Yan Xiumei, Zhang Yulong, Peng Ying, Li Xiaobo
School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang District, Shanghai, 200240, China.
School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang District, Shanghai, 200240, China.
J Ethnopharmacol. 2022 Jul 15;293:115238. doi: 10.1016/j.jep.2022.115238. Epub 2022 Mar 26.
Radix scutellariae (the root of Scutellaria baicalensis Georgi), is a traditional Chinese medicine (TCM) used to treat type 2 diabetes mellitus (T2DM). Abundant flavonoids are the antidiabetic components of Radix scutellariae, of which baicalin (Baicalein 7-O-glucuronide, BG) is the major bioactive component. Our previous studies found that the water extract of Radix scutellariae (WESB) could exert hypoglycemic and hypolipidemic efficacies by adjusting the ileum FXR-medicated interaction between gut microbiota and bile acid (BA) metabolism. However, it remains unclear whether WESB and its biologically active ingredients exert an antidiabetic effect through bile acid signaling mediated by FXR-CYP7A1.
To explore the mechanism of WESB and its total flavonoids (TF) further and BG on BA signals and glycolipid metabolism in T2DM mice.
The antidiabetic effects of WESB, TF and BG were evaluated by indexing the body weight, fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) in HFD/STZ-induced (high-fat diet and streptozocin) diabetic mice, and comparing them with the positive control (metformin). The lipids in the mouse liver and the total bile acids (TBA) in the mouse liver and bile were detected by commercial kits. The concentration of BAs in the mouse feces was determined by liquid chromatography-tandem mass spectrometry. The protein expression levels of cholesterol 7α-hydroxylase (CYP7A1), farnesol X receptor (FXR), etc., in the liver and/or ileum, play a key role in the BAs metabolism of T2DM mice were evaluated by immunoblot analysis.
The hyperglycemia and impaired glucose tolerance of T2DM mice were improved after WESB, TF and BG treatment. Especially after BG administration, the levels of low-density lipoprotein-cholesterol (LDL-c) and total glyceride (TG) in the T2DM mouse liver were significantly decreased (p < 0.05). While the level of high-density lipoprotein cholesterol (HDL-c) was significant increased (p < 0.001). Meanwhile, the levels of TBA in both the liver and bile of T2DM mice were significantly decreased by BG (p < 0.05). Moreover, the high expression of CYP7A1 in the liver of T2DM mice was significantly inhibited by WESB, TF and BG (p < 0.05), and the high expression of FXR in the ileum of T2DM mice was significantly inhibited by TF (p < 0.05).
These results indicated that the hypoglycemic effects of WESB, TF and BG might be exerted by inhibiting the expression of CYP7A1 in T2DM mice, and TF inhibited expression of intestinal FXR by inducing changes in fecal BA profile. BG significantly improved hepatic lipid metabolism. Moreover, BG reduced lipid accumulation in the liver and bile by inhibiting the expression of CYP7A1 in T2DM mice. These findings provide useful explanations for the antidiabetic mechanism of Radix scutellariae.
黄芩（黄芩的根）是一种用于治疗2型糖尿病（T2DM）的传统中药。丰富的黄酮类化合物是黄芩的抗糖尿病成分，其中黄芩苷（黄芩素7 - O - 葡萄糖醛酸苷，BG）是主要的生物活性成分。我们之前的研究发现，黄芩水提取物（WESB）可通过调节回肠FXR介导的肠道微生物群与胆汁酸（BA）代谢之间的相互作用发挥降血糖和降血脂功效。然而，WESB及其生物活性成分是否通过FXR - CYP7A1介导的胆汁酸信号发挥抗糖尿病作用仍不清楚。
进一步探讨WESB及其总黄酮（TF）和BG对T2DM小鼠胆汁酸信号和糖脂代谢的作用机制。
通过对高脂饮食/链脲佐菌素诱导的糖尿病小鼠的体重、空腹血糖（FBG）和口服葡萄糖耐量试验（OGTT）进行指标化评估WESB、TF和BG的抗糖尿病作用，并与阳性对照（二甲双胍）进行比较。使用商业试剂盒检测小鼠肝脏中的脂质以及小鼠肝脏和胆汁中的总胆汁酸（TBA）。通过液相色谱 - 串联质谱法测定小鼠粪便中胆汁酸的浓度。通过免疫印迹分析评估肝脏和/或回肠中胆固醇7α - 羟化酶（CYP7A1）、法尼醇X受体（FXR）等在T2DM小鼠胆汁酸代谢中起关键作用的蛋白质表达水平。
WESB、TF和BG治疗后，T2DM小鼠的高血糖和葡萄糖耐量受损得到改善。特别是给予BG后，T2DM小鼠肝脏中低密度脂蛋白胆固醇（LDL - c）和总甘油三酯（TG）水平显著降低（p < 0.05）。而高密度脂蛋白胆固醇（HDL - c）水平显著升高（p < 0.001）。同时，BG使T2DM小鼠肝脏和胆汁中的TBA水平均显著降低（p < 0.05）。此外，WESB、TF和BG显著抑制T2DM小鼠肝脏中CYP7A1的高表达（p < 0.05），TF显著抑制T2DM小鼠回肠中FXR的高表达（p < 0.05）。
这些结果表明，WESB、TF和BG的降血糖作用可能是通过抑制T2DM小鼠中CYP7A1的表达来实现的，TF通过诱导粪便胆汁酸谱的变化抑制肠道FXR的表达。BG显著改善肝脏脂质代谢。此外，BG通过抑制T2DM小鼠中CYP7A1的表达减少肝脏和胆汁中的脂质积累。这些发现为黄芩的抗糖尿病机制提供了有益的解释。
