Li Ziru, Zhang Jing, Mulholland Michael, Zhang Weizhen
Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA
FASEB J. 2017 Jul;31(7):3018-3026. doi: 10.1096/fj.201601278R. Epub 2017 Mar 29.
Hepatic steatosis renders liver more vulnerable to ischemia/reperfusion injury (IRI), which commonly occurs in transplantation, trauma, and liver resection. The underlying mechanism is not fully characterized. We aimed to clarify the role of mechanistic target of rapamycin (mTOR) signaling in hepatic ischemia/reperfusion injury (HIRI) in normal and steatotic liver using - (AT) and (Am) transgenic mice. Steatotic liver induced by high-fat diet was more vulnerable to IRI. Activation of hepatic mTOR in AT mice decreased lipid accumulation attenuated HIRI as measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, circulating levels of alanine aminotransferase and lactate dehydrogenase, and inflammatory mediators such as monocyte chemoattractant protein 1 (MCP-1), TNF-α, and IL-6 and hepatic cleaved caspase 3 in mice fed either a normal chow diet or a high-fat diet. The effects of mTOR activation on hepatic cleaved caspase 3 were reversed by rapamycin, an inhibitor of mTOR signaling. Inhibition of hepatic mTOR in Am mice increased hepatic lipid deposition and HIRI. The increment in hepatic susceptibility to IRI was significantly attenuated by pretreatment with IKKβ inhibitor. Further, suppression of mTOR facilitated nuclear translocation of NF-κB p65. In conclusion, our study suggests that mTOR activity in hepatocytes decreases hepatic vulnerability to injury through a mechanism dependent on NF-κB proinflammatory cytokine signaling pathway in both normal and steatotic liver.-Li, Z., Zhang, J., Mulholland, M., Zhang, W. mTOR activation protects liver from ischemia/reperfusion-induced injury through NF-κB pathway.
肝脂肪变性使肝脏更容易受到缺血/再灌注损伤（IRI），这种损伤常见于移植、创伤和肝切除手术中。其潜在机制尚未完全明确。我们旨在使用AT和Am转基因小鼠阐明雷帕霉素靶蛋白（mTOR）信号通路在正常肝脏和脂肪变性肝脏的肝缺血/再灌注损伤（HIRI）中的作用。高脂饮食诱导的脂肪变性肝脏对IRI更敏感。在正常饮食或高脂饮食喂养的小鼠中，AT小鼠肝脏mTOR的激活减少了脂质积累，减轻了HIRI，这通过末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）染色、丙氨酸氨基转移酶和乳酸脱氢酶的循环水平以及单核细胞趋化蛋白1（MCP-1）、TNF-α和IL-6等炎症介质以及肝脏中裂解的半胱天冬酶3来衡量。mTOR信号通路抑制剂雷帕霉素逆转了mTOR激活对肝脏裂解半胱天冬酶3的影响。Am小鼠肝脏mTOR的抑制增加了肝脏脂质沉积和HIRI。用IKKβ抑制剂预处理可显著减轻肝脏对IRI易感性的增加。此外，mTOR的抑制促进了NF-κB p65的核转位。总之，我们的研究表明，在正常肝脏和脂肪变性肝脏中，肝细胞中的mTOR活性通过依赖于NF-κB促炎细胞因子信号通路的机制降低了肝脏对损伤的易感性。-李，Z.，张，J.，马尔霍兰，M.，张，W. mTOR激活通过NF-κB途径保护肝脏免受缺血/再灌注诱导的损伤。
