Abstract：
Metabolic syndrome (MetS) is a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Sirtuin 1 (SIRT1), a highly conserved histone deacetylase, is characterized as a key metabolic regulator and protector against aging-associated pathologies, including MetS. In this study, we investigate the therapeutic potential of activating SIRT1 using small activating RNAs (saRNA), thereby reducing inflammatory-like responses and re-establishing normal lipid metabolism. SIRT1 saRNA significantly increased SIRT1 messenger RNA (mRNA) and protein levels in both lipopolysaccharide-stimulated and nonstimulated macrophages. SIRT1 saRNA significantly decreased inflammatory-like responses, by reducing mRNA levels of key inflammatory cytokines, such as Tumor Necrosis Factor alpha, Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), and chemokines Monocyte Chemoattractant Protein-1 and keratinocyte chemoattractant. SIRT1 overexpression also significantly reduced phosphorylation of nuclear factor-κB and c-Jun N-terminal kinase, both key signaling molecules for the inflammatory pathway. To investigate the therapeutic effect of SIRT1 upregulation, we treated a high-fat diet model with SIRT1 saRNA conjugated to a transferrin receptor aptamer for delivery to the liver and cellular internalization. Animals in the SIRT1 saRNA treatment arm demonstrated significantly decreased weight gain with a significant reduction in white adipose tissue, triglycerides, fasting glucose levels, and intracellular lipid accumulation. These suggest treatment-induced changes to lipid and glucose metabolism in the animals. The results of this study demonstrate that targeted activation of SIRT1 by saRNAs is a potential strategy to reverse MetS.
摘要：
代谢综合征（MetS）是一种以腹部肥胖为特征的病理状态，胰岛素抵抗，高血压,和高脂血症。Sirtuin1(SIRT1),一种高度保守的组蛋白脱乙酰酶，其特征是作为一个关键的代谢调节剂和保护老化相关的病理，包括MetS。在这项研究中,我们研究了使用小激活RNA（saRNA）激活SIRT1的治疗潜力，从而减少炎症样反应并重建正常的脂质代谢。SIRT1saRNA显着增加脂多糖刺激和非刺激巨噬细胞中SIRT1信使RNA（mRNA）和蛋白质水平。SIRT1saRNA显著降低炎症样反应，通过降低关键炎症细胞因子的mRNA水平，如肿瘤坏死因子α，白细胞介素1β（IL-1β），白细胞介素6(IL-6),和趋化因子单核细胞化学引诱物蛋白-1和角质形成细胞化学引诱物。SIRT1过表达也显著降低核因子-κB和c-Jun氨基末端激酶的磷酸化,都是炎症途径的关键信号分子。探讨SIRT1上调的治疗效果,我们使用与转铁蛋白受体适体缀合的SIRT1saRNA治疗高脂饮食模型,用于递送至肝脏和细胞内化.SIRT1saRNA治疗组中的动物表现出显著减少的体重增加，白色脂肪组织显著减少，甘油三酯，空腹血糖水平,和细胞内脂质积累。这些表明治疗诱导的动物中脂质和葡萄糖代谢的变化。这项研究的结果表明，saRNA对SIRT1的靶向激活是逆转MetS的潜在策略。
