Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure
Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure
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DOI：
10.1002/hep.32119
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发表时间：
2021-12-14
期刊：
影响因子：
13.5
通讯作者：
Weng, Hong-Lei
中科院分区：
文献类型：
--
作者：
Lin, Tao;Wang, Shanshan;Weng, Hong-Lei
背景与目的在急性肝衰竭（ALF）患者中，肝细胞大量丧失，肝祖细胞（LPCs）接管了关键的肝细胞功能，最终决定了患者的生存。本研究探讨肝细胞核因子4 α (HNF4 α)及其调节因子和靶点在LPCs中的表达如何决定ALF患者的临床预后。方法与结果对19例ALF患者（9例康复，10例接受肝移植）进行临床病理相关性分析。在体外和甲硝唑处理的斑马鱼中研究了卵泡抑素、激活素、HNF4 α和LPC中凝血因子表达的调节机制。一项前瞻性临床研究对186例肝硬化患者进行了为期80个月的随访，观察卵泡抑素水平与急性慢性肝衰竭患病率和死亡率的相关性。恢复后的ALF患者在LPCs或剩余肝细胞中均强烈表达HNF4 α。与肝细胞一样，HNF4 α通过与LPC中的凝血因子启动子结合来控制凝血因子的表达。在LPCs中，HNF4 α的表达需要叉头盒蛋白H1-Sma和Mad同源物2/3/4转录因子复合物，该复合物由tgf - β超家族成员激活素促进。卵泡抑素是一种由胰岛素和胰高血糖素控制的肝细胞来源的激素，可负调控LPCs中的激活素信号。与需要肝移植的患者相比，恢复的患者表现出正常的激活素/卵泡抑素比率，激活素效应物磷酸化LPCs中的Sma和Mad同源物2和HNF4 α的丰富度，导致凝血功能显着改善。一项随访研究表明，血清卵泡抑素水平可以预测急性慢性肝衰竭的发病率和死亡率。这些结果突出了卵泡抑素控制的激活素- hnf4 α -凝血轴在决定大量肝细胞损失诱导的ALF临床预后中的关键作用。胰岛素和胰高血糖素对卵泡抑素的影响提示在ALF的全身代谢状态中起关键作用。
Background and Aims In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4 alpha (HNF4 alpha), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. Approach and Results Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4 alpha, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4 alpha in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4 alpha controls the expression of coagulation factors by binding to their promoters in LPC. HNF4 alpha expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-beta superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4 alpha in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. Conclusions These results highlight a crucial role of the follistatin-controlled activin-HNF4 alpha-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.