Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury
Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury
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DOI：
10.2353/ajpath.2009.080976
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发表时间：
2009-09-01
影响因子：
6
通讯作者：
Monga, Satdarshan P. S.
中科院分区：
文献类型：
--
作者：
Apte, Udayan;Singh, Sucha;Monga, Satdarshan P. S.
急性肝衰竭（ALF）仍然是一种患者预后不良的疾病。改善的预后与自发性肝再生有关，这支持了探索“再生”疗法的相关性。因此，研究了Wnt/β-连环蛋白途径在ALF后肝再生中的作用。对乙酰氨基酚过量在小鼠中诱导ALF，这也是患者肝功能衰竭的主要原因。还在对乙酰氨基酚诱导的ALF患者的肝切片中研究了β-连环蛋白分布。非致死剂量的对乙酰氨基酚可诱导肝再生，导致β-连环蛋白稳定和激活1至12小时。这些数据也通过β-连环蛋白替代靶谷氨酰胺合成酶的表达增加来验证。β-连环蛋白激活发生在糖原合成酶激酶-3 β失活和酪蛋白激酶2 α水平增加之后，并导致另一种已知的β-连环蛋白靶细胞周期蛋白-D1增加。这些观察结果随后在β-连环蛋白条件磨小鼠（β-连环蛋白-null）中得到证实，这些小鼠在诱导CYP 2 e1/1a 2表达后对乙酰氨基酚损伤后表现出再生抑制。鉴于β-连环蛋白缺失小鼠中对乙酰氨基酚损伤的减少，尽管进行了β-连环蛋白诱导，但在对照小鼠中进行了等毒性研究。在β-连环蛋白缺失和对照动物中，再生的显著差异在可比的损伤后持续存在。对对乙酰氨基酚过量患者的肝脏样本的回顾性分析表明，细胞核β-连环蛋白、增殖和自发性肝再生之间呈正相关。因此，我们的研究表明，在对乙酰氨基酚诱导的损伤过程中，β-连环蛋白信号的早期激活有助于肝再生。(Am J Pathol 2009，175：1056-1065; DOI：10.2353/ajpath.2009.080976）
Acute liver failure (ALF) remains a disease with poor patient outcome. improved prognosis is associated with spontaneous liver regeneration, which supports the relevance of exploring 'regenerative' therapies. Therefore, the role of the Wnt/beta-catenin pathway in liver regeneration following ALF was investigated. ALF was induced in mice by acetaminophen overdose, which is also a leading cause of liver failure in patients. beta-catenin distribution was also studied in liver sections from acetaminophen-induced ALF patients. A nonlethal dose of acetaminophen, which induces liver regeneration, led to stabilization and activation of beta-catenin for 1 to 12 hours. These data were also verified by increased expression of the beta-catenin surrogate target glutamine synthetase. beta-Catenin activation occurred secondary to the inactivation of glycogen synthase kinase-3 beta and an increase in levels of casein kinase 2 alpha, and led to increased cyclin-D1, another known beta-catenin target. These observations were next substantiated in beta-catenin conditional-mill mice (beta-catenin-null), which show dampened regeneration after acetaminophen injury following induction of CYP2e1/1a2 expression. In light of decreased acetaminophen injury in beta-catenin-null mice despite CYP induction, equitoxic studies in control mice were performed. Significant differences in regeneration persisted following comparable injury in beta-catenin-null and control animals. Retrospective analysis of liver samples from acetaminophen-overdose patients demonstrated a positive correlation between nuclear beta-catenin, proliferation, and spontaneous liver regeneration. Thus, our studies demonstrate early activation of beta-catenin signaling during acetaminophen-induced injury, which contributes to hepatic regeneration. (Am J Pathol 2009, 175:1056-1065; DOI: 10.2353/ajpath.2009.080976)