Elsevier

Journal of Hepatology

Volume 54, Issue 4, April 2011, Pages 795-809
Journal of Hepatology

Review
Endoplasmic reticulum stress in liver disease

https://doi.org/10.1016/j.jhep.2010.11.005Get rights and content
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The unfolded protein response (UPR) is activated upon the accumulation of misfolded proteins in the endoplasmic reticulum (ER) that are sensed by the binding immunoglobulin protein (BiP)/glucose-regulated protein 78 (GRP78). The accumulation of unfolded proteins sequesters BiP so it dissociates from three ER-transmembrane transducers leading to their activation. These transducers are inositol requiring (IRE) 1α, PKR-like ER kinase (PERK), and activating transcription factor (ATF) 6α. PERK phosphorylates eukaryotic initiation factor 2 alpha (eIF2α) resulting in global mRNA translation attenuation, and concurrently selectively increases the translation of several mRNAs, including the transcription factor ATF4, and its downstream target CHOP. IRE1α has kinase and endoribonuclease (RNase) activities. IRE1α autophosphorylation activates the RNase activity to splice XBP1 mRNA, to produce the active transcription factor sXBP1. IRE1α activation also recruits and activates the stress kinase JNK. ATF6α transits to the Golgi compartment where it is cleaved by intramembrane proteolysis to generate a soluble active transcription factor. These UPR pathways act in concert to increase ER content, expand the ER protein folding capacity, degrade misfolded proteins, and reduce the load of new proteins entering the ER. All of these are geared toward adaptation to resolve the protein folding defect. Faced with persistent ER stress, adaptation starts to fail and apoptosis occurs, possibly mediated through calcium perturbations, reactive oxygen species, and the proapoptotic transcription factor CHOP. The UPR is activated in several liver diseases; including obesity associated fatty liver disease, viral hepatitis, and alcohol-induced liver injury, all of which are associated with steatosis, raising the possibility that ER stress-dependent alteration in lipid homeostasis is the mechanism that underlies the steatosis. Hepatocyte apoptosis is a pathogenic event in several liver diseases, and may be linked to unresolved ER stress. If this is true, restoration of ER homeostasis prior to ER stress-induced cell death may provide a therapeutic rationale in these diseases. Herein we discuss each branch of the UPR and how they may impact hepatocyte function in different pathologic states.

Abbreviations

ATF4
activating transcription factor-4
ATF6
activating transcription factor-6
ATF6β
activating transcription factor-6β
AMP
adenosine monophosphate
ALT
alanine aminotransferase
ASK1
apoptosis signal regulated kinase 1
BI-1
bax inhibitor-1
CHOP
C/EBP homologues protein
CREBH
cyclic-AMP responsive element-binding protein H
ER
endoplasmic reticulum
ERAD
ER-associated degradation
ERSE
ER stress response element
eIF2
eukaryotic initiation factor 2 alpha
GRP78/BiP
glucose regulated protein 78/binding immunoglobulin protein
GRP94
glucose regulated protein 94
HBV
hepatitis B virus
HCV
hepatitis C virus
4HNE
4-hydroxynonenal
IP3R
inositol 1,4,5-triphosphate receptor
IRE1
inositol requiring 1
IL-6
interleukin-6
JNK
C-jun N-terminal kinase
MDA
malondialdehyde
MTTP
microsomal triglyceride transfer protein
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
PFIC II
progressive familiar intrahepatic cholestasis type II
PERK
protein kinase RNA (PKR)-like ER kinase
ROS
reactive oxygen species
RIP
regulated intramembrane proteolysis
RIDD
regulated IRE1-dependent decay
S1P
site-1 protease
S2P
site-2 protease
SREBP
sterol regulatory element-binding protein
sXBP1
spliced X-box binding protein 1
TNF-α
tumor necrosis factor alpha
TRAF2
tumor necrosis factor receptor-associated factor-2
XBP1
X-box binding protein 1
UPR
unfolded protein response
VLDL
very low density lipoprotein

Keywords

Endoplasmic reticulum stress
Unfolded protein response
Hepatosteatosis
Liver injury

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