The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells.
Chronic hepatitis B virus (HBV) infection is a major cause of liver fibrosis, eventually leading to cirrhosis and hepatocellular carcinoma. Although the involvement of the X protein of HBV (HBx) in viral replication and tumor development has been extensively studied, little is known about its possible role in the development of fibrosis. In this work we show that expression of HBx in hepatocytes results in paracrine activation and proliferation of hepatic stellate cells (HSCs), the main producers of extracellular matrix proteins in the fibrotic liver. Both human primary HSCs and rat HSCs exposed to conditioned medium from HBx-expressing hepatocytes showed increased expression of collagen I, connective tissue growth factor, alpha smooth muscle actin, matrix metalloproteinase-2, and transforming growth factor-beta (TGF-beta), together with an enhanced proliferation rate. We found that HBx induced TGF-beta secretion in hepatocytes and that the activation of HSCs by conditioned medium from HBx-expressing hepatocytes was prevented by a neutralizing anti-TGF-beta antibody, indicating the involvement of this profibrotic factor in the process.


CONCLUSIONS
Our results propose a direct role for HBx in the development of liver fibrosis by the paracrine activation of stellate cells and reinforce the indication of antiviral treatment in patients with advanced HBV-related chronic liver disease and persistent liver replication.
Martín-Vílchez
Samuel
S
Gastroenterology and Hepatology Service, Hospital Universitario La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
Sanz-Cameno
Paloma
P
Rodríguez-Muñoz
Yolanda
Y
Majano
Pedro L
PL
Molina-Jiménez
Francisca
F
López-Cabrera
Manuel
M
Moreno-Otero
Ricardo
R
Lara-Pezzi
Enrique
E
D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
D000199:Actins; C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D024042:Collagen Type I; D017077:Culture Media, Conditioned; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D055513:Connective Tissue Growth Factor; D020778:Matrix Metalloproteinase 2