PMID- 24329853
OWN - NLM
STAT- MEDLINE
DCOM- 20140730
LR  - 20161125
IS  - 1365-2893 (Electronic)
IS  - 1352-0504 (Linking)
VI  - 21
IP  - 1
DP  - 2014 Jan
TI  - Hepatitis C virus dysregulates glucose homeostasis by a dual mechanism involving 
      induction of PGC1alpha and dephosphorylation of FoxO1.
PG  - 9-18
LID - 10.1111/jvh.12208 [doi]
AB  - The maintenance of glucose homeostasis is a complex process in which the insulin 
      signalling pathway plays a major role. Disruption of insulin-regulated glucose 
      homeostasis is frequently observed in chronic hepatitis C (CHC) infection and 
      might potentially contribute to type 2 diabetes mellitus (T2DM) development. 
      Presently, the mechanism that links HCV infection to insulin resistance remains 
      unclear. Previously, we have reported that HCV protein expression in HCV 
      transgenic mice (B6HCV) leads to an overexpression of protein phosphatase 2A 
      (PP2A) through an ER stress response. In the present work, we describe an 
      association of FoxO1 hypophosphorylation and upregulation of both PGC-1alpha and 
      G6Pase to phenotypic hyperglycaemia and insulin resistance in B6HCV mice. In 
      vitro, we observed that PGC1alpha is concomitantly induced with PP2A. Moreover, we 
      show that the enhanced PP2A expression is sufficient to inhibit insulin-induced 
      FoxO1 phosphorylation via blockade of insulin-mediated Akt activation or/and 
      through direct association and dephosphorylation of pS-FoxO1. Consequently, we 
      found that the gluconeogenic gene glucose-6-phosphatase is upregulated. These 
      observations were confirmed in liver biopsies obtained from CHC patients. In 
      summary, our results show that HCV-mediated upregulation of PP2A catalytic 
      subunit alters signalling pathways that control hepatic glucose homeostasis by 
      inhibiting Akt and dephosphorylation of FoxO1.
CI  - (c) 2013 John Wiley & Sons Ltd.
FAU - Bernsmeier, C
AU  - Bernsmeier C
AD  - Department of Biomedicine, University and University Hospital Basel, Basel, 
      Switzerland; Division of Gastroenterology and Hepatology, University of Basel, 
      Basel, Switzerland.
FAU - Calabrese, D
AU  - Calabrese D
FAU - Heim, M H
AU  - Heim MH
FAU - Duong, H T F
AU  - Duong HT
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131106
PL  - England
TA  - J Viral Hepat
JT  - Journal of viral hepatitis
JID - 9435672
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxo1 protein, mouse)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (Transcription Factors)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
RN  - EC 3.1.3.9 (Glucose-6-Phosphatase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Biopsy
MH  - Disease Models, Animal
MH  - Forkhead Box Protein O1
MH  - Forkhead Transcription Factors/*metabolism
MH  - Glucose/*metabolism
MH  - Glucose-6-Phosphatase/metabolism
MH  - Hepatitis C, Chronic/*pathology
MH  - *Homeostasis
MH  - Humans
MH  - Insulin Resistance
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - Protein Phosphatase 2/*metabolism
MH  - Transcription Factors/*metabolism
OTO - NOTNLM
OT  - FoxO1
OT  - PGC1alpha
OT  - chronic hepatitis C
OT  - diabetes mellitus
OT  - insulin resistance
EDAT- 2013/12/18 06:00
MHDA- 2014/07/31 06:00
CRDT- 2013/12/17 06:00
PHST- 2013/07/03 00:00 [received]
PHST- 2013/10/15 00:00 [accepted]
PHST- 2013/12/17 06:00 [entrez]
PHST- 2013/12/18 06:00 [pubmed]
PHST- 2014/07/31 06:00 [medline]
AID - 10.1111/jvh.12208 [doi]
PST - ppublish
SO  - J Viral Hepat. 2014 Jan;21(1):9-18. doi: 10.1111/jvh.12208. Epub 2013 Nov 6.