Protein tyrosine phosphatase 1B modulates GSK3β/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity.
Protein tyrosine phosphatase 1B modulates GSK3β/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity.
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DOI：
10.1038/cddis.2013.150
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发表时间：
2013-05-09
影响因子：
9
通讯作者：
Valverde, A. M.
中科院分区：
文献类型：
--
作者：
Mobasher, M. A.;Gonzalez-Rodriguez, A.;Santamaria, B.;Ramos, S.;Martin, M. A.;Goya, L.;Rada, P.;Letzig, L.;James, L. P.;Cuadrado, A.;Martin-perez, J.;Simpson, K. J.;Muntane, J.;Valverde, A. M.
对乙酰氨基酚（APAP）中毒继发急性肝功能衰竭与高死亡率相关。蛋白酪氨酸磷酸酶1B（PTP 1B）是酪氨酸激酶生长因子信号传导的负调节因子。在肝脏中，这一途径提供保护免受损伤。然而，PTP 1B参与APAP激活的细胞内网络尚不清楚。我们评估了PTP 1B在APAP诱导的人类肝衰竭中的表达及其在调节人和小鼠肝细胞细胞死亡和存活之间平衡的分子机制中的作用，以及在APAP诱导的肝毒性小鼠模型中的作用。PTP 1B表达在APAP过量患者的肝移植期间取出的人肝组织中增加。在原代人和小鼠肝细胞中，APAP上调PTP 1B，同时激活c-jun（NH 2）末端激酶（JNK）和p38丝裂原活化蛋白激酶（p38 MAPK），导致细胞死亡。相反，Akt磷酸化和抗凋亡Bcl 2家族成员BclxL和Mcl 1减少。小鼠中的PTP 1B缺陷可保护肝细胞免受APAP诱导的细胞死亡，防止谷胱甘肽耗尽、活性氧簇（ROS）产生以及JNK和p38 MAPK的激活。APAP处理的PTP 1B −/−肝细胞通过糖原合成酶激酶3（GSK 3）β/Src激酶家族（SKF）轴表现出增强的抗氧化防御，延迟转录因子核因子-红细胞2相关因子（Nrf 2）的酪氨酸磷酸化及其核排斥、泛素化和降解。胰岛素样生长因子-I受体介导的信号在APAP处理的野生型肝细胞中减少，但在PTP 1B −/−细胞或通过RNA干扰降低PTP 1B水平的野生型肝细胞中维持。同样，两种信号级联在小鼠中都受到调节，导致PTP 1B −/−小鼠中APAP肝毒性不太严重。我们的研究结果表明，PTP 1B是APAP肝毒性机制的核心球员，这表明APAP诱导的肝衰竭的新的治疗靶点。
Acute hepatic failure secondary to acetaminophen (APAP) poisoning is associated with high mortality. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of tyrosine kinase growth factor signaling. In the liver, this pathway confers protection against injury. However, the involvement of PTP1B in the intracellular networks activated by APAP is unknown. We have assessed PTP1B expression in APAP-induced liver failure in humans and its role in the molecular mechanisms that regulate the balance between cell death and survival in human and mouse hepatocytes, as well as in a mouse model of APAP-induced hepatotoxicity. PTP1B expression was increased in human liver tissue removed during liver transplant from patients for APAP overdose. PTP1B was upregulated by APAP in primary human and mouse hepatocytes together with the activation of c-jun (NH2) terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), resulting in cell death. Conversely, Akt phosphorylation and the antiapoptotic Bcl2 family members BclxL and Mcl1 were decreased. PTP1B deficiency in mouse protects hepatocytes against APAP-induced cell death, preventing glutathione depletion, reactive oxygen species (ROS) generation and activation of JNK and p38 MAPK. APAP-treated PTP1B−/− hepatocytes showed enhanced antioxidant defense through the glycogen synthase kinase 3 (GSK3)β/Src kinase family (SKF) axis, delaying tyrosine phosphorylation of the transcription factor nuclear factor-erythroid 2-related factor (Nrf2) and its nuclear exclusion, ubiquitination and degradation. Insulin-like growth factor-I receptor-mediated signaling decreased in APAP-treated wild-type hepatocytes, but was maintained in PTP1B−/− cells or in wild-type hepatocytes with reduced PTP1B levels by RNA interference. Likewise, both signaling cascades were modulated in mice, resulting in less severe APAP hepatotoxicity in PTP1B−/− mice. Our results demonstrated that PTP1B is a central player of the mechanisms triggered by APAP in hepatotoxicity, suggesting a novel therapeutic target against APAP-induced liver failure.
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5.9
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