Sun Runbin, Kong Bo, Yang Na, Cao Bei, Feng Dong, Yu Xiaoyi, Ge Chun, Feng Siqi, Fei Fei, Huang Jingqiu, Lu Zhenyao, Xie Yuan, Yang Chung S, Guo Grace L, Wang Guangji, Aa Jiye
Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; and Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China (N.Y., B.C., F.F.).
Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; and Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China (N.Y., B.C., F.F.)
Drug Metab Dispos. 2021 Mar;49(3):276-286. doi: 10.1124/dmd.120.000215. Epub 2020 Dec 29.
Our previous study suggests that berberine (BBR) lowers lipids by modulating bile acids and activating intestinal farnesoid X receptor (FXR). However, to what extent this pathway contributes to the hypoglycemic effect of BBR has not been determined. In this study, the glucose-lowering effects of BBR and its primary metabolites, berberrubine (M1) and demethyleneberberine, in a high-fat diet-induced obese mouse model were studied, and their modulation of the global metabolic profile of mouse livers and systemic bile acids was 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 effect 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 and phosphoenolpyruvate carboxykinase, 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, achieving a hypoglycemic effect. BBR and M1 may function as new, natural, and intestinal-specific FXR agonists with a potential clinical application to treat hyperglycemia and obesity. SIGNIFICANCE STATEMENT: This investigation revealed that BBR and its metabolite, berberrubine, significantly lowered blood glucose, mainly through activating intestinal farnesoid X receptor signaling pathway, either directly by themselves or indirectly by modulating the composition of systemic bile acids, thus inhibiting the expression of gluconeogenic genes in the liver and, finally, reducing hepatic gluconeogenesis and lowering 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.
我们之前的研究表明，黄连素（BBR）通过调节胆汁酸和激活肠道法尼酯X受体（FXR）来降低血脂。然而，该途径对BBR降血糖作用的贡献程度尚未确定。在本研究中，我们研究了BBR及其主要代谢产物小檗红碱（M1）和去甲基黄连素在高脂饮食诱导的肥胖小鼠模型中的降血糖作用，并确定了它们对小鼠肝脏整体代谢谱和全身胆汁酸的调节作用。结果显示，BBR（150 mg/kg）和M1（50 mg/kg）分别使小鼠血清葡萄糖水平降低了23.15%和48.14%。BBR和M1均显著调节了参与糖异生以及氨基酸、脂肪酸和嘌呤代谢的肝脏基因表达。BBR对全身胆汁酸的调节作用比其代谢产物更强。此外，体内和体外的分子对接及基因表达分析表明，BBR和M1是FXR激动剂。BBR和M1显著降低了肝脏中糖异生基因、葡萄糖-6-磷酸酶和磷酸烯醇式丙酮酸羧激酶的mRNA水平。总之，BBR和M1调节全身胆汁酸并激活肠道FXR信号通路，通过抑制糖异生基因的表达减少肝脏糖异生，从而实现降血糖作用。BBR和M1可能作为新型、天然且具有肠道特异性的FXR激动剂，在治疗高血糖和肥胖方面具有潜在的临床应用价值。重要声明：本研究表明，BBR及其代谢产物小檗红碱通过激活肠道法尼酯X受体信号通路显著降低血糖，其作用方式既可以是直接激活，也可以是通过调节全身胆汁酸的组成间接激活，从而抑制肝脏中糖异生基因的表达，最终减少肝脏糖异生并降低血糖。该结果将有助于阐明BBR的作用机制，并为解释其他生物利用度低的天然产物的作用机制提供参考。
