ER Stress Signaling in Hepatic Injury

  • Cheng JiEmail author
  • Neil Kaplowitz


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.


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.



alanine aminotransferase


adenosine monophosphate


antioxidant response element


apoptosis signal regulated kinase 1


activating transcription factor




betaine homocysteine methyltransferase


Bax inhibitor-1


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


cystathionine β-synthase


C/EBP-homologous protein


cyclic-AMP responsive element binding protein H

eIF2αeukaryotic translation initiation factor 2

alpha subunit


ER overload response


ER oxidase 1


endoplasmic reticulum


ER associated degradation


endoplasmic reticulum stress response element


forkhead box protein


general control of nitrogen protein kinase


glucose-regulated protein 78




glycogen synthase kinase


hepatitis B virus


hepatitis C virus


homocysteine-induced ER protein






inhibitor of κB kinase


inositol requiring enzyme


insulin receptor substrate-1


c-jun-N-terminal kinase


major histocompatability complex


5,10-methylenetetrahydrofolate reductase


microsomal triglyceride transfer protein


nonalcoholic fatty liver disease


nonalcoholic steatohepatitis


nuclear factor κB


NF-E2-related factor-2




old astrocyte specifically induced substance


oxygen-regulated protein 150


protein disulphide isomerase


phosphatidyl ethanolamine methyl transferase


protein kinase ds RNA-dependent-like ER kinase


protein kinase B


protein kinase dsRNA-dependent


peroxisome proliferator-activated receptor-alpha


reverse transcriptase–polymerase chain reaction


reactive oxygen species






sterol regulatory element binding protein


spliced XBP1


tumor necrosis factor receptor-associated factor-2


tribbles 3


tumor necrosis factor


TNF receptor 1


target of rapamycin


unfolded protein response


X box binding protein 1



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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