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ER Stress Signaling in Hepatic Injury

  • Cheng JiEmail author
  • Neil Kaplowitz
Chapter

Abstract

The endoplasmic reticulum (ER) is an essential membrane-bound organelle for protein synthesis, oxidative protein folding, and posttranslational modifications, most notably the addition of oligosaccharides and the formation of disulfide bonds [1–6]. The ER is also a site for biosynthesis of lipids and sterols and for storing and releasing Ca2+ which is involved in numerous cellular signal transduction pathways. Molecular chaperones in the ER ensure proper folding and targeting of nascent proteins. Unfolded or malfolded proteins (as high as 30% of nascent proteins) are retained in the ER and targeted for retrotranslocation to the cytoplasm by the machinery of ER associated degradation (ERAD), and rapidly degraded through the ubiquitin-­proteosomal pathways [7, 8]. Physiological or pathological conditions such as increased translation of secretory proteins, reduced capacity of folding and proteasomal degradation, alterations of redox state and Ca2+ levels, ATP depletion, and improper posttranslational modifications perturb the homeostasis of ER and cause accumulation of unfolded proteins which stresses the ER leading to an adaptive response (referred to as the unfolding protein response, UPR) to dampen the stress. Prolonged or severe UPR can lead to an attempt to delete the cell which is termed ER stress response [1–6]. Both responses are critical for the survival of the organism and an intricate relationship exists due to overlap and interplay between the two responses. In this chapter, we highlight the general signaling pathways of UPR and ER stress response, summarize the role of ER stress in a number of experimental or naturally occurring models of liver disease, and discuss our recent advances in alcohol or homocysteine-induced ER stress response and hepatic injury.

Keywords

Endoplasmic Reticulum Endoplasmic Reticulum Stress Alcoholic Liver Disease Endoplasmic Reticulum Stress Response Alcoholic Liver Injury 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ALT

alanine aminotransferase

AMP

adenosine monophosphate

ARE

antioxidant response element

ASK1

apoptosis signal regulated kinase 1

ATF

activating transcription factor

Atg

autophagy

BHMT

betaine homocysteine methyltransferase

BI-1

Bax inhibitor-1

Bim

a proapoptotic BH3-only member of the Bcl-2 family

CBS

cystathionine β-synthase

CHOP

C/EBP-homologous protein

CREBH

cyclic-AMP responsive element binding protein H

eIF2αeukaryotic translation initiation factor 2

alpha subunit

EOR

ER overload response

ERO1

ER oxidase 1

ER

endoplasmic reticulum

ERAD

ER associated degradation

ERSE

endoplasmic reticulum stress response element

Foxa

forkhead box protein

GCN2

general control of nitrogen protein kinase

GRP78

glucose-regulated protein 78

GSH

glutathione

GSK

glycogen synthase kinase

HBV

hepatitis B virus

HCV

hepatitis C virus

HERP

homocysteine-induced ER protein

Hcy

homocysteine

HHcy

hyperhomocysteinemia

IKK

inhibitor of κB kinase

IRE

inositol requiring enzyme

IRS-1

insulin receptor substrate-1

JNK

c-jun-N-terminal kinase

MHC

major histocompatability complex

MTHFR

5,10-methylenetetrahydrofolate reductase

MTP

microsomal triglyceride transfer protein

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

NF-κB

nuclear factor κB

Nrf-2

NF-E2-related factor-2

NTBC

2-(2-nitro-4-trifluoromethylbenzyol)-1,3-cyclohexanedione

OASIS

old astrocyte specifically induced substance

ORP150

oxygen-regulated protein 150

PDI

protein disulphide isomerase

PEMT

phosphatidyl ethanolamine methyl transferase

PERK

protein kinase ds RNA-dependent-like ER kinase

PKB

protein kinase B

PKR

protein kinase dsRNA-dependent

PPARα

peroxisome proliferator-activated receptor-alpha

RT-PCR

reverse transcriptase–polymerase chain reaction

ROS

reactive oxygen species

SAH

S-adenosylhomocysteine

SAM

S-adenosylmethionine

SREBP

sterol regulatory element binding protein

sXBP1

spliced XBP1

TRAF2

tumor necrosis factor receptor-associated factor-2

TRB3

tribbles 3

TNF

tumor necrosis factor

TNFR1

TNF receptor 1

TOR

target of rapamycin

UPR

unfolded protein response

XBP1

X box binding protein 1

Notes

Acknowledgments

This work was supported by NIH grants R01 AA014428, R01 AA018612, P50 AA11999, and P30 DK48522.

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© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA

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