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.
State Key Laboratory of Virology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China.
Oxid Med Cell Longev. 2020 Mar 20;2020:5849794. doi: 10.1155/2020/5849794. eCollection 2020.
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 -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.
肝缺血再灌注（IR）损伤是一种临床问题，目前导致不良后果，缺乏有效治疗方法。轻度低体温（32-35°C）是一种生理疗法，据报道可显著减轻 IR 损伤，其保护作用归因于多种机制，其中一种可能是调节脂肪酸氧化（FAO）。本研究旨在探讨 FAO 在轻度低体温保护作用中的作用及其潜在机制。我们使用雄性小鼠建立了如前所述的实验模型。简而言之，在原位缺血 1 小时和再灌注 6 小时之前，小鼠分别接受 2 小时的轻度低体温预处理和 1 小时的 etomoxir（FAO 抑制剂）或 leptin（FAO 激活剂）预处理。然后，收集组织和血液样本以评估肝损伤、氧化应激和肝 FAO 变化。我们发现，轻度低体温显著降低了肝酶水平和肝病理损伤评分、肝细胞凋亡、氧化应激和线粒体损伤。此外，IR 使肝 FAO 的限速酶（CPT1a）的表达下调近两倍，而这种抑制作用可被轻度低体温显著逆转。使用 leptin 和 etomoxir 的实验证实，FAO 的激活也可以降低由 IR 诱导的肝酶水平和肝病理损伤评分、肝细胞凋亡、氧化应激和线粒体损伤，其作用与轻度低体温相似，而 FAO 的抑制则产生负面影响。此外，轻度低体温和 leptin 可以促进 JAK2/STAT3 的磷酸化，上调 BCL-2/BAX 的比值，抑制肝细胞凋亡。因此，我们得出结论，FAO 在肝 IR 损伤中起重要作用，轻度低体温主要通过调节 JAK2/STAT3-CPT1a 依赖性 FAO 来减轻肝 IR 损伤。
