https://scholars.lib.ntu.edu.tw/handle/123456789/629344
標題: | Enhancing SIRT1 Gene Expression Using Small Activating RNAs: A Novel Approach for Reversing Metabolic Syndrome | 作者: | Andrikakou, Pinelopi Reebye, Vikash Vasconcelos, Daniel Yoon, Sorah Voutila, Jon George, Andrew J T Swiderski, Piotr Habib, Robert Catley, Matthew Blakey, David Habib, Nagy A Rossi, John J KAI-WEN HUANG |
關鍵字: | LPS; SIRT1; metabolic syndrome; small activating RNA; transferrin receptor aptamer | 公開日期: | 十二月-2022 | 出版社: | MARY ANN LIEBERT, INC | 卷: | 32 | 期: | 6 | 起(迄)頁: | 486 | 來源出版物: | Nucleic acid therapeutics | 摘要: | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/629344 | ISSN: | 2159-3337 | DOI: | 10.1089/nat.2021.0115 |
顯示於: | 醫學系 |
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