Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Medical Engineering and Technology Center of Organ Transplantation, Zhengzhou, Henan, China; Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Medical Engineering and Technology Center of Organ Transplantation, Zhengzhou, Henan, China; Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, China.
Biochem Biophys Res Commun. 2021 May 7;552:150-156. doi: 10.1016/j.bbrc.2021.03.048. Epub 2021 Mar 19.
Hepatocyte apoptosis is a crucial factor affecting liver quality in brain-dead donors. The identification of key molecular proteins involved in brain-death (BD)-induced hepatocyte apoptosis may help determine an effective method for improving the quality of livers from brain-dead donors. In this study, we used in vivo and in vitro models to investigate the role of chitinase-3-like protein 1 (CHI3L1) in promoting liver cell apoptosis after BD. Chitin was used to inhibit CHI3L1 in a rat model of BD. Macrophage polarization of THP-1 cells and hypoxia/reoxygenation (H/R) of LO-2 cells were used to mimic BD-induced cell stress in liver. We found that CHI3L1 played a vital role in promoting liver cell apoptosis. Six hours after BD, CHI3L1 expression was significantly upregulated in liver macrophages and was associated with BD-induced M1 polarization of these cells. In liver cells cultured under H/R conditions, recombinant CHI3L1 activated the protease-activated receptor 2 (PAR2)/c-June N-terminal kinase (JNK) apoptotic pathway and aggravated apoptosis. Compared with the control group, chitin particles inhibited the expression of CHI3L1 in the liver of brain dead rats, thereby reducing activation of the hepatocyte surface receptor, PAR2, and its downstream JNK/caspase-3 signaling pathway, ultimately reducing hepatocyte apoptosis. In conclusion, our results indicate that CHI3L1 relies on a PAR2/JNK-mediated mechanism to promote BD-induced hepatocyte apoptosis.
肝细胞凋亡是影响脑死亡供体肝脏质量的关键因素。鉴定脑死亡（BD）诱导的肝细胞凋亡中涉及的关键分子蛋白，可能有助于确定改善脑死亡供体肝脏质量的有效方法。在这项研究中，我们使用体内和体外模型来研究几丁质酶 3 样蛋白 1（CHI3L1）在 BD 后促进肝细胞凋亡中的作用。使用几丁质抑制 BD 大鼠模型中的 CHI3L1。用 THP-1 细胞的巨噬细胞极化和 LO-2 细胞的缺氧/复氧（H/R）模拟 BD 诱导的肝细胞应激。我们发现 CHI3L1 在促进肝细胞凋亡中起着至关重要的作用。BD 后 6 小时，肝巨噬细胞中 CHI3L1 的表达显著上调，并与这些细胞的 BD 诱导的 M1 极化相关。在 H/R 条件下培养的肝细胞中，重组 CHI3L1 激活蛋白酶激活受体 2（PAR2）/c-Jun N-末端激酶（JNK）凋亡途径并加重凋亡。与对照组相比，壳聚糖颗粒抑制脑死亡大鼠肝脏中 CHI3L1 的表达，从而减少肝细胞表面受体 PAR2 的激活及其下游 JNK/caspase-3 信号通路，最终减少肝细胞凋亡。总之，我们的结果表明，CHI3L1 依赖 PAR2/JNK 介导的机制来促进 BD 诱导的肝细胞凋亡。
