(3
): 1134-42
PMID19944696
show ga
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.
free
free
free
