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.

Keywords: ischaemia-reperfusion injury; liver transplantation; necroptosis; non-alcoholic fatty liver disease; steatosis.

Figure 1

Overview of the process of ischemia-reperfusion (IR) injury. Upon depletion of oxygen during the ischaemic stage, mitochondria initiate anaerobic metabolism and ATP production decreases. Further, ion-exchange pump channel dysfunction and pH level decreases leading to cell swelling. During the reperfusion stage, mitochondrial swelling and accumulation of H⁺, Na⁺ and K⁺ result in oxidative stress leading to the excessive production of ROS. This induces cell injury, leading to cell death. The figure is modified from Reference [48].

Figure 2

TNFα-induced cell death pathway. TNFα stimulates TNFR1 to generate complex I by recruiting TRADD, TRAF2 and 5, RIPK1 and cIAP1/2. Polyubiquitination of RIPK1 in complex I will activate the NF-κB pathway, whereas polyubiquitination of RIPK1 by CLYD shifts complex I to cytoplasm to form complex II. Activation of CASPASE8 will result in activation of CASPASE3 and cells undergo apoptosis. Upon inhibition of CASPASE8, activation and phosphorylation of RIPK1 leads to recruitment of RIPK3 and further recruits MLKL to form the necrosome. Further activation of PGAM5 and DRP1 results in ROS production in mitochondria and induces necroptosis. Activation of TLR3/ TLR4 by PAMPs or LPS, activates Toll–IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF) and RIPK3 binding and triggers necroptosis. Abbreviations: TNF, tumour necrosis factor; TRADD, TNFRSF1A-associated via death domain; TRAF, TNF receptor-associated factors; cIAP, cellular inhibitor of apoptosis protein; CYLD, deubiquitinase cylindromatosis; FADD, FAS-associated death domain; MLKL, mediator mixed-lineage kinase domain like; RIPK, receptor-interacting protein kinase; PGAM5, phosphoglycerate mutase 5; Drp1, dynamin-related protein 1; ROS, reactive oxygen species; TLR3/4, TNF-like death receptors 3/4; PAMPs, pathogen-associated molecular patterns; LPS, lipopolysaccharide. Figure is modified from References [84,91,92].