RT Journal Article
SR Electronic
T1 The Hypoglycemic Effect of Berberine and Berberrubine Involves Modulation of Intestinal FXR Signaling Pathway and Inhibition of Hepatic Gluconeogenesis
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2020-000215
DO 10.1124/dmd.120.000215
A1 Runbin Sun
A1 Bo Kong
A1 Na Yang
A1 Bei Cao
A1 Dong Feng
A1 Xiaoyi Yu
A1 Chun Ge
A1 Siqi Feng
A1 Fei Fei
A1 Jingqiu Huang
A1 Zhenyao Lu
A1 Yuan Xie
A1 Chung S. Yang
A1 Grace L. Guo
A1 Guangji Wang
A1 Jiye Aa
YR 2020
UL http://dmd.aspetjournals.org/content/early/2020/12/29/dmd.120.000215.abstract
AB 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.