Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
Interuniversity Center for the Promotion of the 3Rs Principles in Teaching and Research (Centro 3R), 56122 Pisa, Italy.
Int J Mol Sci. 2023 Jun 6;24(12):9808. doi: 10.3390/ijms24129808.
The endogenous antioxidant defense plays a big part in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a common metabolic disorder that can lead to serious complications such as cirrhosis and cancer. HuR, an RNA-binding protein of the ELAV family, controls, among others, the stability of MnSOD and HO-1 mRNA. These two enzymes protect the liver cells from oxidative damage caused by excessive fat accumulation. Our aim was to investigate the expression of HuR and its targets in a methionine-choline deficient (MCD) model of NAFLD. To this aim, we fed male Wistar rats with an MCD diet for 3 and 6 weeks to induce NAFLD; then, we evaluated the expression of HuR, MnSOD, and HO-1. The MCD diet induced fat accumulation, hepatic injury, oxidative stress, and mitochondrial dysfunction. A HuR downregulation was also observed in association with a reduced expression of MnSOD and HO-1. Moreover, the changes in the expression of HuR and its targets were significantly correlated with oxidative stress and mitochondrial injury. Since HuR plays a protective role against oxidative stress, targeting this protein could be a therapeutic strategy to both prevent and counteract NAFLD.
内源性抗氧化防御在非酒精性脂肪性肝病（NAFLD）的发病机制中起着重要作用，NAFLD 是一种常见的代谢紊乱疾病，可导致肝硬化和癌症等严重并发症。ELAV 家族的 RNA 结合蛋白 HuR 除其他外，还控制 MnSOD 和 HO-1 mRNA 的稳定性。这两种酶可保护肝细胞免受过量脂肪积累引起的氧化损伤。我们的目的是研究 HuR 及其靶标在蛋氨酸-胆碱缺乏（MCD）NAFLD 模型中的表达。为此，我们用 MCD 饮食喂养雄性 Wistar 大鼠 3 周和 6 周，以诱导 NAFLD；然后，我们评估了 HuR、MnSOD 和 HO-1 的表达。MCD 饮食可诱导脂肪堆积、肝损伤、氧化应激和线粒体功能障碍。还观察到 HuR 下调与 MnSOD 和 HO-1 表达减少相关。此外，HuR 及其靶标的表达变化与氧化应激和线粒体损伤显著相关。由于 HuR 可防止氧化应激，因此靶向该蛋白可能是预防和对抗 NAFLD 的一种治疗策略。
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