Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China.
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China.
Chem Biol Interact. 2019 May 1;304:124-130. doi: 10.1016/j.cbi.2019.02.012. Epub 2019 Mar 6.
4-Hydroxynonenal (HNE), an end-product of lipid peroxidation generated in response to oxidative stress, has been implicated in the pathophysiology of chronic liver diseases. HNE is very reactive that forms Michael adducts with nucleophilic sites in DNA, lipids and proteins. At high concentrations, HNE causes rapid cell death associated with depletion of sulfhydryl groups and inhibition of key metabolic enzymes. At low concentrations, HNE stimulates expression of genes that are part of an adaptive response. In this study, we show that sub-lethal concentrations of HNE induce mRNA expression levels of heme oxygenase-1 (HO-1) (2.5-fold), NADPH:quinone oxidoreductase (NQO1) (4.5-fold), AKR1C3 (2-fold) and AKR7A2 (3-fold) enzymes. Protein expression levels of AKR1C and AKR7A2 are induced by 2- and 1.5-fold following exposure to HNE. The role of AKR1C3 and AKR7A2 in protecting HepG2 cells against HNE toxicity was investigated through using RNAi. Results show that AKR7A2, but not AKR1C3 contributes to the protection against HNE toxicity in HepG2 cells. Moreover, transcriptional factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is activated by HNE through translocation to the nucleus. Overexpressing AKR7A2 could rescue the effect of knocking down Nrf2 on HNE-induced cytotoxicity. Furthermore, a natural compound 7-hydroxycoumain, an AKR7A2 inducer, shows hepatoprotection against HNE via AKR7A2 induction. Hence, the inducible AKR7A2 has provided a new therapeutic target to treat chronic liver disease.
4-羟基壬烯醛（HNE）是一种脂质过氧化反应的终产物，在慢性肝病的病理生理学中起作用。HNE 非常活跃，可与 DNA、脂质和蛋白质中的亲核部位形成迈克尔加成物。在高浓度下，HNE 会导致快速的细胞死亡，伴随着巯基耗竭和关键代谢酶的抑制。在低浓度下，HNE 会刺激部分适应性反应基因的表达。在这项研究中，我们发现亚致死浓度的 HNE 可诱导血红素加氧酶-1（HO-1）（2.5 倍）、NADPH：醌氧化还原酶（NQO1）（4.5 倍）、AKR1C3（2 倍）和 AKR7A2（3 倍）的 mRNA 表达水平。HNE 暴露后，AKR1C 和 AKR7A2 的蛋白表达水平分别增加了 2 倍和 1.5 倍。通过 RNAi 研究 AKR1C3 和 AKR7A2 在保护 HepG2 细胞免受 HNE 毒性中的作用。结果表明，AKR7A2 而不是 AKR1C3 有助于 HepG2 细胞抵抗 HNE 毒性。此外，转录因子红细胞核因子 2 p45 相关因子 2（Nrf2）通过向核内转移而被 HNE 激活。过表达 AKR7A2 可以挽救敲低 Nrf2 对 HNE 诱导的细胞毒性的影响。此外，一种天然化合物 7-羟基香豆素，AKR7A2 的诱导剂，通过诱导 AKR7A2 显示出对 HNE 的肝保护作用。因此，可诱导的 AKR7A2 为治疗慢性肝病提供了一个新的治疗靶点。
