Liver Department, Xi'an Hospital of Traditional Chinese Medicine, Xi'an 710021, China.
Department of Vascular Surgery, Yidu Central Hospital of Weifang, Weifang 262500, China.
Biomed Pharmacother. 2020 Sep;129:110455. doi: 10.1016/j.biopha.2020.110455. Epub 2020 Jul 9.
Hepatic ischemia-reperfusion (IR) injury is characterized by severe inflammation and cell death. However, very few effective therapies are presently available for hepatic IR injury treatment. Here, we reported a protective function and the underlying mechanism of myotubularin-related protein 14 (MTMR14) during hepatic IR injury. Hepatocyte-specific MTMR14 knockout (HKO) and transgenic (TG) mice were subjected to hepatic IR operation to explore MTMR14 function in vivo. Primary hepatocytes isolated from MTMR14-HKO and MTMR14-TG mice were subjected to hypoxia/reoxygenation (HR) insult in vitro. We found that MTMR14 expression in liver tissues from individuals with hepatic IR was markedly decreased, and similar results were detected in mice with hepatic IR surgery. MTMR14-TG mice following hepatic IR operation had obviously ameliorated liver pathological changes, along with improved hepatic dysfunction, which was proved by the decreased serum alanine amino transferase (ALT) and aspartate amino transferase (AST) levels. MTMR14-HKO and MTMR14-TG animal models indicated that MTMR14 alleviated cell death and inflammatory response. In addition, MTMR14 inhibited nuclear transcription factor κB (NF-κB) signaling. Of note, promoting MTMR14 expression improved phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) pathway through a physical interaction with AKT, subsequently reducing cell death and inflammation. Therefore, MTMR14 is a protective factor during hepatic IR injury, and the MTMR14/AKT signaling is involved the pathogenesis hepatic IR injury. Improvement of this axis might be a novel therapeutic strategy for the prevention of this pathological process.
肝缺血再灌注（IR）损伤的特征是严重的炎症和细胞死亡。然而，目前可用的治疗肝 IR 损伤的有效疗法很少。在这里，我们报道了肌管相关蛋白 14（MTMR14）在肝 IR 损伤中的保护作用及其潜在机制。肝细胞特异性 MTMR14 敲除（HKO）和转基因（TG）小鼠接受肝 IR 手术，以在体内探索 MTMR14 功能。从 MTMR14-HKO 和 MTMR14-TG 小鼠分离的原代肝细胞在体外进行缺氧/复氧（HR）损伤。我们发现，肝 IR 个体肝组织中的 MTMR14 表达明显降低，肝 IR 手术小鼠也检测到类似结果。肝 IR 手术后的 MTMR14-TG 小鼠肝脏病理变化明显改善，肝功能障碍改善，血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平降低证明了这一点。MTMR14-HKO 和 MTMR14-TG 动物模型表明，MTMR14 减轻了细胞死亡和炎症反应。此外，MTMR14 抑制了核转录因子 κB（NF-κB）信号。值得注意的是，通过与 AKT 的物理相互作用促进 MTMR14 表达可激活磷酸肌醇 3-激酶/蛋白激酶 B（PI3K/AKT）途径，从而减少细胞死亡和炎症。因此，MTMR14 是肝 IR 损伤过程中的保护因子，MTMR14/AKT 信号通路参与了肝 IR 损伤的发病机制。改善该轴可能是预防这种病理过程的一种新的治疗策略。
