Qin Shasha, Tian Jingzhuo, Zhao Yong, Wang Lianmei, Wang Jinyu, Liu Suyan, Meng Jing, Wang Fang, Liu Chenyue, Han Jiayin, Pan Chen, Zhang Yushi, Yi Yan, Li Chunying, Liu Meiting, Liang Aihua
Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei Ave, Beijing, 100700, China.
Research Center for Traditional Chinese Medicine Preparations, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei Ave, Beijing, 100700, China.
J Ethnopharmacol. 2024 Jan 30;319(Pt 1):117083. doi: 10.1016/j.jep.2023.117083. Epub 2023 Aug 25.
Cholestasis is the main manifestation of cholestatic liver disease, which has a risk of progression to end-stage liver disease. Gardeniae Fructus is the dried fruit of Gardeniae jasminoides Ellis, a plant of the Rubiaceae family. Gardeniae Fructus has shown therapeutic potential in cholestasis-related liver diseases and it is generally believed that Gardeniae Fructus ameliorates cholestasis, which could be related to its influence on bile acids (BAs) metabolism. However, the specific targets of Gardeniae Fructus and its impact on enterohepatic circulation of BAs have not yet been fully elucidated.
To systematically elucidate the mechanism by which Gardenia extract (GE, total iridoids in Gardeniae Fructus, which contains the predominant and characteristic phytoconstituents of Gardeniae Fructus) ameliorates alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury.
Sprague-Dawley rats were orally administered water, obeticholic acid (OCA, 2 mg/kg), or GE (21 and 42 mg/kg) once daily for five days. On the third day, the model was established by administration of a single dose of ANIT (40 mg/kg) by oral gavage. Biochemical and pathological analyses, BA metabolomics, transcriptomics, and qRT-PCR were performed.
The profile of BAs in serum and liver confirmed that GE attenuated ANIT-induced acute cholestasis by affecting BA metabolism in a dose-dependent manner. Liver transcriptomic analysis indicated that GE mainly influenced the primary bile acid (PBA) biosynthesis and bile secretion pathways. GE mainly affected PBA biosynthesis in liver by upregulating Cyp8b1 gene expression, thereby significantly reducing the level of total bile acids (TBA). GE mainly promoted PBA excretion from liver into duodenum by upregulating Fxr and Oatp1 gene expression, thereby increasing the excretion of PBA in feces, and inhibiting PBA in liver entering the blood by alternative routes to reduce TBA levels in serum and urine and improve the enterohepatic circulation of BAs.
GE attenuated ANIT-induced hepatotoxicity and cholestasis in rats by upregulating Cyp8b1 expression to inhibit BA synthesis in the liver, while also promoting BA excretion via the intestinal-fecal route, and improving enterohepatic circulation of BAs.
胆汁淤积是胆汁淤积性肝病的主要表现，存在进展为终末期肝病的风险。栀子是茜草科植物栀子的干燥果实。栀子在胆汁淤积相关肝病中已显示出治疗潜力，一般认为栀子可改善胆汁淤积，这可能与其对胆汁酸（BAs）代谢的影响有关。然而，栀子的具体作用靶点及其对BAs肝肠循环的影响尚未完全阐明。
系统阐明栀子提取物（GE，栀子中的总环烯醚萜类成分，包含栀子的主要和特征性植物成分）改善α-萘异硫氰酸酯（ANIT）诱导的胆汁淤积性肝损伤的机制。
将Sprague-Dawley大鼠每日口服给予水、奥贝胆酸（OCA，2mg/kg）或GE（21mg/kg和42mg/kg），连续5天。在第3天，通过单次口服灌胃给予ANIT（40mg/kg）建立模型。进行生化和病理分析、BA代谢组学、转录组学和qRT-PCR检测。
血清和肝脏中的BAs谱证实，GE通过剂量依赖性地影响BA代谢减轻了ANIT诱导的急性胆汁淤积。肝脏转录组分析表明，GE主要影响初级胆汁酸（PBA）生物合成和胆汁分泌途径。GE主要通过上调Cyp8b1基因表达影响肝脏中PBA生物合成，从而显著降低总胆汁酸（TBA）水平。GE主要通过上调Fxr和Oatp1基因表达促进肝脏中PBA排泄至十二指肠，从而增加粪便中PBA排泄，并抑制肝脏中PBA通过其他途径进入血液，以降低血清和尿液中TBA水平，改善BAs肝肠循环。
GE通过上调Cyp8b1表达抑制肝脏中BA合成，同时促进BA经肠-粪途径排泄，改善BAs肝肠循环，减轻ANIT诱导的大鼠肝毒性和胆汁淤积。
