Qian Fei, Ouyang Bingchen, Cai Zuhuan, Zhu Dan, Yu Simiao, Zhao Jingcheng, Wei Naijie, Wang Guangji, Wang Lin, Zhang Jingwei
Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Nanjing, China.
Phytomedicine. 2024 Jul;129:155691. doi: 10.1016/j.phymed.2024.155691. Epub 2024 Apr 29.
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with few therapeutic options currently available. Traditional Chinese medicine has been used for thousands of years and exhibited remarkable advantages against such complicated disease for its "multi-component, multi-target and multi-pathway" characteristics. Compound Shouwu Jiangzhi Granule (CSJG) is a clinical empirical prescription for the treatment of NAFLD, but its pharmacological mechanism remains unknown.
The clinical efficacy of CSJG was retrospectively analyzed in NAFLD patients by comparing blood biomarkers levels and liver MR images before and after CSJG treatment. Then, high-fat/high-fructose (HFHF) diet-induced NAFLD mice were used to further confirm CSJG's effect against hepatic lipid accumulation through hepatic lipid determination and histopathological staining of liver samples. Next, the ingredients of CSJG were determined, and network pharmacology analysis was performed to predict potential targets of CSJG, followed by quantitative PCR (qPCR) and western blotting for verification. Then, lipidomics study was carried out to further explore the anti-NAFLD mechanism of CSJG from the perspective of triacylglyceride (TAG) synthesis but not free fatty acid (FFA) synthesis. The enzymes involved in this process were assayed by qPCR and western blotting. The potential interactions between the key enzymes of TAG synthesis and the active ingredients of CSJG were analyzed by molecular docking.
CSJG attenuated blood lipid levels and hepatic fat accumulation in both NAFLD patients and mice. Although network pharmacology analysis revealed the FFA synthesis pathway, CSJG only slightly affected it. Through lipidomics analysis, GSJG was found to significantly block the synthesis of diglycerides (DAGs) and TAGs in the liver, with decreased DGAT2 and increased PLD1 protein expression, which diverted DAGs from the synthesis of TAGs to the production of PEs, PCs and PAs and thus lowed TAGs level. Molecular docking suggested that rhein, luteolin and liquiritigenin from CSJG might be involved in this regulation.
Clinical and experimental evidence demonstrated that CSJG is a promising agent for the treatment of NAFLD. CSJG regulated TAGs synthesis to alleviate hepatic lipid accumulation. Rhein, luteolin and liquiritigenin from CSJG might play a role in it.
非酒精性脂肪性肝病（NAFLD）是一种常见的慢性肝病，目前治疗选择有限。中药已经使用了数千年，因其“多成分、多靶点、多途径”的特点，在治疗此类复杂疾病方面显示出显著优势。复方首乌降脂颗粒（CSJG）是治疗NAFLD的临床经验方，但其药理机制尚不清楚。
通过比较CSJG治疗前后NAFLD患者的血液生物标志物水平和肝脏磁共振图像，回顾性分析CSJG的临床疗效。然后，使用高脂/高果糖（HFHF）饮食诱导的NAFLD小鼠，通过肝脏脂质测定和肝脏样本的组织病理学染色进一步证实CSJG对肝脏脂质积累的作用。接下来，确定CSJG的成分，并进行网络药理学分析以预测CSJG的潜在靶点，随后进行定量PCR（qPCR）和蛋白质印迹法进行验证。然后，进行脂质组学研究，从甘油三酯（TAG）合成而非游离脂肪酸（FFA）合成的角度进一步探索CSJG的抗NAFLD机制。通过qPCR和蛋白质印迹法检测参与该过程的酶。通过分子对接分析TAG合成关键酶与CSJG活性成分之间的潜在相互作用。
CSJG降低了NAFLD患者和小鼠的血脂水平和肝脏脂肪积累。虽然网络药理学分析揭示了FFA合成途径，但CSJG对其影响较小。通过脂质组学分析，发现GSJG显著阻断肝脏中二酰甘油（DAGs）和TAGs的合成，DGAT2蛋白表达降低，PLD1蛋白表达增加，这将DAGs从TAGs的合成转向磷脂酰乙醇胺（PEs）、磷脂酰胆碱（PCs）和磷脂酸（PAs）的产生，从而降低TAGs水平。分子对接表明，CSJG中的大黄酸、木犀草素和甘草素可能参与了这种调节。
临床和实验证据表明，CSJG是一种有前途的NAFLD治疗药物。CSJG通过调节TAGs合成来减轻肝脏脂质积累。CSJG中的大黄酸、木犀草素和甘草素可能在其中发挥作用。
