PDF(Pubmed)
Abstract：
The prevalence of excessive drinking-related alcoholic liver disease (ALD) is rising, yet therapeutic options remain limited. High alcohol consumption and consequent oxidative metabolism by cytochrome P450 (CYP) can lead to extremely high levels of reactive oxygen species, which overwhelm cellular defenses and harm hepatocytes. Our previous investigations showed that inhibiting Cyp2e1 using RNA interference reduced the incidence of ALD. However, compensatory mechanisms other than CYP2E1 contribute to oxidative stress in the liver. Therefore, we coupled triple siRNA lipid nanoparticles (LNPs) targeting Cyp2e1 with two isoenzymes Cyp4a10 and Cyp4a14 to treat ALD mouse models fed with Lieber-Decarli ethanol liquid diet for 12 weeks at the early (1st week), middle (5th week), and late (9th week) stages. The administration of triple siRNA LNPs significantly ameliorated chronic alcoholic liver injury in mice, and early treatment achieved the most profound effects. These effects can be attributed to a reduction in oxidative stress and increased expression of antioxidant genes, including Gsh-Px, Gsh-Rd, and Sod1. Moreover, we observed the alleviation of inflammation, evidenced by the downregulation of Il-1β, Il-6, Tnf-α, and Tgf-β, and the prevention of excessive lipid synthesis, evidenced by the restoration of the expression of Srebp1c, Acc, and Fas. Finally, triple siRNA treatment maintained normal metabolism in lipid oxidation. In brief, our research examined the possible targets for clinical intervention in ALD by examining the therapeutic effects of triple siRNA LNPs targeting Cyp2e1, Cyp4a10, and Cyp4a14. The in vivo knockdown of the three genes in this study is suggested as a promising siRNA therapeutic approach for ALD.
摘要：
过度饮酒相关的酒精性肝病（ALD）的患病率正在上升，然而，治疗选择仍然有限。高酒精消耗和细胞色素P450（CYP）的氧化代谢可导致极高的活性氧水平，压倒细胞防御和伤害肝细胞。我们之前的研究表明，使用RNA干扰抑制Cyp2e1可以降低ALD的发生率。然而,CYP2E1以外的代偿机制有助于肝脏中的氧化应激。因此,我们将靶向Cyp2e1的三重siRNA脂质纳米颗粒（LNPs）与两种同工酶Cyp4a10和Cyp4a14偶联，以治疗早期（第1周）喂食Lieber-Decarli乙醇液体饮食12周的ALD小鼠模型，中间（第5周），和后期（第9周）阶段。三联siRNALNPs显著改善小鼠慢性酒精性肝损伤,早期治疗取得了最深远的效果。这些影响可以归因于氧化应激的减少和抗氧化基因表达的增加，包括Gsh-Px,Gsh-Rd,Sod1此外，我们观察到炎症的缓解，IL-1β的下调证明，Il-6,Tnf-α,和Tgf-β，和预防过度的脂质合成，Srebp1c表达的恢复证明，Acc,和Fas。最后,三联siRNA处理维持脂质氧化的正常代谢。简而言之,我们的研究通过检查靶向Cyp2e1,Cyp4a10和Cyp4a14的三重siRNALNP的治疗效果,检查了ALD临床干预的可能靶点.本研究中三个基因的体内敲除被认为是ALD的有希望的siRNA治疗方法。
