Liver Activation of Hepatocellular Nuclear Factor-4α by Small Activating RNA Rescues Dyslipidemia and Improves Metabolic Profile

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 foc...

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Published in:Molecular therapy. Nucleic acids 2020-03, Vol.19, p.361-370
Main Authors: Huang, Kai-Wen, Reebye, Vikash, Czysz, Katherine, Ciriello, Simona, Dorman, Stephanie, Reccia, Isabella, Lai, Hong-Shiee, Peng, Ling, Kostomitsopoulos, Nikos, Nicholls, Joanna, Habib, Robert S., Tomalia, Donald A., Sætrom, Pål, Wilkes, Edmund, Cutillas, Pedro, Rossi, John J., Habib, Nagy A.
Format: Article
Language:English
Subjects:
fatty liver disease
HNF4A
Life Sciences
NAFLD
nanoparticles
oligonucleotides
small activating RNA
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Summary: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.
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2019.10.044