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

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.

Power and Promise of Next-Generation Sequencing in Liquid Biopsies and Cancer Control

“…[1][2][3] Normal cells can become cancerous due to genetic mutations and epigenetic modifications. [4][5][6] Patients with different cancer have different genetic mutations and epigenetic modifications, which increase the complexity and heterogeneity of tumors. 7,8 In addition, intratumoral heterogeneity increases over the course of disease development, making the treatment of tumors particularly challenging.…”

Low molecular weight fucoidan inhibits hepatocarcinogenesis and nonalcoholic fatty liver disease in zebrafish via ASGR/STAT3/HNF4A signaling

“…HNF4A by small activating RNA could prevent NAFLD and improve metabolic profile. 56 In this study, we reveal OF treatment could induce the expression of P1-HNF4A through activating pSTAT3 binding to the P1promoter, this discovery may emphasize the therapeutic roles of OF on anti-fatty liver, anti-fibrosis, anti-HCC in different genetic, and diet insults. Recently, fucoidan has been reported as a new, natural anti-obesity agent that reduces fat absorption and inhibits adipose-related gene expression.…”

“…HNF4A plays crucial role in liver inflammatory networks, 54 suppresses liver cancer formation 55 and activation. HNF4A by small activating RNA could prevent NAFLD and improve metabolic profile 56 . In this study, we reveal OF treatment could induce the expression of P1‐HNF4A through activating pSTAT3 binding to the P1‐promoter, this discovery may emphasize the therapeutic roles of OF on anti‐fatty liver, anti‐fibrosis, anti‐HCC in different genetic, and diet insults.…”

Hepatocyte nuclear factor 4a and glucocorticoid receptor coordinately regulate lipid metabolism in mice fed a high-fat-high-sugar diet

“…The identification of partial deficiency of HNF4α and GR as potential key drivers of NAFLD and hyperlipidemia may help develop novel pharmaceutical and dietary interventions for HFHS-induced NAFLD and CAD. Although the activating ligand for HNF4α has not been identified, small activating RNA for HNF4α has been used to successfully induce HNF4α and ameliorate hyperlipidemia and fatty liver in HFD-fed rats (52). In view of GC’s potent anti-inflammatory effects, liver-specific activation of GR may protect against HFHS-induced NAFLD and the progression from NAFLD to NASH and cirrhosis.…”