Steatotic livers are susceptible to normothermic ischemia-reperfusion injury from mitochondrial Complex-I dysfunction

Chu, Michael J. J.; Premkumar, Rakesh; Hickey, Anthony J. R.; Jiang, Yannan; Delahunt, Brett; Phillips, Anthony R.J.; Bartlett, Adam

doi:10.3748/wjg.v22.i19.4673

Cited by 20 publications

(21 citation statements)

References 27 publications

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“…Although steatotic livers are highly sensitive to injury, some pre‐conditional protocols are also effective in improving mitochondrial function and liver function after hepatic IR injury. Although IPC exerts no effect on mitochondrial function, it significantly normalizes the function of fatty livers . The protective effect of suppressing mitochondrial MPT in pre‐conditional protocols is more significant in young rats than in old rats after hepatic IR injury .…”

Section: Hepatic Ir Exerts Various Effects According To Liver Healthmentioning

confidence: 96%

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

Hu¹

2017

J Cellular Molecular Medi

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The liver, the largest organ with multiple synthesis and secretion functions in mammals, consists of hepatocytes and Kupffer, stem, endothelial, stellate and other parenchymal cells. Because of early and extensive contact with the external environment, hepatic ischaemia reperfusion (IR) may result in mitochondrial dysfunction, autophagy and apoptosis of cells and tissues under various pathological conditions. Because the liver requires a high oxygen supply to maintain normal detoxification and synthesis functions, it is extremely susceptible to ischaemia and subsequent reperfusion with blood. Consequently, hepatic IR leads to acute or chronic liver failure and significantly increases the total rate of morbidity and mortality through multiple regulatory mechanisms. An increasing number of studies indicate that mitochondrial structure and function are impaired after hepatic IR, but that the health of liver tissues or liver grafts can be effectively rescued by attenuation of mitochondrial dysfunction. In this review, we mainly focus on the subsequent therapeutic interventions related to the conservation of mitochondrial function involved in mitigating hepatic IR injury and the potential mechanisms of protection. Because mitochondria are abundant in liver tissue, clarification of the regulatory mechanisms between mitochondrial dysfunction and hepatic IR should shed light on clinical therapies for alleviating hepatic IR‐induced injury.

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Section: Hepatic Ir Exerts Various Effects According To Liver Healthmentioning

confidence: 96%

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

Hu¹

2017

J Cellular Molecular Medi

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“…Generally speaking, fatty livers are particularly susceptible to IR damage. Animal experimental results have shown that the IR damage mechanism differs between normal and fatty liver [ 38 ]. NFκB subunit p65 activation plays a key role in steatotic liver transplantation-induced IR injury [ 39 ].…”

Section: Underlying Mechanism and Approaches To Treating Hepatic Ir Imentioning

confidence: 99%

Protective role of heme oxygenase-1 in fatty liver ischemia–reperfusion injury

Fujino

Takahara

et al. 2018

Med Mol Morphol

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Ischemia-reperfusion (IR) injury is a kind of injury resulting from the restoration of the blood supply after blood vessel closure during liver transplantation and is the main cause of graft failure. The pathophysiological mechanisms of hepatic IR include a variety of oxidative stress responses. Hepatic IR is characterized by ischemia and hypoxia inducing oxidative stress, immune response and apoptosis. Fat-denatured livers are also used as donors due to the lack of liver donors. Fatty liver is less tolerant to IR than normal liver. Heme oxygenase (HO) is an enzyme that breaks down hemoglobin to bilirubin, ferrous iron and carbon monoxide (CO). Inducible HO subtype HO-1 is an important protective molecule in mammalian cells used to improve acute and chronic liver injury owing to its characteristic anti-inflammatory and anti-apoptotic qualities. HO-1 degrades heme, and its reaction product CO has been shown to reduce hepatic IR injury and increase the survival rate of grafts. As an induced form of HO, HO-1 also exerts a protective effect against liver IR injury and may be useful as a new strategy of ameliorating this kind of damage. This review summarizes the protective effects of HO-1 in liver IR injury, especially in fatty liver.

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“…However, despite some limited improvement in some liver damage biomarkers (ie ATL), the lack of significant positive effect in clinical outcome have so far prevented its translation to the clinical setting, possibly related to the failure to recover the mitochondrial CI activity noted for the steatotic liver following IR [13] and the associated loss in ROS homeostasis.…”

Section: Ischemic-preconditioningmentioning

confidence: 99%

ROS homeostasis, a key determinant in liver ischemic-preconditioning

Prieto

Monsalve

2017

Redox Biology

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Reactive Oxygen Species (ROS) are key mediators of ischemia-reperfusion injury but also required for the induction of the stress response that limits tissue injury and underlies the protection provided by ischemic-preconditioning protocols. Liver steatosis is an important risk factor for liver transplant failure. Liver steatosis is associated with mitochondrial dysfunction and excessive mitochondrial ROS production. Studies aiming at decreasing the sensibility of the steatotic liver to ischemia-reperfusion injury using pre-conditioning protocols, have shown that the steatotic liver has a reduced capacity to respond to these protocols. Recent studies indicate that these effects are related to a reduced capacity of the steatotic liver to respond to elevated ROS levels following reperfusion by inducing a compensatory response. This failure to respond to ROS is associated with reduced levels of antioxidants, mitochondrial damage, hepatocyte cell death, activation of the immune system and induction of pro-fibrotic mediators.

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Steatotic livers are susceptible to normothermic ischemia-reperfusion injury from mitochondrial Complex-I dysfunction

Abstract: Warm IRI impairs steatotic liver Complex-I activity and function. The protective effects of IPC in steatotic livers may not be mediated through mitochondria.

Cited by 20 publications

References 27 publications

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

Protective role of heme oxygenase-1 in fatty liver ischemia–reperfusion injury

ROS homeostasis, a key determinant in liver ischemic-preconditioning

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