Department of Medical Biology Laboratory, Pomeranian Medical University, Szczecin, Poland.
Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland.
Sci Rep. 2017 Mar 23;7:44769. doi: 10.1038/srep44769.
In response to oxidative stress, nuclear factor (erythroid-derived 2)-like2 (Nrf2) induces expression of cytoprotective genes. The Nrf2 pathway is controlled by microRNAs and Kelch-like ECH-associated protein1 (Keap1). Nrf2 is stabilized when Keap1 is degraded through the autophagy pathway in a p62-dependent manner. The inhibition of autophagy causes protein accumulation, and Keap1 is inactivated by binding to p62. We investigated the role of the Nrf2/Keap1 axis in the amelioration of oxidative stress in primary biliary cholangitis (PBC). Liver specimens from patients with PBC, with (n = 24) or without cirrhosis (n = 14), and from controls (n = 16) were used for molecular analyses. We found that Nrf2 protein levels were elevated in PBC compared to controls, but Nrf2 gene expression was significantly reduced in cirrhotic PBC. Nrf2 target gene products, HO-1 and GCLC proteins, were reduced compared to controls and reduction of Nrf2 gene expression was associated with elevated levels of microRNA-132 and microRNA-34a. Both Keap1 and p62 protein levels were substantially increased in PBC compared to controls. PBC was associated with reduced Nrf2 expression and autophagy deterioration and these impairments were more advanced in patients with cirrhosis. Aberrant Nrf2/Keap1 system integrity may affect self-defence mechanisms against oxidative stress in PBC.
针对氧化应激，核因子 (红细胞衍生 2)-样 2 (Nrf2) 会诱导细胞保护基因的表达。Nrf2 通路受 microRNAs 和 Kelch-like ECH 相关蛋白 1 (Keap1) 调控。当 Keap1 通过自噬途径被 p62 依赖性降解时，Nrf2 会被稳定下来。自噬的抑制会导致蛋白质堆积，而 Keap1 则通过与 p62 结合而失活。我们研究了 Nrf2/Keap1 轴在原发性胆汁性胆管炎 (PBC) 氧化应激缓解中的作用。我们使用了来自 PBC 患者（有肝硬化的患者 n=24，无肝硬化的患者 n=14）和对照者（n=16）的肝组织标本进行分子分析。我们发现，与对照者相比，PBC 中的 Nrf2 蛋白水平升高，但 Nrf2 基因表达在肝硬化的 PBC 中显著降低。Nrf2 靶基因产物 HO-1 和 GCLC 蛋白的水平与对照者相比降低，并且 Nrf2 基因表达的减少与 microRNA-132 和 microRNA-34a 水平的升高相关。与对照者相比，Keap1 和 p62 蛋白水平在 PBC 中均显著增加。PBC 与 Nrf2 表达和自噬恶化减少相关，而在肝硬化患者中，这些损伤更为严重。异常的 Nrf2/Keap1 系统完整性可能会影响 PBC 中针对氧化应激的自我防御机制。
