The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells
The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells
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DOI：
10.1002/hep.22265
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发表时间：
2008-06-01
期刊：
影响因子：
13.5
通讯作者：
Lara-Pezzi, Enrique
中科院分区：
文献类型：
--
作者：
Martin-Vilchez, Samuel;Sanz-Cameno, Paloma;Lara-Pezzi, Enrique
慢性B型肝炎病毒（HBV）感染是肝纤维化的主要原因，最终导致肝硬化和肝细胞癌。尽管HBV X蛋白（HBx）在病毒复制和肿瘤发展中的作用已被广泛研究，但对其在纤维化发展中的可能作用知之甚少。在这项工作中，我们表明，肝细胞中HBx的表达导致肝星状细胞（HSC）的旁分泌激活和增殖，肝星状细胞是纤维化肝脏中细胞外基质蛋白的主要生产者。暴露于来自HBx表达肝细胞的条件培养基的人原代HSC和大鼠HSC均显示胶原蛋白1、结缔组织生长因子、α平滑肌肌动蛋白、基质金属蛋白酶-2和转化生长因子-β（TGF-β）的表达增加，以及增殖率增加。我们发现HBx诱导肝细胞中TGF-β分泌，并且通过来自HBx表达肝细胞的条件培养基激活HSC被中和抗TGF-β抗体阻止，表明该促纤维化因子参与该过程。结论：我们的研究结果提出了HBx通过旁分泌激活星状细胞在肝纤维化发展中的直接作用，并加强了晚期HBV相关慢性肝病和持续肝脏复制患者抗病毒治疗的适应症。
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 1, 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. Conclusion: 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.