Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis.
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
Gabriel
G
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
Sabile
Abdelmajid
A
Letteron
Philippe
P
Vona
Giovanna
G
Topilco
André
A
Chrétien
Yves
Y
Koike
Kazuhiko
K
Pessayre
Dominique
D
Chapman
John
J
Barba
Giovanna
G
Bréchot
Christian
C
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*
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