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

Kai-Wen Huang (1) , Vikash Reebye (2) , Katherine Czysz (2) , Simona Ciriello (2) , Stephanie Dorman (2) , Isabella Reccia (2) , Hong-Shiee Lai (1) , Ling Peng (3) , Nikos Kostomitsopoulos (4) , Joanna Nicholls (2) , Robert S Habib , Donald A Tomalia , Pål Sætrom , Edmund Wilkes , Pedro Cutillas , John J Rossi , Nagy A Habib

1 National Taiwan University Hospital and National Taiwan University College of Medicine
2 Imperial College London
3 CINaM - Centre Interdisciplinaire de Nanoscience de Marseille
4 BRFAA - Biomedical Research Foundation of the Academy of Athens

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.

Domaines: Sciences du Vivant [q-bio]

Kai-Wen Huang, Vikash Reebye, Katherine Czysz, Simona Ciriello, Stephanie Dorman, et al.. Liver Activation of Hepatocellular Nuclear Factor-4α by Small Activating RNA Rescues Dyslipidemia and Improves Metabolic Profile. Molecular Therapy - Nucleic Acids, 2020, 19, pp.361 - 370. ⟨10.1016/j.omtn.2019.10.044⟩. ⟨hal-02992731⟩