Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P.R. China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, P.R. China.
First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, P.R. China.
Phytomedicine. 2020 Nov;78:153292. doi: 10.1016/j.phymed.2020.153292. Epub 2020 Jul 25.
Brown adipose tissue (BAT) activation is a promising therapeutic target to treat hyperlipidemia with obesity. Huang-Qi San (HQS), an traditional Chinese medicine, can ameliorate hyperlipidemia with obesity, but its mechanism of action (MOA) is not understood.
To articulate the MOA for HQS with animal models.
The main chemical constituents of HQS were identified by high-performance liquid chromatography (HPLC) based assay. Hyperlipidemia with obesity rat models induced by high-fat diet were employed in the study. The levels of the fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) were measured to evaluate the ability of HQS to ameliorate hyperlipidemia with obesity. Pathological analyses of organs were conducted with Oil Red O staining, hematoxylin-eosin (H&E) staining and transmission electron microscopy. The expression of mRNAs related to thermogenic genes, fatty acid oxidation-related genes and mitochondria biogenic genes were examined by quantitative real-time PCR. The protein expressions of uncoupling protein 1 (UCP1) were investigated by immunohistochemistry and western blot. Simultaneously, the protein expression of PR domain containing 16 (PRDM16), ATP synthase F1 subunit alpha (ATP5A) was detected by western blot.
HQS ameliorates metabolic disorder, lipid ectopic deposition, obesity and maintained glucose homeostasis in hyperlipidemia with obesity rats. HQS can significantly increase the number of mitochondria and reduced the size of the intracellular lipid droplets in BAT, and increase the expression of BAT activation-related genes (UCP1, PGC1α, PGC1β, Prdm16, CD137, TBX1, CPT1a, PPARα, Tfam, NRF1 and NRF2) in vivo. Furthermore, UCP1, PRDM16 and ATP5A proteins of BAT were increased.
HQS can activate BAT and browning of S-WAT (subcutaneous white adipose tissue) through activating the PRDM16/PGC1α/UCP1 pathway, augmenting mitochondrial biogenesis and fatty acid oxidation to increase thermogenesis and energy expenditure, resulting in a significant amelioration of hyperlipidemia with obesity. Therefore, HQS is an effective therapeutic medicine for the treatment of hyperlipidemia with obesity.
棕色脂肪组织（BAT）的激活是治疗肥胖伴高血脂的有前途的治疗靶点。黄耆散（HQS）是一种中药，可改善肥胖伴高血脂，但作用机制（MOA）尚不清楚。
用动物模型阐明 HQS 的 MOA。
采用高效液相色谱（HPLC）法鉴定 HQS 的主要化学成分。采用高脂饮食诱导的肥胖伴高血脂大鼠模型进行研究。测定空腹血糖（FPG）、甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）和高密度脂蛋白胆固醇（HDL-C）水平，以评价 HQS 改善肥胖伴高血脂的能力。用油红 O 染色、苏木精-伊红（H&E）染色和透射电镜对器官进行病理分析。通过定量实时 PCR 检测与产热基因、脂肪酸氧化相关基因和线粒体生物发生基因相关的 mRNA 的表达。通过免疫组织化学和 Western blot 检测解偶联蛋白 1（UCP1）的蛋白表达。同时，通过 Western blot 检测 PR 结构域包含 16（PRDM16）和 ATP 合酶 F1 亚基α（ATP5A）的蛋白表达。
HQS 改善了高脂血症伴肥胖大鼠的代谢紊乱、脂质异位沉积、肥胖和葡萄糖稳态。HQS 可显著增加 BAT 中线粒体的数量并减少细胞内脂滴的大小，并增加 BAT 激活相关基因（UCP1、PGC1α、PGC1β、PRDM16、CD137、TBX1、CPT1a、PPARα、Tfam、NRF1 和 NRF2）的表达。此外，BAT 的 UCP1、PRDM16 和 ATP5A 蛋白增加。
HQS 通过激活 PRDM16/PGC1α/UCP1 通路激活 BAT 和 S-WAT（皮下白色脂肪组织）的褐色化，增加线粒体生物发生和脂肪酸氧化，增加产热和能量消耗，从而显著改善肥胖伴高血脂。因此，HQS 是治疗肥胖伴高血脂的有效治疗药物。
