Dataset Information

Liver Activation of Hepatocellular Nuclear Factor-4? 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 ?-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.

SUBMITTER: Huang KW

PROVIDER: S-EPMC6938799 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Huang Kai-Wen KW Reebye Vikash V Czysz Katherine K Ciriello Simona S Dorman Stephanie S Reccia Isabella I Lai Hong-Shiee HS Peng Ling L Kostomitsopoulos Nikos N Nicholls Joanna J Habib Robert S RS Tomalia Donald A DA Sætrom Pål P Wilkes Edmund E Cutillas Pedro P Rossi John J JJ Habib Nagy A NA

Molecular therapy. Nucleic acids 20191121

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. Reset ...[more]

PMID: 31877412

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Project description:Resveratrol is a polyphenol with a well-established beneficial effect on dyslipidemia and hyperuricemia in preclinical experiments. Nonetheless, its efficacy and dose-response relationship in clinical trials remains unclear. This study examined whether resveratrol supplement improves the serum lipid profile and other metabolic markers in a dose-response manner in individuals with dyslipidemia. A total of 168 subjects were randomly assigned to placebo (n = 43) and resveratrol treatment groups of 100 mg/d (n = 41), 300 mg/d (n = 43), and 600 mg/d (n = 41). Anthropometric and biochemical parameters were analyzed at baseline and 4 and 8 weeks. Resveratrol supplementation for 8 weeks did not significantly change the lipid profile compared with the placebo. However, a significant decrease of serum uric acid was observed at 8 weeks in 300 mg/d (-23.60 ± 61.53 μmol/L, p < 0.05) and 600 mg/d resveratrol groups (-24.37 ± 64.24 μmol/L, p < 0.01) compared to placebo (8.19 ± 44.60 μmol/L). Furthermore, xanthine oxidase (XO) activity decreased significantly in the 600 mg/d resveratrol group (-0.09 ± 0.29 U/mL, p < 0.05) compared with placebo (0.03 ± 0.20 U/mL) after 8 weeks. The reduction of uric acid and XO activity exhibited a dose-response relationship (p for trend, <0.05). Furthermore, a marked correlation was found between the changes in uric acid and XO activity in the resveratrol groups (r = 0.254, p < 0.01). Resveratrol (10 μmol/L) treatment to HepG2 cells significantly reduced the uric acid levels and intracellular XO activity. Nevertheless, we failed to detect significant differences in glucose, insulin, or oxidative stress biomarkers between the resveratrol groups and placebo. In conclusion, resveratrol supplementation for 8 weeks had no significant effect on lipid profile but decreased uric acid in a dose-response manner, possibly due to XO inhibition in subjects with dyslipidemia. The trial was registered on ClinicalTrials.gov (NCT04886297).

Dataset Information

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

Publications

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

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