Abstract
The endoplasmic reticulum (ER) is involved in calcium homeostasis, protein folding and lipid biosynthesis. Perturbations in its normal functions lead to a condition called endoplasmic reticulum stress (ERS). This can be triggered by many physiopathological conditions such as alcoholic steatohepatitis, insulin resistance or ischemia-reperfusion injury. The cell reacts to ERS by initiating a defensive process known as the unfolded protein response (UPR), which comprises cellular mechanisms for adaptation and the safeguarding of cell survival or, in cases of excessively severe stress, for the initiation of the cell death program. Recent experimental data suggest the involvement of ERS in ischemia/reperfusion injury (IRI) of the liver graft, which has been considered as one of major problems influencing outcome after liver transplantation. The purpose of this review is to summarize updated data on the molecular mechanisms of ERS/UPR and the consequences of this pathology, focusing specifically on solid organ preservation and liver transplantation models. We will also discuss the potential role of ERS, beyond the simple adaptive response and the regulation of cell death, in the modification of cell functional properties and phenotypic changes.
Highlights
The endoplasmic reticulum (ER) is an important intracellular organelle mainly responsible for the synthesis, folding and trafficking of a wide variety of proteins, including hormones, enzymes, receptors, ion channels and transporters
The adaptive phase is characterized by the proteasome degradation of proteins and the subsequent overall inhibition of protein transduction that leads to increases in the chaperone pool and protein enzymes such as X box binding protein 1 (XBP-1) and activating transcription factor 4 (ATF4) [2]
In the part of this review, we describe the relevance of the unfolded protein response (UPR)/endoplasmic reticulum stress (ERS) changes that occur during liver cold ischemia-reperfusion injury
Summary
The endoplasmic reticulum (ER) is an important intracellular organelle mainly responsible for the synthesis, folding and trafficking of a wide variety of proteins, including hormones, enzymes, receptors, ion channels and transporters. These investigations suggest that the use of proteasome inhibitors may help to maintain the physiological ubiquitin-protein conjugate pool during cold storage in organ preservation solutions, prolonging liver graft conservation and preventing subsequent cold IRI Besides this ATP depletion, during cold ischemia other cyto-protective factors such as adenosine mono phosphate protein kinase (AMPK) are activated as a self-response of the organ to oxygen deprivation. We have reported that IGL-1 solution prevented ERS more efficiently than UW by reducing the activation of three pathways of the UPR (IRE1, PERK and ATF6), as well as their effector molecules caspase 12-CHOP, XBP-1, tumor necrosis factors-associate factor 2 and eukaryotic translation initiation factor 2 [37] This was associated with a reduction in liver injury and apoptosis.
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