1. Liver Activation of Hepatocellular Nuclear Factor-4α by Small Activating RNA Rescues Dyslipidemia and Improves Metabolic Profile
- Author
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Ling Peng, Nikos Kostomitsopoulos, Stephanie Dorman, Edmund Wilkes, Joanna Nicholls, Isabella Reccia, Katherine Czysz, John J. Rossi, Vikash Reebye, Pål Sætrom, Nagy A. Habib, Simona Ciriello, Hong-Shiee Lai, Donald A. Tomalia, Pedro R. Cutillas, Robert Habib, Kai-Wen Huang, National Taiwan University Hospital and National Taiwan University College of Medicine, Imperial College London, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Biomedical Research Foundation of the Academy of Athens (BRFAA), MiNA Therapeutics Limited, Department of Chemistry, The Pennsylvania State University, Pennsylvania State University (Penn State), Penn State System-Penn State System, Norwegian University of Science and Technology (NTNU), Cell Signalling & Proteomics Group [Londres, Royayme-Uni], Barts Cancer Institute [Londres, Royayme-Uni], Queen Mary University of London (QMUL)-Queen Mary University of London (QMUL), Beckman Research Institute of City of Hope, and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
- Subjects
0301 basic medicine ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Research & Experimental Medicine ,0601 Biochemistry and Cell Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,NAFLD ,Internal medicine ,Drug Discovery ,Ketogenesis ,medicine ,[CHIM]Chemical Sciences ,ComputingMilieux_MISCELLANEOUS ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Science & Technology ,oligonucleotides ,Chemistry ,small activating RNA ,Fatty liver ,1103 Clinical Sciences ,Lipid metabolism ,medicine.disease ,HNF4A ,3. Good health ,Hepatocyte nuclear factors ,030104 developmental biology ,Endocrinology ,Medicine, Research & Experimental ,030220 oncology & carcinogenesis ,fatty liver disease ,Molecular Medicine ,nanoparticles ,Metabolic syndrome ,Steatohepatitis ,Life Sciences & Biomedicine ,Lipoprotein - Abstract
International audience; 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-(G 5)-triethanolamine-core pol-yamidoamine (PAMAM) dendrimers. We observed a significant reduction in liver triglyceride, increased high-density lipopro-tein/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 b-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.
- Published
- 2020
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