Abstract

Our previous study suggests that berberine (BBR) lowers lipid by modulating bile acids and activating intestinal farnesoid X receptor (FXR). However, to what extent this pathway contributes to the hypoglycemia effect of BBR has not been determined. In this study, the glucose-lowering effects of BBR and its primary metabolites, berberrubine (M1) and demethyleneberberine (M3) in a high-fat diet-induced obese mouse model were studied, and their modulation on the global metabolic profile of mouse livers and the systemic bile acids were determined. The results revealed that BBR (150 mg/Kg) and M1 (50 mg/Kg) decreased mouse serum glucose levels by 23.15% and 48.14%, respectively. Both BBR and M1 markedly modulated the hepatic expression of genes involved in gluconeogenesis and metabolism of amino acids, fatty acids and purine. BBR showed a stronger modulatory effects on systemic bile acids than its metabolites. Moreover, molecular docking and gene expression analysis in vivo and in vitro suggest that BBR and M1 are FXR agonists. The mRNA levels of gluconeogenesis genes in the liver, glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (Pepck), were significantly decreased by BBR and M1. In summary, BBR and M1 modulate systemic bile acids and activate the intestinal FXR signaling pathway, which reduces hepatic gluconeogenesis by inhibiting the gene expression of gluconeogenesis genes, and achieve a hypoglycemia effect. BBR and M1 may function as new natural intestinal specific FXR agonists with a potential clinical application to treat hyperglycemia and obesity.

Significance Statement This investigation revealed BBR and its metabolite, BRB, significantly lowered blood glucose, mainly through activating intestinal FXR signaling pathway directly by themselves or indirectly by modulating the composition of systemic bile acids, thus inhibited the expression of gluconeogenic genes in the liver, finally reduced hepatic gluconeogenesis and lowered blood glucose. The results will help elucidate the mechanism of BBR and provide a reference for mechanism interpretation of other natural products with low bioavailability.