https://scholars.lib.ntu.edu.tw/handle/123456789/462644
標題: | Liver Activation of Hepatocellular Nuclear Factor-4α by Small Activating RNA Rescues Dyslipidemia and Improves Metabolic Profile | 作者: | KAI-WEN HUANG Reebye V. Czysz K. Ciriello S. Dorman S. Reccia I. HONG-SHIEE LAI Peng L. Kostomitsopoulos N. Nicholls J. Habib R.S. Tomalia D.A. S?trom P. Wilkes E. Cutillas P. Rossi J.J. Habib N.A. |
公開日期: | 2020 | 出版社: | Cell Press | 卷: | 19 | 起(迄)頁: | 361-370 | 來源出版物: | Molecular Therapy - Nucleic Acids | 摘要: | Non-alcoholic fatty liver disease (NAFLD) culminates in insulin resistance and metabolic syndrome. Because there are no approved pharmacological treatment agents for non-alcoholic steatohepatitis (NASH) and NAFLD, different signaling pathways are under investigation for drug development with the focus on metabolic pathways. Hepatocyte nuclear factor 4-alpha (HNF4A) is at the center of a complex transcriptional network where its disruption is directly linked to glucose and lipid metabolism. Resetting HNF4A expression in NAFLD is therefore crucial for re-establishing normal liver function. Here, small activating RNA (saRNA) specific for upregulating HNF4A was injected into rats fed a high-fat diet for 16 weeks. Intravenous delivery was carried out using 5-(G5)-triethanolamine-core polyamidoamine (PAMAM) dendrimers. We observed a significant reduction in liver triglyceride, increased high-density lipoprotein/low-density lipoprotein (HDL/LDL) ratio, and decreased white adipose tissue/body weight ratio, all parameters to suggest that HNF4A-saRNA treatment induced a favorable metabolic profile. Proteomic analysis showed significant regulation of genes involved in sphingolipid metabolism, fatty acid β-oxidation, ketogenesis, detoxification of reactive oxygen species, and lipid transport. We demonstrate that HNF4A activation by oligonucleotide therapy may represent a novel single agent for the treatment of NAFLD and insulin resistance. ? 2019 The Author(s) |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85076717809&doi=10.1016%2fj.omtn.2019.10.044&partnerID=40&md5=3b07c55ddd6b914faafe805dea6c7252 https://scholars.lib.ntu.edu.tw/handle/123456789/462644 |
ISSN: | 2162-2531 | DOI: | 10.1016/j.omtn.2019.10.044 | SDG/關鍵字: | albumin; cyclic AMP dependent protein kinase regulatory subunit Ialpha; cyclic AMP dependent protein kinase regulatory subunit Ibeta; cyclic AMP responsive element binding protein; cytochrome P450 3A4; cytochrome P450 3A5; cytochrome P450 3A7; dendrimer; glycogen synthase kinase 3beta; heat shock protein 90; hepatocyte nuclear factor 4alpha; high density lipoprotein; interleukin 6; low density lipoprotein; messenger RNA; polyamidoamine; protein Cdc42; reactive oxygen metabolite; rifampicin; RNA; small activating RNA; triacylglycerol; triethanolamine; unclassified drug; animal experiment; animal model; animal tissue; Article; body weight; controlled study; dyslipidemia; glucose metabolism; glucose transport; Hep-G2 cell line; hippo signaling; human; human cell; insulin resistance; ketogenesis; lipid blood level; lipid diet; lipid metabolism; lipid transport; liver histology; male; nonalcoholic fatty liver; nonhuman; oligonucleotide therapy; priority journal; protein expression; protein protein interaction; proteomics; rat; real time polymerase chain reaction; sphingolipid metabolism; upregulation; Western blotting; white adipose tissue |
顯示於: | 醫學系 |
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