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Hepatitis C virus proteins induce lipogenesis and defective triglyceride secretion in transgenic mice

Authors :
Stanley M. Lemon
Emilie Mérour
Hervé Lerat
Hélène L. Kammoun
Celine Callens
Martin R. Higgs
Jean-Michel Pawlotsky
Fabienne Foufelle
Isabelle Hainault
Institut Mondor de Recherche Biomédicale (IMRB)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10
Centre de Recherche des Cordeliers (CRC (UMR_S 872))
Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Institute of Human Infections and Immunity
The University of Texas Medical Branch (UTMB)
Service de bactériologie, virologie, hygiène [Mondor]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Institut Mondor de Recherche Biomédicale ( IMRB )
Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 )
Centre de Recherche des Cordeliers ( CRC (UMR_S 872) )
Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
The University of Texas Medical Branch ( UTMB )
Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 )
Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Guellaen, Georges
Source :
Journal of Biological Chemistry, Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2009, 284 (48), pp.33466-74. ⟨10.1074/jbc.M109.019810⟩, Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2009, 284 (48), pp.33466-74. 〈10.1074/jbc.M109.019810〉, Journal of Biological Chemistry, 2009, 284 (48), pp.33466-74. ⟨10.1074/jbc.M109.019810⟩
Publication Year :
2009
Publisher :
HAL CCSD, 2009.

Abstract

This research was originally published in The Journal of Biological Chemistry. © the American Society for Biochemistry and Molecular Biology; International audience; Chronic hepatitis C virus (HCV) infection is associated with altered lipid metabolism and hepatocellular steatosis. Virus-induced steatosis is a cytopathic effect of HCV replication. The goal of this study was to examine the mechanisms underlying HCV-induced lipid metabolic defects in a transgenic mouse model expressing the full HCV protein repertoire at levels corresponding to natural human infection. In this model, expression of the HCV full-length open reading frame was associated with hepatocellular steatosis and reduced plasma triglyceride levels. Triglyceride secretion was impaired, whereas lipogenesis was activated. Increased lipogenic enzyme transcription was observed, resulting from maturational activation and nuclear translocation of sterol regulatory element-binding protein 1c (SREBP1c). However, endoplasmic reticulum (ER) stress markers were expressed at similar levels in both HCV transgenic mice and their wild type counterparts, suggesting that SREBP1c proteolytic cleavage in the presence of HCV proteins was independent of ER stress. In conclusion, transgenic mice expressing the HCV full-length polyprotein at low levels have decreased plasma triglyceride levels and develop hepatocellular steatosis in the same way as HCV-infected patients. In these mice, SREBP1c activation by one or several HCV proteins induces de novo triglyceride synthesis via the lipogenic pathway, in a manner independent of ER stress, whereas triglyceride secretion is simultaneously reduced.

Details

Language :
English
ISSN :
00219258 and 1083351X
Database :
OpenAIRE
Journal :
Journal of Biological Chemistry, Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2009, 284 (48), pp.33466-74. ⟨10.1074/jbc.M109.019810⟩, Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2009, 284 (48), pp.33466-74. 〈10.1074/jbc.M109.019810〉, Journal of Biological Chemistry, 2009, 284 (48), pp.33466-74. ⟨10.1074/jbc.M109.019810⟩
Accession number :
edsair.doi.dedup.....c526df4a2c168878bfbf2cc1b469d6d2
Full Text :
https://doi.org/10.1074/jbc.M109.019810⟩