Andrikakou, PinelopiPinelopiAndrikakouReebye, VikashVikashReebyeVasconcelos, DanielDanielVasconcelosYoon, SorahSorahYoonVoutila, JonJonVoutilaGeorge, Andrew J TAndrew J TGeorgeSwiderski, PiotrPiotrSwiderskiHabib, RobertRobertHabibCatley, MatthewMatthewCatleyBlakey, DavidDavidBlakeyHabib, Nagy ANagy AHabibRossi, John JJohn JRossiKAI-WEN HUANG2023-03-172023-03-172022-122159-3337https://scholars.lib.ntu.edu.tw/handle/123456789/629344Metabolic 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.enLPSSIRT1metabolic syndromesmall activating RNAtransferrin receptor aptamerjournal article10.1089/nat.2021.0115358955112-s2.0-85138513066WOS:000838921100001