PMID- 18160431
OWN - NLM
STAT- MEDLINE
DCOM- 20080331
LR  - 20181113
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 82
IP  - 6
DP  - 2008 Mar
TI  - Hepatitis C virus core protein upregulates serine phosphorylation of insulin 
      receptor substrate-1 and impairs the downstream akt/protein kinase B signaling 
      pathway for insulin resistance.
PG  - 2606-12
AB  - Chronic hepatitis C virus (HCV) infection has a significantly increased 
      prevalence of type 2 diabetes mellitus (T2DM). Insulin resistance is a critical 
      component of T2DM pathogenesis. Several mechanisms are likely to be involved in 
      the pathogenesis of HCV-related insulin resistance. Since we and others have 
      previously observed that HCV core protein activates c-Jun N-terminal kinase (JNK) 
      and mitogen-activated protein kinase, we examined the contribution of these 
      pathways to insulin resistance in hepatocytes. Our experimental findings suggest 
      that HCV core protein alone or in the presence of other viral proteins increases 
      Ser(312) phosphorylation of the insulin receptor substrate-1 (IRS-1). Hepatocytes 
      infected with cell culture-grown HCV genotype 1a or 2a displayed a significant 
      increase in the Ser(473) phosphorylation status of the Ser/Thr kinase protein 
      kinase B (Akt/PKB), while Thr(308) phosphorylation was not significantly altered. 
      HCV core protein-mediated Ser(312) phosphorylation of IRS-1 was inhibited by JNK 
      (SP600125) and phosphatidylinositol-3 kinase (LY294002) inhibitors. A functional 
      assay also suggested that hepatocytes expressing HCV core protein alone or 
      infected with cell culture-grown HCV exhibited a suppression of 
      2-deoxy-d-[(3)H]glucose uptake. Inhibition of the JNK signaling pathway 
      significantly restored glucose uptake despite HCV core expression in hepatocytes. 
      Taken together, our results demonstrated that HCV core protein increases IRS-1 
      phosphorylation at Ser(312) which may contribute in part to the mechanism of 
      insulin resistance.
FAU - Banerjee, Sutapa
AU  - Banerjee S
AD  - Division of Infectious Diseases and Immunology, Center for Vaccine Development, 
      Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 
      63104, USA.
FAU - Saito, Kousuke
AU  - Saito K
FAU - Ait-Goughoulte, Malika
AU  - Ait-Goughoulte M
FAU - Meyer, Keith
AU  - Meyer K
FAU - Ray, Ratna B
AU  - Ray RB
FAU - Ray, Ranjit
AU  - Ray R
LA  - eng
GR  - R01 AI045144/AI/NIAID NIH HHS/United States
GR  - R56 AI045144/AI/NIAID NIH HHS/United States
GR  - R01 CA085486/CA/NCI NIH HHS/United States
GR  - AI45144/AI/NIAID NIH HHS/United States
GR  - CA85486/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20071226
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Hepatitis C Antigens)
RN  - 0 (IRS1 protein, human)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Viral Core Proteins)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Cell Line
MH  - Glucose/metabolism
MH  - Hepatitis C Antigens/*physiology
MH  - Hepatocytes/metabolism
MH  - Humans
MH  - Insulin/pharmacology
MH  - Insulin Receptor Substrate Proteins
MH  - *Insulin Resistance
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/*metabolism
MH  - Serine/*metabolism
MH  - Signal Transduction/*physiology
MH  - Viral Core Proteins/*physiology
PMC - PMC2258989
EDAT- 2007/12/28 09:00
MHDA- 2008/04/01 09:00
PMCR- 2008/07/01
CRDT- 2007/12/28 09:00
PHST- 2007/12/28 09:00 [pubmed]
PHST- 2008/04/01 09:00 [medline]
PHST- 2007/12/28 09:00 [entrez]
PHST- 2008/07/01 00:00 [pmc-release]
AID - JVI.01672-07 [pii]
AID - 1672-07 [pii]
AID - 10.1128/JVI.01672-07 [doi]
PST - ppublish
SO  - J Virol. 2008 Mar;82(6):2606-12. doi: 10.1128/JVI.01672-07. Epub 2007 Dec 26.