Influence of the hepatic eukaryotic initiation factor 2alpha (eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism.

Details

Serval ID
serval:BIB_71B0AA93E117
Type
Article: article from journal or magazin.
Collection
Publications
Title
Influence of the hepatic eukaryotic initiation factor 2alpha (eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism.
Journal
Journal of Biological Chemistry
Author(s)
Birkenfeld A.L., Lee H.Y., Majumdar S., Jurczak M.J., Camporez J.P., Jornayvaz F.R., Frederick D.W., Guigni B., Kahn M., Zhang D., Weismann D., Arafat A.M., Pfeiffer A.F., Lieske S., Oyadomari S., Ron D., Samuel V.T., Shulman G.I.
ISSN
1083-351X (Electronic)
ISSN-L
0021-9258
Publication state
Published
Issued date
2011
Peer-reviewed
Oui
Volume
286
Number
42
Pages
36163-36170
Language
english
Abstract
Recent studies have implicated endoplasmic reticulum (ER) stress in insulin resistance associated with caloric excess. In mice placed on a 3-day high fat diet, we find augmented eIF2α signaling, together with hepatic lipid accumulation and insulin resistance. To clarify the role of the liver ER stress-dependent phospho-eIF2α (eIF2α-P) pathway in response to acute caloric excess on liver and muscle glucose and lipid metabolism, we studied transgenic mice in which the hepatic ER stress-dependent eIF2α-P pathway was inhibited by overexpressing a constitutively active C-terminal fragment of GADD34/PPP1R15a, a regulatory subunit of phosphatase that terminates ER stress signaling by phospho-eIF2α. Inhibition of the eIF2α-P signaling in liver led to a decrease in hepatic glucose production in the basal and clamped state, which could be attributed to reduced gluconeogenic gene expression, resulting in reduced basal plasma glucose concentrations. Surprisingly, hepatic eIF2α inhibition also impaired insulin-stimulated muscle and adipose tissue insulin sensitivity. This latter effect could be attributed at least in part by an increase in circulating IGFBP-3 levels in the transgenic animals. In addition, infusion of insulin during a hyperinsulinemic-euglycemic clamp induced conspicuous ER stress in the 3-day high fat diet-fed mice, which was aggravated through continuous dephosphorylation of eIF2α. Together, these data imply that the hepatic ER stress eIF2α signaling pathway affects hepatic glucose production without altering hepatic insulin sensitivity. Moreover, hepatic ER stress-dependent eIF2α-P signaling is implicated in an unanticipated cross-talk between the liver and peripheral organs to influence insulin sensitivity, probably via IGFBP-3. Finally, eIF2α is crucial for proper resolution of insulin-induced ER stress.
Keywords
Adipose Tissue/metabolism, Animals, Endoplasmic Reticulum/genetics, Endoplasmic Reticulum/metabolism, Eukaryotic Initiation Factor-2/genetics, Eukaryotic Initiation Factor-2/metabolism, Glucose/metabolism, Insulin/genetics, Insulin/metabolism, Insulin-Like Growth Factor Binding Protein 3/genetics, Insulin-Like Growth Factor Binding Protein 3/metabolism, Liver/metabolism, Mice, Mice, Transgenic, Muscle, Skeletal/metabolism, Phosphorylation/physiology, Protein Phosphatase 1/genetics, Protein Phosphatase 1/metabolism, Signal Transduction/physiology, Unfolded Protein Response/physiology
Pubmed
Web of science
Open Access
Yes
Create date
10/09/2015 12:26
Last modification date
20/08/2019 14:30
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