Liver Activation of Hepatocellular Nuclear Factor-4α by Small Activating RNA Rescues Dyslipidemia and Improves Metabolic Profile
Journal
Molecular Therapy - Nucleic Acids
Journal Volume
19
Pages
361-370
Date Issued
2020
Author(s)
Reebye V.
Czysz K.
Ciriello S.
Dorman S.
Reccia I.
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.
Abstract
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)
SDGs
Other Subjects
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
Publisher
Cell Press
Type
journal article