PMID- 22732512
OWN - NLM
STAT- MEDLINE
DCOM- 20130402
LR  - 20220410
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 57
IP  - 4
DP  - 2012 Oct
TI  - The metabolic regulator PGC-1alpha links hepatitis C virus infection to hepatic 
      insulin resistance.
PG  - 867-73
LID - 10.1016/j.jhep.2012.06.021 [doi]
AB  - BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection is strongly 
      associated with insulin resistance and diabetes mellitus. Peroxisome 
      proliferator-activated receptor-gamma co-activator 1alpha (PGC-1alpha) is a 
      transcriptional co-activator involved in the initiation of gluconeogenesis in the 
      liver. Increased hepatic expression of PGC-1alpha has been implicated in insulin 
      resistance. We investigated whether modulation of PGC-1alpha levels following HCV 
      infection underlies HCV-associated hepatic insulin resistance. METHODS: HCV 
      genomes were expressed in hepatoma cells followed by analysis of PGC-1alpha and 
      gluconeogenesis levels. RESULTS: PGC-1alpha was robustly induced in HCV infected 
      cells. PGC-1alpha induction was accompanied by an elevated expression of the 
      gluconeogenic gene glucose-6 phosphatase (G6Pase) and increased glucose 
      production. The induction of gluconeogenesis is HCV dependent, since interferon 
      treatment abolishes PGC-1alpha and G6Pase elevation and decreases glucose output. 
      Moreover, PGC-1alpha knockdown resulted in a significant reduction of G6Pase levels 
      in HCV full length replicon cells, emphasizing the central role of PGC-1alpha in the 
      exaggerated gluconeogenic response observed in HCV patients. Treatment of HCV 
      replicon cells with the antioxidant N-acetylcysteine resulted in reduction of 
      PGC-1alpha levels, suggesting that HCV-induced oxidative stress promoted PGC-1alpha 
      upregulation. Finally, both PGC-1alpha and G6Pase RNA levels were significantly 
      elevated in liver samples of HCV infected patients, highlighting the clinical 
      relevance of these results. CONCLUSIONS: PGC-1alpha is robustly induced following HCV 
      infection, resulting in an upregulated gluconeogenic response, thereby linking 
      HCV infection to hepatic insulin resistance. Our results suggest that PGC-1alpha is a 
      potential molecular target for the treatment of HCV-associated insulin 
      resistance.
CI  - Copyright (c) 2012 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Shlomai, Amir
AU  - Shlomai A
AD  - The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky 
      Medical Center and The Sackler Faculty of Medicine, Tel-Aviv University, 
      Tel-Aviv, Israel.
FAU - Rechtman, Maya Mouler
AU  - Rechtman MM
FAU - Burdelova, Ela Olga
AU  - Burdelova EO
FAU - Zilberberg, Alona
AU  - Zilberberg A
FAU - Hoffman, Sarit
AU  - Hoffman S
FAU - Solar, Irit
AU  - Solar I
FAU - Fishman, Sigal
AU  - Fishman S
FAU - Halpern, Zamir
AU  - Halpern Z
FAU - Sklan, Ella H
AU  - Sklan EH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120623
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Interferon-alpha)
RN  - 0 (PPARGC1A protein, human)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Viral)
RN  - 0 (Transcription Factors)
RN  - EC 3.1.3.9 (Glucose-6-Phosphatase)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/pharmacology
MH  - Cell Line, Tumor
MH  - Electroporation
MH  - Gene Knockdown Techniques
MH  - Genotype
MH  - Gluconeogenesis/genetics
MH  - Glucose-6-Phosphatase/genetics/metabolism
MH  - Heat-Shock Proteins/*genetics/*metabolism
MH  - Hepacivirus/genetics/*metabolism/physiology
MH  - Hepatitis C, Chronic/*metabolism
MH  - Humans
MH  - *Insulin Resistance
MH  - Interferon-alpha/pharmacology
MH  - Liver/cytology/metabolism/*virology
MH  - Oxidative Stress
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - RNA, Messenger/metabolism
MH  - RNA, Viral/metabolism
MH  - Replicon
MH  - Transcription Factors/*genetics/*metabolism
MH  - Transcriptional Activation/drug effects
MH  - Up-Regulation
MH  - Virus Replication
EDAT- 2012/06/27 06:00
MHDA- 2013/04/03 06:00
CRDT- 2012/06/27 06:00
PHST- 2011/12/17 00:00 [received]
PHST- 2012/05/19 00:00 [revised]
PHST- 2012/06/14 00:00 [accepted]
PHST- 2012/06/27 06:00 [entrez]
PHST- 2012/06/27 06:00 [pubmed]
PHST- 2013/04/03 06:00 [medline]
AID - S0168-8278(12)00447-3 [pii]
AID - 10.1016/j.jhep.2012.06.021 [doi]
PST - ppublish
SO  - J Hepatol. 2012 Oct;57(4):867-73. doi: 10.1016/j.jhep.2012.06.021. Epub 2012 Jun 
      23.