Li Yan-Ni, Su Ya
Department of Endocrinology, Hanzhong Central Hospital Shaanxi Province, Hanzhong, 723000, China.
Department of Endocrinology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China.
Biochem Biophys Res Commun. 2020 May 28;526(2):381-388. doi: 10.1016/j.bbrc.2020.03.034. Epub 2020 Mar 27.
High-fat diet (HFD) is a predisposing factor for metabolic syndrome-related systemic inflammation and non-alcoholic fatty liver disease (NAFLD). However, there is still no effective therapeutic treatment for NAFLD. Here, we showed that remdesivir (RDV, GS-5734), as a broad-spectrum antiviral nucleotide prodrug with anti-inflammatory effects, was effective for attenuating HFD-induced metabolic disorder and insulin resistance. Results revealed that the liver weight, hepatic dysfunction and lipid accumulation were markedly increased compared with that of the Control group, while that of the RDV group exhibited significant reduction, accompanied by the improved signaling pathway regulating fatty acid metabolism. In agreement with reduced lipid deposition, RDV supplementation suppressed the systematic and hepatic inflammation, as evidenced by reduction of inflammatory cytokines and the blockage of nuclear factor κB (NF-κB) signaling. In addition, stimulator of interferon genes (STING) and its down-streaming factor interferon regulatory factor 3 (IRF3) were greatly increased in livers of HFD-fed mice, which were considerably restrained by RDV treatment. The in vitro analysis suggested that RDV functioned as an inhibitor of STING, contributing to the suppression of dyslipidemia and inflammation induced by palmitate (PA). However, PA-triggered lipid deposition and inflammatory response was further accelerated in hepatocytes with STING over-expression. Notably, RDV-attenuated lipid disorder and inflammation were significantly abrogated by the over-expression of STING in PA-stimulated hepatocytes. Taken together, these findings indicated that RDV exhibited protective effects against NAFLD development mainly through repressing STING signaling, and thus could be considered as a potential therapeutic strategy.
高脂饮食（HFD）是代谢综合征相关全身炎症和非酒精性脂肪性肝病（NAFLD）的一个诱发因素。然而，目前仍没有针对NAFLD的有效治疗方法。在此，我们表明瑞德西韦（RDV，GS - 5734）作为一种具有抗炎作用的广谱抗病毒核苷酸前药，对减轻HFD诱导的代谢紊乱和胰岛素抵抗有效。结果显示，与对照组相比，肝脏重量、肝功能障碍和脂质积累显著增加，而RDV组则显著降低，同时调节脂肪酸代谢的信号通路得到改善。与脂质沉积减少一致，补充RDV可抑制全身和肝脏炎症，炎症细胞因子的减少和核因子κB（NF - κB）信号通路的阻断证明了这一点。此外，在喂食HFD的小鼠肝脏中，干扰素基因刺激因子（STING）及其下游因子干扰素调节因子3（IRF3）大幅增加，而RDV治疗可显著抑制它们。体外分析表明，RDV作为STING的抑制剂发挥作用，有助于抑制棕榈酸（PA）诱导的血脂异常和炎症。然而，在STING过表达的肝细胞中，PA引发的脂质沉积和炎症反应进一步加速。值得注意的是，在PA刺激的肝细胞中，STING过表达显著消除了RDV减轻脂质紊乱和炎症的作用。综上所述，这些发现表明RDV主要通过抑制STING信号通路对NAFLD的发展具有保护作用，因此可被视为一种潜在的治疗策略。
