title: Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis.
abstract: 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.
authors.affiliation: 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
authors.forename: Gabriel
authors.initials: G
authors.lastname: Perlemuter
authors.forename: Abdelmajid
authors.initials: A
authors.lastname: Sabile
authors.forename: Philippe
authors.initials: P
authors.lastname: Letteron
authors.forename: Giovanna
authors.initials: G
authors.lastname: Vona
authors.forename: André
authors.initials: A
authors.lastname: Topilco
authors.forename: Yves
authors.initials: Y
authors.lastname: Chrétien
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.forename: Dominique
authors.initials: D
authors.lastname: Pessayre
authors.forename: John
authors.initials: J
authors.lastname: Chapman
authors.forename: Giovanna
authors.initials: G
authors.lastname: Barba
authors.forename: Christian
authors.initials: C
authors.lastname: Bréchot
mesh_terms: D000818:Animals; D016633:Apolipoprotein A-II / Q000235:genetics / Q000502:physiology; D001055:Apolipoproteins B / Q000097:blood / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000150:complications; D006801:Humans; D015227:Lipid Peroxidation; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D014758:Viral Core Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D016633:Apolipoprotein A-II; D001055:Apolipoproteins B; D002352:Carrier Proteins; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D014758:Viral Core Proteins; C106092:microsomal triglyceride transfer protein; C069130:nucleocapsid protein, Hepatitis C virus; D019704:Protein Disulfide-Isomerases