College of Pharmacy, Southwest Minzu University, Chengdu, 610041, China.
College of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
J Ethnopharmacol. 2025 Jan 30;337(Pt 2):118894. doi: 10.1016/j.jep.2024.118894. Epub 2024 Oct 5.
Herpetospermum pedunculosum (Ser.) C.B. Clarke (HP), a traditional Tibetan medicine used to treat hepatobiliary diseases, was confirmed that lignans-enriched ethyl acetate extract of HP (EAHP) could alleviate the hepatic injury by modern pharmacological evidence. However, the effects and potential mechanisms of EAHP against nonalcoholic fatty liver disease (NAFLD) are still unknown.
To reveal the effects of EAHP on NAFLD and explore the potential mechanisms from the perspective of lipidomics and transcriptomics.
UPLC‒Q-TOF‒MS analysis was carried out to investigate the chemical components of EAHP. A Choline-deficient, L-amino acid defined, high fat diet (CDAHFD) was used to establish a NAFLD mouse model. The anti-NAFLD effects of various dosages of EAHP were evaluated by biochemical indexes and histological analysis. Hepatic lipidomic and transcriptomic analysis and multiple bioinformatics methods were used to screen biomarkers and signaling pathways. The levels of the corresponding genes were verified by qPCR.
36 kinds of compounds were identified by UPLC‒Q-TOF‒MS analysis. Oral treatment with EAHP significantly decrease the liver index and the levels of ALT and AST in the serum. The measurements lipid content and Oil Red O staining results suggested that EAHP ameliorated lipid metabolism disorders by reducing the content of TG and LDL-C, increasing HDL-C in the liver. H&E staining and ELISA revealed that EAHP restored hepatic inflammatory infiltration and decrease the levels of IL-1β, IL-6, TNF-α, and increase IL-10 in the serum. Lipidomic analysis showed that EAHP could regulate CDAHFD-induced lipid metabolic disorder. The different lipid metabolites included TG, phosphatidyl choline (PC), diacylglycerol (DG), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide (Cer). Transcriptomic analysis revealed that Bmp8b, Nbl1, Rgma, Sphk1, Thbs1, and Ugt8a were important regulators, which were associated with TGF-β signaling pathway and sphingolipid metabolism. The expressions of above genes detected by were qPCR consistent with transcriptomic data.
The ameliorative effects of EAHP on NAFLD are potentially attributable to the regulation of sphingolipid metabolism and TGF-β signaling pathway, etc., which results in abnormal hepatic lipid metabolism and inflammatory response.
ETHNOPHARMACOLOGICAL 相关性：Herpetospermum pedunculosum（Ser.）C.B.Clarke（HP）是一种传统的藏药，用于治疗肝胆疾病，现代药理学证据证实富含木脂素的 HP 乙酸乙酯提取物（EAHP）可减轻肝损伤。然而，EAHP 对非酒精性脂肪性肝病（NAFLD）的作用及其潜在机制仍不清楚。
从脂质组学和转录组学的角度揭示 EAHP 对 NAFLD 的作用，并探讨其潜在机制。
采用 UPLC-Q-TOF-MS 分析方法对 EAHP 的化学成分进行分析。采用胆碱缺乏、L-氨基酸定义、高脂肪饮食（CDAHFD）建立 NAFLD 小鼠模型。通过生化指标和组织学分析评价 EAHP 不同剂量的抗 NAFLD 作用。采用肝脂质组学和转录组学分析及多种生物信息学方法筛选生物标志物和信号通路。通过 qPCR 验证相应基因的水平。
通过 UPLC-Q-TOF-MS 分析鉴定出 36 种化合物。EAHP 口服治疗可显著降低血清 ALT 和 AST 水平，降低肝指数。脂质含量和油红 O 染色结果表明，EAHP 通过降低 TG 和 LDL-C 含量，增加肝内 HDL-C，改善脂质代谢紊乱。H&E 染色和 ELISA 显示，EAHP 恢复了肝内炎症浸润，降低了血清中 IL-1β、IL-6、TNF-α的水平，增加了 IL-10 的水平。脂质组学分析表明，EAHP 可调节 CDAHFD 诱导的脂质代谢紊乱。不同的脂质代谢物包括 TG、磷脂酰胆碱（PC）、二酰基甘油（DG）、磷脂酰乙醇胺（PE）、磷脂酰肌醇（PI）、神经酰胺（Cer）。转录组分析显示，Bmp8b、Nbl1、Rgma、Sphk1、Thbs1 和 Ugt8a 是重要的调节剂，与 TGF-β 信号通路和鞘脂代谢有关。通过 qPCR 检测到的上述基因的表达与转录组数据一致。
EAHP 对 NAFLD 的改善作用可能归因于对鞘脂代谢和 TGF-β 信号通路等的调节，从而导致异常的肝脂质代谢和炎症反应。
