Abstract 17298: MicroRNA-411 Targets Foxo1 to Induce Hepatic Glucose Production in Type 2 Diabetes
Introduction: miRNAs are a class of short, NC, single-stranded RNA molecules that negatively regulate gene expression. A hallmark of T2D is excessive HGP that plays an important role in the development of hyperglycemia and hyperlipidemia. FOXO1 has been shown to bind directly to the promoters of gluconeogenic genes and activate HGP.
Hypothesis: miR-411 is down regulated in liver of mice with polygenic susceptibility for T2D leading to FOXO1 OE and induction of gluconeogenesis.
Methods: NONcNZO10 (NZ10) mice with polygenic susceptibility to T2D or SWR controls were fed Control (CD) or South Beach (SD; high protein/unsaturated fat) diets for 25 weeks. After 12 hr. fasting the mice were sacrificed and liver was collected. Total RNA was isolated and subjected to Sanger 14 multi-species miRNA microarray.
RESULTS: Diabesity was not induced in control SWR mice fed either diet or in NZ10 mice fed SD as evidenced by serum glucose and insulin levels and normal GTT. NZ10 mice fed CD were hyperglycemic (blood glucose >350mg/dL) with impaired GTT and hyperinsulinemia; gene expression analysis showed significant induction of key gluconeogenic genes; PEPCK, G6Pase and FBP1 in the livers of these mice (all, p<0.05). Protein and mRNA levels of FOXO1 were significantly up-regulated in the liver of these mice (p<0.05). Western blot analysis showed significantly increased glycogen phosphorylase and decreased glycogen synthase in livers of insulin-treated NZ10 mice fed CD, with increased CREB-133 phosphorylation and suppressed phosphorylation of AMPKα (all p<0.05). NZ10 mice fed CD had fatty liver and elevated gene transcripts of SREBF1 and PGC1alpha. miRNA analysis showed significant down-regulation of miR-411 in liver of NZ10 mice fed CD (p<0.05). In Silico analysis using Targetscan revealed FOXO1 as a target for miR-411. Overexpression of miR-411 in HepG2 cells eliminated FOXO1 expression and suppressed the expression of gluconeogenic enzymes.
Conclusions: miR-411 targets FOXO1 and negatively regulates the expression of gluconeogenic genes. In NZ10 mice fed CD miR-411 is down-regulated causing hyperglycemia; this can be prevented by SD that promotes glucose homeostasis and reversal of the diabetic phenotype.
- © 2011 by American Heart Association, Inc.