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* 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;
INSERM U 481, Hôpital Beaujon, 92118 Clichy, France;
Electron Microscopy Laboratory, Institut Pasteur, 75015 Paris, France;
Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, Japan; and
INSERM U 321, Hôpital Pitié-Salpétrière, 75013 Paris, France
3Correspondence: Carcinogenèse Hépatique et Virologie Moléculaire, INSERM U 370, Faculté de Médecine Necker-Enfants Malades, 156 rue de Vaugirard, 75730 Paris Cedex 15, France. E-mail: brechot{at}necker.fr
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.—Perlemuter, G., Sabile, A., Letteron, P., Vona, G., Topilco, A., Chrétien, Y., Koike, K., Pessayre, D., Chapman, J., Barba, G., Bréchot, C. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis
Key Words: HCV • VLDL • MTP
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