Necroptosis in Hepatosteatotic Ischaemia-Reperfusion Injury

Abstract

While liver transplantation remains the sole treatment option for patients with end-stage liver disease, there are numerous limitations to liver transplantation including the scarcity of donor livers and a rise in livers that are unsuitable to transplant such as those with excess steatosis. Fatty livers are susceptible to ischaemia-reperfusion (IR) injury during transplantation and IR injury results in primary graft non-function, graft failure and mortality. Recent studies have described new cell death pathways which differ from the traditional apoptotic pathway. Necroptosis, a regulated form of cell death, has been associated with hepatic IR injury. Receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL) are thought to be instrumental in the execution of necroptosis. The study of hepatic necroptosis and potential therapeutic approaches to attenuate IR injury will be a key factor in improving our knowledge regarding liver transplantation with fatty donor livers. In this review, we focus on the effect of hepatic steatosis during liver transplantation as well as molecular mechanisms of necroptosis and its involvement during liver IR injury. We also discuss the immune responses triggered during necroptosis and examine the utility of necroptosis inhibitors as potential therapeutic approaches to alleviate IR injury.

Inhibition of MLKL Attenuates Necroptotic Cell Death in a Murine Cell Model of Hepatic Ischaemia Injury

“…For a long period of time, apoptosis was the most widely understood mode of regulated cell death as it plays a critical role during tissue development and morphogenesis of multicellular eukaryotes [ 51 , 56 ]. On the other hand, necroptosis has been identified as a novel form of programmed cell death that involves many proteins that been suggested to play a role as instigators, executors and effectors of necroptosis [ 57 , 58 , 59 , 60 , 61 ]. Only recently, have key molecular mechanisms of necroptosis been established.…”

“…At the cellular level, necroptosis is characterized by cytoplasmic granule formation, organelle swelling leading to loss of membrane permeability and disintegration of the plasma membrane [ 62 , 63 , 64 ]. This is followed by release of intracellular organelles and damage- associated molecular pattern molecules (DAMPs), sending inflammatory signals to adjacent cells [ 61 , 65 , 66 ]. Overexpression of inflammatory cytokines such as TNFα and IL6 in steatotic liver has been previously well-documented, as has increased production of TNFα and IL6 in IR injury [ 67 ].…”

Methods of Attenuating Ischemia-Reperfusion Injury in Liver Transplantation for Hepatocellular Carcinoma

“…Oxidative stress causes cell death by the mechanisms of apoptosis, necrosis, and autophagy [ 8 , 9 , 10 ]. Necroptosis, one of the other types of programmed cell death, also plays a role [ 11 ].…”

“…In steatotic livers, the production of free oxygen radicals increases as a result of lipid peroxidation. Another mechanism is related to microcirculation disturbances [ 11 , 18 ]. In DCD organs, the greater susceptibility to IRI is mainly related to the long duration of warm ischemia time [ 21 ].…”

Bone marrow mesenchymal stem cells stimulated by tumor necrosis factor-α can promote the repair of fatty liver cell oxidative stress injury and fatty liver ischemia-reperfusion injury

“…Liver transplantation is the only effective way to treat end-stage liver disease. With the increasing maturity of liver transplantation technology and the increasing number of liver transplant patients, the shortage of donor livers has become more prominent 1 . How to safely use marginal donor liver has become a research hotspot.…”