Protective Role of mTOR in Liver Ischemia/Reperfusion Injury: Involvement of Inflammation and Autophagy.

Tao Zhang,Jiliang Wang,Jian Gu,Ke Chen,Jianrong Guo,Huili Li

doi:10.1155/2019/7861290

Tao Zhang, Jiliang Wang + Show 4 more

Open Access

https://doi.org/10.1155/2019/7861290

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Abstract

Liver ischemia/reperfusion (IR) injury is a common phenomenon after liver resection and transplantation, which often results in liver graft dysfunction such as delayed graft function and primary nonfunction. The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved serine/threonine protein kinase, which coordinates cell growth and metabolism through sensing environmental inputs under physiological or pathological conditions, involved in the pathophysiological process of IR injury. In this review, we mainly present current evidence of the beneficial role of mTOR in modulating inflammation and autophagy under liver IR to provide some evidence for the potential therapies for liver IR injury.

Highlights

Liver resection and transplantation are the most effective approaches for liver cancer and other end-stage liver diseases
There exist four major upstream signaling pathways of mTOR complexes 1 (mTORC1), including the insulin/phosphatidylinositol-3 kinase/protein kinase B signaling pathway, epidermal growth factor (EGF)/Ras/Raf/mitogen activated protein kinase (EGF/Ras/Raf/Mek/Erk) signaling pathway, Wnt/glycogen synthase kinase-3β (Wnt/GSK-3β) signaling pathway, and adenosine monophosphate-activated protein kinase (AMPK) signaling pathway [12, 15]. All of these four axes are converged at least partially on tuberous sclerosis complex (TSC), which is composed of TSC1, TSC2, and TBC1D7 and functions as a GTPase activating protein (GAP) of the Ras homolog enriched in brain (Rheb) GTPase
We believe that moderate regulation of autophagy through modulating the PI3K/Akt/mTORC1 pathway or mTORC1/mTORC2 balancing may serve as a potential strategy for attenuating liver IR injury

Summary

Introduction

Liver resection and transplantation are the most effective approaches for liver cancer and other end-stage liver diseases. Various factors are involved in the pathophysiological process of liver IR injury, including active oxygen species (ROS) overproduction, excessive inflammatory response (redundant inflammatory cytokine release and activation of complement system), the overactivation of autophagy and endoplasmic reticulum stress (ERS), and mitochondrial dysfunction [2]. There exist four major upstream signaling pathways of mTORC1, including the insulin/phosphatidylinositol-3 kinase/protein kinase B (insulin/PI3K/Akt) signaling pathway, EGF/Ras/Raf/mitogen activated protein kinase (EGF/Ras/Raf/Mek/Erk) signaling pathway, Wnt/glycogen synthase kinase-3β (Wnt/GSK-3β) signaling pathway, and adenosine monophosphate-activated protein kinase (AMPK) signaling pathway [12, 15] All of these four axes are converged at least partially on tuberous sclerosis complex (TSC), which is composed of TSC1, TSC2, and TBC1D7 and functions as a GTPase activating protein (GAP) of the Ras homolog enriched in brain (Rheb) GTPase. As a GAP of Rheb, TSC converts GTP-Rheb into its inactive GDP-bound form to inhibit the activity of mTORC1 [10] (Figure 1)

The mTOR Signaling and Liver IR

Findings

Conclusions