IRE1 impairs insulin signaling transduction of fructose-fed mice via JNK independent of excess lipid

https://doi.org/10.1016/j.bbadis.2014.11.017Get rights and content
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Highlights

  • IRE1 arm is activated first of UPR pathways in the liver in high fructose-fed mice.

  • One day of high fructose feeding leads to hepatic steatosis.

  • One day of high fructose feeding blunts insulin signal transduction.

  • Inhibition of IRE1 phosphorylation overcomes fructose-induced impairment of hepatic insulin signaling transduction.

Abstract

The unfolded protein response (UPR) pathways have been implicated in the development of hepatic insulin resistance during high fructose (HFru) feeding. The present study investigated their roles in initiating impaired insulin signaling transduction in the liver induced by HFru feeding in mice. HFru feeding resulted in hepatic steatosis, increased de novo lipogenesis and activation of two arms of the UPR pathways (IRE1/XBP1 and PERK/eIF2α) in similar patterns from 3 days to 8 weeks. In order to identify the earliest trigger of impaired insulin signaling in the liver, we fed mice a HFru diet for one day and revealed that only the IRE1 branch was activated (by 2-fold) and insulin-mediated Akt phosphorylation was blunted (~ 25%) in the liver. There were significant increases in phosphorylation of JNK (~ 50%) and IRS at serine site (~ 50%), protein content of ACC and FAS (up to 2.5-fold) and triglyceride level (2-fold) in liver (but not in muscle or fat). Blocking IRE1 activity abolished increases in JNK activity, IRS serine phosphorylation and protected insulin-stimulated Akt phosphorylation without altering hepatic steatosis or PKCε activity, a key link between lipids and insulin resistance. Our findings together suggest that activation of IRE1–JNK pathway is a key linker of impaired hepatic insulin signaling transduction induced by HFru feeding.

Abbreviations

CH
chow
HFru
high fructose
DAG
diacylglycerol
PKCε
protein kinase C epsilon
IRS
insulin receptor substrate
UPR
unfolded protein response
IRE1
inositol-requiring protein 1
PERK
protein kinase RNA-like ER kinase
ATF6
activating transcription factor 6
DNL
de novo lipogenesis
SREBP1c
sterol regulatory element-binding protein 1c
ACC
acetyl-CoA carboxylase
FAS
fatty acid synthase
SCD1
stearoyl-CoA desaturase 1
XBP1
X-box binding protein 1
eIF2α
eukaryotic translation initiation factor 2α
CHOP
C/EBP homologous protein
JNK
c-Jun N-terminal kinase
TUDCA
Tauroursodeoxycholic acid

Keywords

High carbohydrate diet
Hepatic steatosis
Insulin signaling
UPR signaling pathways

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1

These authors contributed equally to this study.