Zhu Lili, Zhu Xiaoyun, Sun Guibo, Meng Xiangbao, Wang Min, Cui Hanming, Wang Jialong, Zhai Yadong, Yang Ke, Tang Yang, Sun Xiaobo, Liu Ximing
Graduate School, Beijing University of Chinese Medicine, Beijing, China.
Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Front Physiol. 2018 Mar 14;9:224. doi: 10.3389/fphys.2018.00224. eCollection 2018.
Intricate health problems, such as insulin resistance (IR) and its associated diseases, call for multi-targeted therapies with few side effects. Based on traditional Chinese medicine (TCM), Dai-Zong-Fang (DZF) is an herbal formula mainly composed of Rhizoma Coptidis (Huanglian) and Fructus Aurantii Immaturus (Zhishi), of which berberine and naringin are the main constituents. Though DZF has been clinically used for treatment of IR and metabolic syndrome for decades, its mechanism remains unknown. In the present study, we observed that both DZF and metformin, the first-line drug for type 2 diabetes, ameliorated insulin resistance with significant improvement of oral glucose tolerance test (OGTT) and homeostasis model assessment of IR (HOMA-IR) level in diabetic C57BL/Ksj-Lepr () mice. Low-density lipoprotein cholesterol (LDL-C) and fatty acids (FAs) also decreased in the blood. Higher dose of DZF (1 g·kg), but not metformin (0.25 g·kg), alleviated hepatic steatosis with reduced liver weight and hepatic lipid accumulation and provided protection from hepatic injury with lower alanine aminotransferase and aspartate aminotransferase and increased hepatic superoxide dismutase activity in mice. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed a decrease in FA synthase gene () and an increase in FA oxidation gene expression. Western blot demonstrated that both DZF and metformin activated 5' AMP-activated protein kinase (AMPK) but inhibited Notch intracellular domain (NICD) and Hairy/enhancer-of-split 1 (Hes1) of Notch signaling pathway in the liver. DZF also dramatically improved the ultrastructure of skeletal muscles, AMPK phosphorylation, and GLUT4 translocation. DZF also promoted FA transport and oxidation with and up-regulation in the skeletal muscle. In conclusion, DZF improves insulin sensitivity by reducing hepatic lipids through AMPK activation and Notch signal pathway inhibition and enhancing energy metabolism in the skeletal muscle via AMPK. This study provides insights into the treatment of complex conditions, such as IR, where TCM herbal formulas exert multipronged effects through correlating pathways.
复杂的健康问题，如胰岛素抵抗（IR）及其相关疾病，需要副作用少的多靶点治疗方法。基于传统中医（TCM），代宗方（DZF）是一种主要由黄连（Huanglian）和枳实（Zhishi）组成的中药配方，其中黄连素和柚皮苷是主要成分。尽管DZF已在临床上用于治疗IR和代谢综合征数十年，但其作用机制仍不清楚。在本研究中，我们观察到DZF和2型糖尿病一线药物二甲双胍均可改善糖尿病C57BL/Ksj-Lepr（）小鼠的胰岛素抵抗，口服葡萄糖耐量试验（OGTT）和IR的稳态模型评估（HOMA-IR）水平显著改善。血液中的低密度脂蛋白胆固醇（LDL-C）和脂肪酸（FAs）也有所下降。高剂量的DZF（1 g·kg），而非二甲双胍（0.25 g·kg），减轻了肝脂肪变性，肝脏重量和肝脏脂质积累减少，并通过降低丙氨酸转氨酶和天冬氨酸转氨酶以及增加小鼠肝脏超氧化物歧化酶活性来提供肝脏损伤保护。定量逆转录聚合酶链反应（qRT-PCR）显示脂肪酸合酶基因（）表达下降，脂肪酸氧化基因表达增加。蛋白质免疫印迹法表明，DZF和二甲双胍均可激活肝脏中的5'AMP激活蛋白激酶（AMPK），但抑制Notch信号通路的Notch细胞内结构域（NICD）和Hairy/增强子分裂1（Hes1）。DZF还显著改善了骨骼肌的超微结构、AMPK磷酸化和GLUT4转位。DZF还通过上调骨骼肌中的和促进脂肪酸转运和氧化。总之，DZF通过激活AMPK和抑制Notch信号通路减少肝脏脂质，以及通过AMPK增强骨骼肌能量代谢来提高胰岛素敏感性。本研究为治疗复杂病症，如IR，提供了见解，其中中药配方通过相关途径发挥多方面作用。
