AMPK activation by pterostilbene contributes to suppression of hepatic gluconeogenic gene expression and glucose production in H4IIE cells

Authors: REN, GUANG - AUBURN UNIVERSITY; RIMANDO, AGNES; MATHEWS, SURESH - MCWHORTER SCHOOL OF PHARMACY, SAMFORD UNIVERSITY

Submitted to: Biochemical and Biophysical Research Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/6/2018
Publication Date: 3/9/2018
Citation: Ren, G., Rimando, A.M., Mathews, S.T. 2018. AMPK activation by pterostilbene contributes to suppression of hepatic gluconeogenic gene expression and glucose production in H4IIE cells. Biochemical and Biophysical Research Communications. 498:640-645.
DOI: https://doi.org/10.1016/j.bbrc.2018.03.035

Interpretive Summary: This study examined potential mechanisms that may contribute to the lipid- and glucose-lowering properties of pterostilbene, a phenolic compound found in blueberries and grapes. Because pterostilbene was previously reported to activate a protein (PPAR-alpha) involved in fatty acid breakdown we examined the effect of pterostilbene on some target genes of PPAR-alpha. Pterostilbene significantly increased gene expression of acyl-CoA oxidase (ACO), carnitine palmitoyl transferase-1 (CPT1), and uncoupling protein-2 (UCP2). Since pterostilbene up-regulated the expression of these genes, and since this is also known to be regulated by AMP-activated kinase (AMPK), the cellular energy sensor, we speculated that pterostilbene would activate AMPK. Pterostilbene treatment demonstrated potent activation of AMPK at lower concentrations than the clinically-used antidiabetic medications AICAR or metformin. AMPK activators have been shown to mimic the actions of insulin in terms of repressing glucose production. We therefore examined the effect of pterostilbene on genes involved in glucose synthesis in the liver. Pterostilbene treatment significantly repressed gene expression of some genes and decreased glucose production in rat liver cell lines. Our studies demonstrate that pterostilbene modulates several metabolic functions and suppresses hepatic glucose production, indicating it may have potential use in the prevention and management of Type 2 diabetes.

Technical Abstract: Pterostilbene, a bioactive component of blueberries and grapes, shows structural similarity to resveratrol, and exhibits antioxidant, anti-inflammatory, anti-cancer, hypoglycemic, and cholesterol lowering effects. This study examined potential mechanisms that may contribute to its lipid- and glucose-lowering properties. Methods and results: Since pterostilbene is a peroxisome proliferator-activated receptor-alpha (PPAR-a) agonist, we examined the expression of genes involved in fatty acid oxidation in H4IIE cells. Pterostilbene treatment, at concentrations that demonstrated over 75% viability, significantly increased ACO, CPT-1, and UCP2 gene expression. Pterostilbene treatment (50 µM) also demonstrated potent activation of AMP-activated kinase (AMPK), compared to AICAR (0.5 mM) or metformin (2 mM), consistent with upregulation of fatty acid oxidation gene expression. Since AMPK activators mimic the actions of insulin by repressing hepatic gluconeogenesis, we examined pterostilbene’s effects on hepatic gluconeogenic gene expression. Pterostilbene treatment significantly repressed dexamethasone-induced phosphoenol pyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), forkhead box O1 (FOXO1), and peroxisome proliferator-activated receptor r coactivator 1 alpha (PGC1- a) gene expression, and decreased glucose production in H4IIE cells. Conclusion: Our studies demonstrate that pterostilbene, a natural compound and PPAR-a agonist, modulate several AMPK-dependent metabolic functions and suppress hepatic glucose production, and may have potential use in the prevention and management of Type 2 diabetes.