Perlemuter Gabriel, Sabile Abdelmajid, Letteron Philippe, Vona Giovanna, Topilco André, Chrétien Yves, Koike Kazuhiko, Pessayre Dominique, Chapman John, Barba Giovanna, Bréchot Christian
Liver Cancer and Molecular Virology, Institut National de la Santé et de la Recherche Médicale Unité 370, Faculté de Médecine Necker-Enfants Malades, 75730 Paris Cedex 15, France
FASEB J. 2002 Feb;16(2):185-94. doi: 10.1096/fj.01-0396com.
Liver steatosis, which involves accumulation of intracytoplasmic lipid droplets, is characteristic of hepatitis C virus (HCV) infection. By use of an in vivo transgenic murine model, we demonstrate that hepatic overexpression of HCV core protein interferes with the hepatic assembly and secretion of triglyceride-rich very low density lipoproteins (VLDL). Core expression led to reduction in microsomal triglyceride transfer protein (MTP) activity and in the particle size of nascent hepatic VLDL without affecting accumulation of MTP and protein disulfide isomerase. Hepatic human apolipoprotein AII (apo AII) expression in double-core/apo AII transgenic mice diminished intrahepatic core protein accumulation and abrogated its effects on VLDL production. Apo AII and HCV core colocalized in human HCV-infected liver biopsies, thus testifying to the relevance of this interaction in productive HCV infection. Our results lead us to propose a new pathophysiological animal model for induction of viral-related steatosis whereby the core protein of HCV targets microsomal triglyceride transfer protein activity and modifies hepatic VLDL assembly and secretion.
肝脂肪变性表现为胞质内脂质小滴的蓄积，是丙型肝炎病毒（HCV）感染的特征。通过使用体内转基因小鼠模型，我们证明HCV核心蛋白在肝脏中的过表达会干扰富含甘油三酯的极低密度脂蛋白（VLDL）的肝脏组装和分泌。核心蛋白的表达导致微粒体甘油三酯转移蛋白（MTP）活性降低以及新生肝脏VLDL的颗粒大小减小，而不影响MTP和蛋白质二硫键异构酶的积累。在双核/载脂蛋白AII（apo AII）转基因小鼠中，肝脏人载脂蛋白AII（apo AII）的表达减少了肝内核心蛋白的积累，并消除了其对VLDL产生的影响。在人类HCV感染的肝脏活检中，apo AII和HCV核心蛋白共定位，从而证明了这种相互作用在HCV有效感染中的相关性。我们的结果使我们提出了一种新的诱导病毒相关性脂肪变性的病理生理动物模型，即HCV的核心蛋白靶向微粒体甘油三酯转移蛋白活性并改变肝脏VLDL的组装和分泌。
