Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea.
College of Pharmacy, Woosuk University, Wanju 55338, Jeonbuk, Korea.
Int J Mol Sci. 2019 Sep 5;20(18):4369. doi: 10.3390/ijms20184369.
Hepatocyte death is critical for the pathogenesis of liver disease progression, which is closely associated with endoplasmic reticulum (ER) stress responses. However, the molecular basis for ER stress-mediated hepatocyte injury remains largely unknown. This study investigated the effect of ER stress on dual-specificity phosphatase 5 (DUSP5) expression and its role in hepatocyte death. Analysis of Gene Expression Omnibus (GEO) database showed that hepatic DUSP5 levels increased in the patients with liver fibrosis, which was verified in mouse models of liver diseases with ER stress. DUSP5 expression was elevated in both fibrotic and acutely injured liver of mice treated with liver toxicants. Treatment of ER stress inducers enhanced DUSP5 expression in hepatocytes, which was validated in vivo condition. The induction of DUSP5 by ER stress was blocked by either treatment with a chemical inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, or knockdown of C/EBP homologous protein (CHOP), whereas it was not affected by the silencing of IRE1 or ATF6. In addition, DUSP5 overexpression decreased extracellular-signal-regulated kinase (ERK) phosphorylation, but increased cleaved caspase-3 levels. Moreover, the reduction of cell viability under ER stress condition was attenuated by DUSP5 knockdown. In conclusion, DUSP5 expression is elevated in hepatocytes by ER stress through the PERK-CHOP pathway, contributing to hepatocyte death possibly through ERK inhibition.
肝细胞死亡对于肝脏疾病进展的发病机制至关重要，而这与内质网（ER）应激反应密切相关。然而，ER 应激介导的肝细胞损伤的分子基础在很大程度上仍不清楚。本研究探讨了 ER 应激对双特异性磷酸酶 5（DUSP5）表达的影响及其在肝细胞死亡中的作用。基因表达综合数据库（GEO）分析显示，肝纤维化患者的肝组织中 DUSP5 水平升高，在具有 ER 应激的肝脏疾病小鼠模型中得到了验证。在用肝毒物处理的小鼠的纤维化和急性损伤的肝脏中，DUSP5 的表达均升高。ER 应激诱导物可增强肝细胞中 DUSP5 的表达，这在体内条件下得到了验证。PERK 通路的蛋白激酶 RNA 样内质网激酶（PERK）化学抑制剂处理或 C/EBP 同源蛋白（CHOP）敲低均可阻断 ER 应激诱导的 DUSP5 表达，但 IRE1 或 ATF6 的沉默则不受影响。此外，DUSP5 的过表达降低了细胞外信号调节激酶（ERK）磷酸化水平，但增加了 cleaved caspase-3 水平。此外，通过 DUSP5 敲低可减轻 ER 应激条件下的细胞活力降低。总之，DUSP5 表达是通过 PERK-CHOP 通路在肝细胞中被 ER 应激上调的，这可能通过 ERK 抑制导致肝细胞死亡。
