Zerumbone modulates O-GlcNAcylation in HepG2 cells in high cholesterol/high fat milieu

Abstract

Unhealthy diet can alter the state of hepatic O-GlcNAcylation, a post-translational modification of proteins driven by diet that is nutrition-driven with consequences on health. Various plant-derived bioactive compounds have demonstrated therapeutic potential in metabolic disorders. Zerumbone (Zer), a sesquiterpenoid from Zingiber zerumbet was earlier determined to be a potent AMPK activator. We hypothesized that targeting AMPK by Zer, O-GlcNAcylation and associated molecules could be modulated, leading to beneficial effects. HepG2 cells was used as a model to evaluate the effect of Zerumbone on O-GlcNAcylation in high fat (HF) and high cholesterol (HC) milieu brought about by Palmitic acid (PA) and water-soluble cholesterol, respectively. PA/HC led to reduced global O-GlcNAcylation, which was prevented on treatment with Zer in therapeutic mode. Associated enzymes ((Glutamine-Fructose Amino transferase-GFAT and O-GlcNAcyl Transferase-OGT)) responsible for O-GlcNAcylation were normalized to control levels that were on par with known AMPK activators metformin and 6,7-dihydro-4-hydroxy-3-(2’-hydroxy[1,1’-biphenyl]-4-yl)-6-oxo-thieno[2,3-b] pyridine-5-carbonitrile (A-769662). Zerumbone potentially normalized O-GlcNAc levels and could aid in reducing complications caused byfaulty diet by targeting AMPK.