Abstract: Objective: This study was designed to determine the effect of p-synephrine, the primary protoalkaloid of bitter orange and other citrus species, on hepatic glucose production in HepG2 cells and to elucidate the underlying mechanisms. Methods: The cell viability was detected by MTS assay. Glucose production and the activity of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were measured by colorimetry. The protein expression levels of adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK), phosphorylated AMPK (p-AMPK), acetyl coenzyme A synthetase (ACC), phosphorylated ACC (p-ACC), forkhead box class O1 (FoxO1) and phosphorylated FoxO1 (p-FoxO1) were analyzed by Western blot. The cells were incubated in the presence of selective AMPK inhibitor Compound C or AMPK siRNA to examine the impact of p-synephrine on glucose production and G6Pase and PEPCK activity. Results: p-Synephrine significantly inhibited hepatic glucose production in a dose-dependent manner. AMPK, ACC and FoxO1 phosphorylation were stimulated by different concentrations of p-synephrine. In addition, both enzyme activities were significantly suppressed (P < 0.01). These effects were partially reversed by Compound C and AMPK siRNA. Conclusion: p-Synephrine suppresses hepatic glucose production via the AMPK-FoxO1 signaling pathway in HepG2 cells.

Key words: p-synephrine, adenosine 5’-monophosphate-activated protein kinase signaling pathway, glucose production