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ER Stress Signaling in Hepatic Injury

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Signaling Pathways in Liver Diseases

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.

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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

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Acknowledgments

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

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  1. Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 101, Los Angeles, CA, 90033, USA

    Cheng Ji & Neil Kaplowitz

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  1. Inselspital, Universität Bern, Murtenstr. 35, Bern, 3010, Switzerland

    Jean-Francois Dufour

  2. Klinik für Viszeral- und, Universitätsspital Zürich, Rämistr. 100, Zürich, 8091, Switzerland

    Pierre-Alain Clavien

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Ji, C., Kaplowitz, N. (2010). ER Stress Signaling in Hepatic Injury. In: Dufour, JF., Clavien, PA. (eds) Signaling Pathways in Liver Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00150-5_19

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