Mild Hypothermia Attenuates Hepatic Ischemia-Reperfusion Injury through Regulating the JAK2/STAT3-CPT1a-Dependent Fatty Acid β-Oxidation.

Wei Wang,Zibiao Zhong,Zhongzhong Liu,Yanfeng Wang,Anxiong Liu,Fan Zhu,Qifa Ye,Xiaoyan Hu,Zhongshan Lu,Qin Cao,Shaojun Ye,Zhiping Xia

doi:10.1155/2020/5849794

Abstract

Hepatic ischemia–reperfusion (IR) injury is a clinical issue that can result in poor outcome and lacks effective therapies at present. Mild hypothermia (32–35°C) is a physiotherapy that has been reported to significantly alleviate IR injury, while its protective effects are attributed to multiple mechanisms, one of which may be the regulation of fatty acid β-oxidation (FAO). The aim of the present study was to investigate the role and underlying mechanisms of FAO in the protective effects of mild hypothermia. We used male mice to establish the experimental models as previously described. In brief, before exposure to in situ ischemia for 1 h and reperfusion for 6 h, mice received pretreatment with mild hypothermia for 2 h and etomoxir (inhibitor of FAO) or leptin (activator of FAO) for 1 h, respectively. Then, tissue and blood samples were collected to evaluate the liver injury, oxidative stress, and changes in hepatic FAO. We found that mild hypothermia significantly reduced the hepatic enzyme levels and the score of hepatic pathological injury, hepatocyte apoptosis, oxidative stress, and mitochondrial injury. In addition, the expression of the rate-limiting enzyme (CPT1a) of hepatic FAO was downregulated almost twofold by IR, while this inhibition could be significantly reversed by mild hypothermia. Experiments with leptin and etomoxir confirmed that activation of FAO could also reduce the hepatic enzyme levels and the score of hepatic pathological injury, hepatocyte apoptosis, oxidative stress, and mitochondrial injury induced by IR, which had the similar effects to mild hypothermia, while inhibition of FAO had negative effects. Furthermore, mild hypothermia and leptin could promote the phosphorylation of JAK2/STAT3 and upregulate the ratio of BCL-2/BAX to suppress hepatocyte apoptosis. Thus, we concluded that FAO played an important role in hepatic IR injury and mild hypothermia attenuated hepatic IR injury mainly via the regulation of JAK2/STAT3-CPT1a-dependent FAO.

Highlights

Hepatic ischemia–reperfusion (IR) injury is a serious clinical problem that can hardly be avoided in certain kinds of surgeries, such as liver transplantation and resection, as well as hemorrhagic shock [1, 2]
The hepatic functional and morphological changes and cell apoptosis did not exhibit a significant difference between the normal group and the mild hypothermia pretreatment group (P > 0:05)
To test whether regulation of fatty acid β-oxidation (FAO) was involved in mild hypothermia which attenuates hepatic IR injury, we evaluated the levels of proteases that are involved in the process of FAO and the associated products of FAO in liver tissue, such as adenosine triphosphate (ATP), Acetyl CoA, and Malonyl CoA

Summary

Introduction

Hepatic ischemia–reperfusion (IR) injury is a serious clinical problem that can hardly be avoided in certain kinds of surgeries, such as liver transplantation and resection, as well as hemorrhagic shock [1, 2]. The paradigm of hepatic IR is based on two apparently separate phases, involving the ischemic phase and the reperfusion phase. The ischemic phase mainly causes cellular metabolic disturbances that result from glycogen consumption, lack of oxygen supply, and ATP depletion, while the reperfusion phase results in metabolic disturbances and in a profound. The complicated IR injury is one of the main reasons for early graft failure and the increased risk of organ rejection and liver dysfunction [3]. More effective strategies that can reduce hepatic IR injury and improve graft viability are urgently needed

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