TY - JOUR
T1 - HCV replication suppresses cellular glucose uptake through down-regulation of cell surface expression of glucose transporters
AU - Kasai, Daisuke
AU - Adachi, Tetsuya
AU - Deng, Lin
AU - Nagano-Fujii, Motoko
AU - Sada, Kiyonao
AU - Ikeda, Masanori
AU - Kato, Nobuyuki
AU - Ide, Yoshi Hiro
AU - Shoji, Ikuo
AU - Hotta, Hak
N1 - Funding Information:
The authors are grateful to Dr. C.M. Rice (The Rockefeller University, New York, NY, USA) for providing pFL-J6/JFH1 and Huh7.5 cells. Thanks are also due to Dr. R. Bartenschlager (University of Heidelberg, Heidelberg, Germany) for providing an HCV subgenomic RNA replicon (pFK5B/2884Gly) and Dr. R. Sato (The University of Tokyo, Tokyo, Japan) for providing a human SREBP-1c expression plasmid (pME-hSREBP-1c). This study was supported in part by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and the Ministry of Health, Labour and Welfare, Japan. This study was also carried out as part of the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases, MEXT, Japan, and the Global Center of Excellence (COE) Program at Kobe University Graduate School of Medicine.
PY - 2009/5
Y1 - 2009/5
N2 - Background/Aims: Persistent infection with hepatitis C virus (HCV) causes extrahepatic diseases, including diabetes. We investigated the possible effect(s) of HCV replication on cellular glucose uptake and expression of the facilitative glucose transporter (GLUT) 2 and 1. Methods: We used Huh-7.5 cells harboring either an HCV subgenomic RNA replicon (SGR) or an HCV full-genomic RNA replicon (FGR), HCV-infected cells, and the respective cells treated with interferon (IFN). We also used liver tissue samples obtained from patients with or without HCV infection. Results: Glucose uptake and surface expression of GLUT2 and GLUT1 were suppressed in SGR, FGR and HCV-infected cells compared to the control cells. Expression levels of GLUT2 mRNA, but not GLUT1 mRNA, were lower in SGR, FGR and HCV-infected cells than in the control. Luciferase reporter assay demonstrated decreased GLUT2 promoter activities in SGR, FGR and HCV-infected cells. IFN treatment restored glucose uptake, GLUT2 surface expression, GLUT2 mRNA expression and GLUT2 promoter activities. Also, GLUT2 expression was reduced in hepatocytes of liver tissues obtained from HCV-infected patients. Conclusions: HCV replication down-regulates cell surface expression of GLUT2 partly at the transcriptional level, and possibly at the intracellular trafficking level as suggested for GLUT1, thereby lowering glucose uptake by hepatocytes.
AB - Background/Aims: Persistent infection with hepatitis C virus (HCV) causes extrahepatic diseases, including diabetes. We investigated the possible effect(s) of HCV replication on cellular glucose uptake and expression of the facilitative glucose transporter (GLUT) 2 and 1. Methods: We used Huh-7.5 cells harboring either an HCV subgenomic RNA replicon (SGR) or an HCV full-genomic RNA replicon (FGR), HCV-infected cells, and the respective cells treated with interferon (IFN). We also used liver tissue samples obtained from patients with or without HCV infection. Results: Glucose uptake and surface expression of GLUT2 and GLUT1 were suppressed in SGR, FGR and HCV-infected cells compared to the control cells. Expression levels of GLUT2 mRNA, but not GLUT1 mRNA, were lower in SGR, FGR and HCV-infected cells than in the control. Luciferase reporter assay demonstrated decreased GLUT2 promoter activities in SGR, FGR and HCV-infected cells. IFN treatment restored glucose uptake, GLUT2 surface expression, GLUT2 mRNA expression and GLUT2 promoter activities. Also, GLUT2 expression was reduced in hepatocytes of liver tissues obtained from HCV-infected patients. Conclusions: HCV replication down-regulates cell surface expression of GLUT2 partly at the transcriptional level, and possibly at the intracellular trafficking level as suggested for GLUT1, thereby lowering glucose uptake by hepatocytes.
KW - Diabetes mellitus
KW - Down-regulation
KW - GLUT1
KW - GLUT2
KW - Glucose uptake
KW - Hepatitis C virus
KW - Hepatocyte
KW - Interferon
KW - Replicon
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U2 - 10.1016/j.jhep.2008.12.029
DO - 10.1016/j.jhep.2008.12.029
M3 - Article
C2 - 19303158
AN - SCOPUS:64549151555
VL - 50
SP - 883
EP - 894
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 5
ER -