Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China.
Institute of Clinical Pharmacology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, 528, Zhangheng Road, Shanghai, China.
J Ethnopharmacol. 2023 Jan 30;301:115806. doi: 10.1016/j.jep.2022.115806. Epub 2022 Oct 8.
Qushi Huayu Decoction (QHD) is a traditional Chinese medicine formula consisting of five herbs, which has been used for non-alcoholic fatty liver disease (NAFLD) treatment in clinic for decades in China and validated in several NAFLD animal models. The hepatic de novo lipogenesis (DNL) is enhanced greatly to contribute to steatosis in NAFLD. The spliced form of X-box binding protein 1 (XBP1s) initiates DNL independently of sterol regulatory element-binding protein (SREBP) and carbohydrate-responsive element-binding protein (ChREBP).
To disclose the mechanism of inhibition on hepatic DNL by QHD and the responsible compounds.
The effects of QHD on hepatic DNL were evaluated in mice induced by high-fructose diet (HFru). The effects of the serum-absorbed compounds of QHD on XBP1s were evaluated in HepG2 cells induced by tunicamycin. Hepatic histology, triglyceride (TG) and nonesterified fatty acids were observed. Hepatic apolipoprotein B100 and very low-density lipoprotein were measured to reflect lipid out-transport. The mRNA expression of XBP1s and its target genes were detected by real-time polymerase chain reaction. The protein expression of TG synthetases and DNL enzymes, and inositol requirement enzyme 1 alpha (IRE1α), phosphorylated IRE1α and XBP1s were detected in liver tissue and HepG2 cells by western-blot. The binding activity of SREBP1, protein expression of ChREBP and XBP1s were detected in the nuclear extracts of liver tissue.
Dynamical observing suggested feeding with HFru for 2 weeks was sufficient to induce hepatic lipogenesis and XBP1s. QHD ameliorated liver steatosis without enhancing out-transport of lipids, accompanied with more inhibitory effects on DNL enzymes than TG synthetases. QHD inhibits the nuclear XBP1s without affecting ChREBP and SREBP1. In QHD, chlorogenic acid, geniposide and polydatin inhibit lipogenesis initiated by XPB1s.
QHD probably decreases hepatic DNL by inhibiting XBP1s independent of SREBP1 and ChREBP. Chlorogenic acid, geniposide and polydatin are the potential responsible compounds.
祛湿化瘀汤（QHD）是一种由五种草药组成的中药配方，在中国临床上用于治疗非酒精性脂肪性肝病（NAFLD）已有数十年的历史，并在几种 NAFLD 动物模型中得到验证。肝从头合成（DNL）大大增强，导致 NAFLD 中的脂肪变性。X 盒结合蛋白 1（XBP1s）的剪接形式独立于固醇调节元件结合蛋白（SREBP）和碳水化合物反应元件结合蛋白（ChREBP）启动 DNL。
揭示 QHD 抑制肝 DNL 的机制及其负责的化合物。
在高果糖饮食（HFru）诱导的小鼠中评估 QHD 对肝 DNL 的影响。在衣霉素诱导的 HepG2 细胞中评估 QHD 的血清吸收化合物对 XBP1s 的影响。观察肝组织学、甘油三酯（TG）和非酯化脂肪酸。测量肝载脂蛋白 B100 和极低密度脂蛋白以反映脂质外转运。实时聚合酶链反应检测 XBP1s 及其靶基因的 mRNA 表达。Western blot 检测肝组织和 HepG2 细胞中 TG 合酶和 DNL 酶的蛋白表达以及肌醇需求酶 1α（IRE1α）、磷酸化 IRE1α 和 XBP1s。用 Western blot 检测肝组织核提取物中 SREBP1 的结合活性、ChREBP 和 XBP1s 的蛋白表达。
动态观察表明，用 HFru 喂养 2 周足以诱导肝脂肪生成和 XBP1s。QHD 改善了肝脂肪变性，而没有增强脂质的外转运，与 TG 合酶相比，对 DNL 酶的抑制作用更强。QHD 抑制核 XBP1s 而不影响 ChREBP 和 SREBP1。在 QHD 中，绿原酸、栀子苷和虎杖苷抑制由 XPB1s 启动的脂肪生成。
QHD 可能通过抑制 XBP1s 而不是 SREBP1 和 ChREBP 来降低肝 DNL。绿原酸、栀子苷和虎杖苷可能是潜在的负责化合物。
