PMID- 16960890
OWN - NLM
STAT- MEDLINE
DCOM- 20070320
LR  - 20161124
IS  - 0730-2312 (Print)
IS  - 0730-2312 (Linking)
VI  - 100
IP  - 3
DP  - 2007 Feb 15
TI  - Long-term effects of tumor necrosis factor-alpha treatment on insulin signaling 
      pathway in HepG2 cells and HepG2 cells overexpressing constitutively active 
      Akt/PKB.
PG  - 593-607
AB  - Tumor necrosis factor-alpha (TNF-alpha) mediated attenuation of insulin signaling 
      pathway is an important cause in several disorders like obesity, obesity linked 
      diabetes mellitus. TNF-alpha actions vary depending upon concentration and time 
      of exposure in various cells. In the present study, the effects of long-term 
      TNF-alpha (1 ng/ml) exposure on the components of insulin signaling pathway in 
      HepG2 and HepG2 cells overexpressing constitutively active Akt1/PKB-alpha 
      (HepG2-CA-Akt/PKB) have been investigated. In parental HepG2 cells, TNF-alpha 
      treatment for 24 h reduced the phosphorylation of Akt1/PKB-alpha and GSK-3beta 
      and under these conditions cells also showed reduced insulin responsiveness in 
      terms of Akt1/PKB-alpha and GSK-3beta phosphorylation. TNF-alpha pre-incubated 
      HepG2-CA-Akt/PKB cells showed lower reduction in Akt1/PKB-alpha and GSK-3beta 
      phosphorylation and insulin responsiveness after 24 h as compared to parental 
      HepG2 cells. We report that the long-term TNF-alpha pre-incubation in both 
      parental HepG2 and HepG2-CA-Akt/PKB-alpha cells leads to the reduction in the 
      levels of IRS-1 without altering the levels of IRS-2. In order to understand the 
      reason for the differential insulin resistance in both the cell types, the effect 
      of long-term TNF-alpha treatment on the proteins upstream to Akt/PKB was 
      investigated. TNF-alpha pre-incubation also showed reduced insulin-stimulated Tyr 
      phosphorylation of insulin receptor (IR-beta) in both the cell types, moreover 
      hyperphosphorylation of IRS-1 at Ser 312 residue was observed in TNF-alpha 
      pre-incubated cells. As hyperphosphorylation of IRS-1 at Ser 312 can induce its 
      degradation, it is possible that reduced insulin responsiveness after long-term 
      TNF-alpha pre-incubation observed in this study is due to the decrease in IRS-1 
      levels.
FAU - Gupta, Dhananjay
AU  - Gupta D
AD  - Department of Biochemistry, College of Medicine, University of Saskatchewan, 
      Saskatoon, Saskatchewan, Canada.
FAU - Varma, Shailly
AU  - Varma S
FAU - Khandelwal, Ramji L
AU  - Khandelwal RL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (IRS1 protein, human)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Cell Line
MH  - Glycogen Synthase Kinase 3/metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - Humans
MH  - Hydrolysis
MH  - Insulin/*metabolism
MH  - Insulin Receptor Substrate Proteins
MH  - Insulin Resistance
MH  - Phosphoproteins/metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 2006/09/09 09:00
MHDA- 2007/03/21 09:00
CRDT- 2006/09/09 09:00
PHST- 2006/09/09 09:00 [pubmed]
PHST- 2007/03/21 09:00 [medline]
PHST- 2006/09/09 09:00 [entrez]
AID - 10.1002/jcb.21080 [doi]
PST - ppublish
SO  - J Cell Biochem. 2007 Feb 15;100(3):593-607. doi: 10.1002/jcb.21080.