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

Oxidative Medicine and Cellular Longevity

Fan Zhu¹  Zhongshan Lu²  Anxiong Liu²  Qin Cao²  Xiaoyan Hu²  Wei Wang²  Shaojun Ye²  Zhiping Xia²  Yanfeng Wang²  Zhongzhong Liu²  Zibiao Zhong²  Qifa Ye³ 

[1]State Key Laboratory of Virology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China, whu.edu.cn

[2]Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Engineering Research Center of Natural Polymer-based Medical Materials in Hubei Province, Wuhan, China, 430071, znhospital.cn

[3]Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Engineering Research Center of Natural Polymer-based Medical Materials in Hubei Province, Wuhan, China, 430071, znhospital.cn

[4]The Third Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China, 410013, csu.edu.cn

DOI  :  10.1155/2020/5849794

来源: publisher

【 摘 要 】

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.

【 授权许可】

Unknown