期刊
JOURNAL OF CLINICAL MEDICINE
卷 10, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/jcm10020212
关键词
ischaemia-reperfusion injury; necroptosis; liver transplantation; steatosis; apoptosis; in vitro
资金
- Gallipoli Medical Research Foundation
- University of Queensland
In an in vitro model of hepatic steatosis and ischemia, upregulation of RIPK3 and MLKL insoluble fraction was induced by ischemia, and intervention with MLKL and RIPK3 significantly reduced cell death. This suggests that necroptosis mediated by RIPK3-MLKL may contribute to cell death in fatty liver ischemic injury.
Background: Steatosis in donor livers poses a major risk of organ dysfunction due to their susceptibility to ischaemia-reperfusion (I/R) injury during transplant. Necroptosis, a novel form of programmed cell death, is orchestrated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), has been implicated in I/R injury. Here we investigated the mechanisms of cell death pathways in an in vitro model of hepato-steatotic ischaemia. Methods: Free fatty acid (FFA) treated alpha mouse liver 12 (AML-12) cells were incubated in oxygen-glucose-deprivation (OGD) conditions as seen during ischaemia. Results: We found that OGD triggered upregulation of insoluble fraction of RIPK3 and MLKL in FFA + OGD cells compared to FFA control cells. We report that intervention with small interfering (si) MLKL and siRIPK3 significantly attenuated cell death in FFA + OGD cells. Absence of activated CASPASE8 and cleaved-CASPASE3, no change in the expression of CASPASE1 and prostaglandin-endoperoxide synthase 2 (Ptgs2) in FFA + OGD treated cells compared to FFA control cells indicated that apoptosis, pyroptosis and ferroptosis, respectively, are unlikely to be active in this model. Conclusion: Our findings indicate that RIPK3-MLKL dependent necroptosis contributed to cell death in our in vitro model. Both MLKL and RIPK3 are promising therapeutic targets to inhibit necroptosis during ischaemic injury in fatty liver.
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