TIPE1 promotes liver regeneration by enhancing ROS‐FoxO1 axis mediated autophagy
TIPE1 promotes liver regeneration by enhancing ROS‐FoxO1 axis mediated autophagy
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DOI：
10.1111/febs.16629
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发表时间：
2022-09
期刊：
影响因子：
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通讯作者：
Xiaodong Zhang;Shuang-jie Li;X. Ren;Peng Xiang;Yankun Zhang;Tixiao Wang;Qinghua Qin;Fengkai Sun-Fen
中科院分区：
文献类型：
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作者：
Xiaodong Zhang;Shuang-jie Li;X. Ren;Peng Xiang;Yankun Zhang;Tixiao Wang;Qinghua Qin;Fengkai Sun-Fen
肝脏强大的再生能力保护着至关重要的肝脏功能。肝细胞增殖和死亡之间的平衡对于恢复肝脏大小和生理至关重要。肿瘤坏死因子α诱导蛋白8样蛋白1(TIPE1)在肝脏中高表达，被认为是细胞增殖和死亡的候选调节因子，参与多种生物学过程和疾病。然而，TIPE1在肝脏再生中的作用尚不清楚。在目前的研究中，我们发现TIPE1在肝部分切除或10%四氯化碳注射诱导的再生肝中的表达增加。肝细胞条件性Tipe1基因敲除的小鼠表现出明显的肝再生受损。从机制上讲，肝脏Tipe1缺陷降低了肝细胞内的活性氧水平，进而导致Forkhead box O1乙酰化和微管相关蛋白1轻链3 I向微管相关蛋白1轻链3 II转化的抑制，以及隔离小体1的积聚。相比之下，TIPE1在肝细胞中的强制表达显著促进了70%肝部分切除后的肝再生，并增强了肝细胞活性氧/乙酰化的Forkhead box O1水平和自噬。这些发现表明，TIPE1通过精细调节氧化应激和自噬，在肝再生中发挥关键作用，是肝再生医学干预的潜在靶点。
The strong regenerative ability of the liver safeguards the crucial hepatic functions. The balance between hepatocyte proliferation and death is critical for restoring liver size and physiology. Tumour necrosis factor (TNF) alpha‐induced protein 8‐like 1 (TIPE1) is highly expressed in liver and has been identified as a candidate regulator for cell proliferation and death, being involved in a variety of biological processes and diseases. However, the role of TIPE1 in liver regeneration remains unexplored. In the present study, we found that TIPE1 expression was elevated in the regenerating liver induced by either partial hepatectomy or 10% carbon tetrachloride administration. Mice with hepatocyte conditional Tipe1 knockout presented significantly impaired liver regeneration. Mechanistically, hepatic Tipe1 deficiency decreased the level of reactive oxygen species in hepatocytes, which in turn led to the inhibition of Forkhead box O1 acetylation and microtubule‐associated protein 1 light chain 3 I to microtubule‐associated protein 1 light chain 3 II conversion, and the accumulation of sequestosome 1. By contrast, forced expression of TIPE1 in hepatocyte significantly promoted liver regeneration following 70% partial hepatectomy and enhanced hepatocyte reactive oxygen species/acetylated‐Forkhead box O1 level and autophagy. These findings indicate that TIPE1 plays a crucial role in liver regeneration by finely regulating the oxidative stress and autophagy and is a potential target for medical intervention of liver regeneration.