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青钱柳总三萜通过调节FXR介导的胆汁酸和脂质代谢途径改善高脂饮食诱导的小鼠代谢相关脂肪性肝病

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中草药 | 药理与临床 2026,57(3): 949-967

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中草药 |药理与临床 2026 , 57 (3) : 949 -967

青钱柳总三萜通过调节FXR介导的胆汁酸和脂质代谢途径改善高脂饮食诱导的小鼠代谢相关脂肪性肝病

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张颖¹, 谈燕清², 刘杰¹, 孔吉旭¹, 许杰², 贺海波¹, 王洪武³, 孟子元¹, 李浩然², 唐海明⁴, 张继红²

作者信息

通讯作者:

贺海波

作者简介:

张颖: 张颖（2001—），女，硕士研究生，主要从事中药药理学研究。E-mail:2826720856@qq.com

Total triterpenoid from Cyclocarya paliurus improves high-fat diet-induced metabolic-associated fatty liver disease in mice by regulating FXR-mediated bile acid and lipid metabolism pathways

ZHANG Ying, TAN Yanqing, LIU Jie, KONG Jixu, XU Jie, HE Haibo, WANG Hongwu, MENG Ziyuan, LI Haoran, TANG Haiming, ZHANG Jihong

Affiliations

doi: 10.7501/j.issn.0253-2670.2026.03.014

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摘要

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目的探讨青钱柳总三萜（total triterpenoid from Cyclocarya paliurus，CPT）对高脂饮食（high-fat diet，HFD）诱导代谢相关脂肪性肝病（metabolic-associated fatty liver disease，MAFLD）小鼠的治疗作用及其机制。方法将C57BL/6J小鼠随机分为对照组、模型组、CPT（100 mg/kg）组、二甲双胍（metformin，MET，100 mg/kg）组和CPT＋MET组。除对照组给予普通饲料喂养外，其余各组给予高脂饲料喂养12周建立MAFLD模型。模型成功建立后，给予药物干预8周。实验期间观察小鼠活动水平，定期测量体质量、进食量。给药结束前1周，利用间接测热法测定小鼠耗氧量（oxygen consumption，VO₂）、二氧化碳生成量（carbon dioxide production，VCO₂）和能量消耗量；给药结束后，进行葡萄糖耐量实验和胰岛素耐受实验，检测葡萄糖耐量；称量肝质量，计算肝脏指数；检测血清丙氨酸氨基转移酶（alanine aminotransferase，ALT）、天冬氨酸氨基转移酶（aspartate aminotransferase，AST）、碱性磷酸酶（alkaline phosphatase，ALP）、γ-谷氨酰转肽酶（γ-glutamyl transpeptidase，γ-GT）、三酰甘油（triglycerides，TG）、总胆固醇（total cholesterol，TC）、低密度脂蛋白胆固醇（low density lipoprotein cholesterol，LDL-C）、高密度脂蛋白胆固醇（high density lipoprotein cholesterol，HDL-C）、空腹血糖（fasting blood glucose，FBG）和空腹胰岛素（fasting insulin，FINS），计算胰岛素抵抗指数（insulin resistance index，HOMA-IR）；检测肝脏和粪便中TC、TG水平，以及血清、肝组织和粪便中总胆汁酸（total bile acids，TBA）水平；采用苏木素-伊红、油红O染色观察小鼠肝脏病理变化；每组随机选取5个肝组织和5个结肠内容物样本进行胆汁酸（bile acids，BAs）代谢组学分析；qRT-PCR测定肝组织中固醇7α-羟化酶（cholesterol 7α-hydoxylase 1，Cyp7a1）、Cyp7b1、Cyp27a1、Cyp8b1、胆汁酰基辅酶A合成酶（bile acid coenzyme A synthetase，Bacs）、氨基酸正酰基转移酶（bile acid coenzyme a: amino acid N-acyltransferase，Baat）、胆盐输出泵（bile salt export pump，Bsep）、钠离子-牛磺胆酸共转运蛋白（recombinant Na⁺ taurocholate cotransporting polypeptide，Ntcp）、法尼醇X受体（farnesoid X receptor，FXR）、小异二聚体伴侣（small heterodimer partner，SHP）、成纤维细胞生长因子受体4（fibroblast growth factor receptor 4，FGFR4）、固醇调节元件结合蛋白-1c（sterol regulatory element-binding protein-1c，SREBP-1c）、硬脂酰辅酶A去饱和酶1（stearoyl-CoA desaturase 1，SCD1）、脂肪酸合成酶（fatty acid synthase，FASN）、过氧化物酶体增殖物激活受体α（peroxisome proliferator-activated receptor α，PPARα）、肉碱棕榈酰转移酶1（carnitine palmitoyltransferase 1，CPT1）、脂蛋白脂肪酶（lipoprotein lipase，LPL）、微粒体甘油三酸酯转运蛋白（microsomal triglyceride transfer protein，MTTP）和回肠组织中FXR、成纤维细胞生长因子15（fibroblast growth factor 15，FGF15）、顶端钠依赖性胆盐转运体（apical sodium-dependent bile acid transporter，Abst）、胆汁酸结合蛋白（intestinal bile acid-binding protein，Ibabp）、有机溶质转运蛋白-α（organic solute transporter-α，Ost-α）、Ost-β mRNA表达；Western blotting测定肝组织中CYP7a1、Cyp7b1、Cyp27a1、Cyp8b1、FXR、SHP、FGFR4、SREBP-1c、SCD1、FASN、PPARα、CPT1、LPL、MTTP和回肠组织中FXR、FGF15、Abst蛋白表达。结果与模型组比较，CPT和CPT与MET联用可显著降低小鼠体质量、改善葡萄糖耐量、提高胰岛素敏感性，降低肝脏质量、肝脏指数，增加VO₂、VCO₂、VO₂/VCO₂值及白天、晚上能量消耗和总能量消耗量（P＜0.01）；降低血清中ALT、AST、ALP、γ-GT、TC、TG、LDL-C、FINS、FBG、TBA和肝组织中TC、TG水平及HOMA-IR，升高血清中HDL-C和粪便中TC、TG、TBA水平，降低肝组织病理学评分、脂质沉积（P＜0.01）；升高肝组织中TBA水平，降低肝组织中非结合BAs、初级BAs、次级BAs含量和初级BAs/次级BAs值及结肠内容物中非结合BAs、次级BAs含量，增加肝组织中结合BAs含量和结合BAs/非结合BAs值及结肠内容物中结合BAs、初级BAs含量、结合BAs/非结合BAs值和初级BAs/次级BAs值（P＜0.01）；上调肝组织中Cyp7a1、Cyp7b1、Cyp27a1、Bacs、Baat、FXR、SHP、Bsep、Ntcp、PPARα、CPT1、LPL、MTTP mRNA和Cyp7a1、Cyp7b1、Cyp27a1、FXR、SHP、PPARα、CPT1、LPL、MTTP蛋白表达，下调肝组织Cyp8b1、FGFR4、SREBP-1c、SCD1、FASN mRNA和蛋白表达，下调回肠组织中FXR、FGF15、Asbt、Ibabp、Ost-α、Ost-β mRNA和FXR、FGF15、Asbt蛋白表达（P＜0.01）。CPT与MET联用较CPT单独使用效果更好（P＜0.05、0.01）。结论 CPT可能通过抑制肠道FXR/FGF15信号传导，进而激活肝脏FXR/SHP通路，促进肝肠循环中BAs合成，抑制其回肠再吸收、促进BAs随粪便排泄；激活的肝脏FXR/SHP通路通过抑制SREBP-1c/SCD1/FASN信号轴来抑制脂质合成，激活的肝脏FXR通过激活PPARα/CPT1和LPL/MTTP信号轴来促进脂质氧化和脂质分解，从而治疗MAFLD。

关键词

青钱柳总三萜 / 代谢相关脂肪性肝病 / 胆汁酸 / 脂质代谢 / 法尼醇X受体

Abstract

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Objective To investigate the therapeutic effect and mechanism of total triterpenoid from Cyclocarya paliurus (CPT) on high-fat diet (HFD)-induced metabolic-associated fatty liver disease (MAFLD) mice. Methods C57BL/6J mice were randomly divided into control group, model group, CPT (100 mg/kg) group, metformin (MET, 100 mg/kg) group and CPT + MET group. Except for the control group receiving regular feeding, all other groups were fed HFD for 12 weeks to establish MAFLD models. After successful establishment of MAFLD model, drugs were given eight weeks. During the experiment, the activity levels of mice were observed, their body weight and food intake were measured regularly. One week before the end of medication, the oxygen consumption (VO₂), carbon dioxide production (VCO₂) and energy consumption of mice were measured using indirect calorimetry. After the end of administration, glucose tolerance test and insulin resistance test were conducted to detect glucose tolerance. Liver weight was measured, and liver index was calculated. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), fasting insulin (FINS) in serum were detected, and insulin resistance index (HOMA-IR) was calculated. The levels of TC and TG in hepatic tissues and feces, as well as the levels of total bile acids (TBA) in serum, hepatic tissues and feces were measured. Hematoxylin-eosin and oil red O staining were used to observe the pathological changes in hepatic tissues of mice. Five hepatic tissue and five colon content samples from each group were randomly selected for bile acid (BAs) metabolomics analysis. The mRNA expressions of cholesterol 7α-hydoxylase 1 (Cyp7a1), Cyp7b1, Cyp27a1, Cyp8b1, bile acid coenzyme A synthetase (Bacs), bile acid coenzyme a: amino acid N-acyltransferase (Baat), bile salt export pump (Bsep), recombinant Na⁺ taurocholate cotransporting polypeptide (Ntcp), farnesoid X receptor (FXR), small heterodimeric partner (SHP), fibroblast growth factor receptor 4 (FGFR4), sterol regulatory element-binding protein-1c (SREBP-1c), stearyl coenzyme A desaturation enzyme 1 (SCD1), fatty acid synthetase (FASN), peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl transferase 1 (CPT1), lipoprotein lipase (LPL), microsomal triglyceride transfer protein (MTTP) in hepatic tissues and FXR, fibroblast growth factor 15 (FGF15), apical sodium-dependent bile acid transporter (Abst), intestinal bile acid-binding protein (Ibabp), organic solute transporter-α (Ost-α), Ost-β in ileum tissues were determined by qRT-PCR. Western blotting was used to detect the protein expressions of CYP7a1, Cyp7b1, Cyp27a1, Cyp8b1, FXR, SHP, FGFR4, SREBP-1c, SCD1, FASN, PPARα, CPT1, LPL, MTTP in hepatic tissues and FXR, FGF15, Abst in ileum tissues. Results Compared with model group, CPT and its association with MET significantly reduced the body weight, improved glucose tolerance, elevated insulin sensitivity, lowered liver weight and liver index, raised VO₂, VCO₂, VO₂/VCO₂, and daytime and nighttime energy consumptions and total energy consumption in mice (P < 0.01). CPT and its association with MET reduced ALT, AST, ALP, γ-GT, TC, TG, LDL-C, FINS, FBG, TBA levels in serum and TC and TG levels in hepatic tissue as well as HOMA-IR, elevated levels of HDL-C in serum and TC, TG, TBA in feces, reduced liver histopathological scores and lipid deposition (P < 0.01). CPT and its association with MET elevated hepatic tissue TBA level, lowered the contents of unconjugated BAs, primary BAs, secondary BAs and the ratio of primary BAs/secondary BAs in hepatic tissues, as well as the levels of unconjugated BAs and secondary BAs in colon contents, elevated the content of conjugated BAs and the ratio of conjugated BAs/unconjugated BAs in hepatic tissue, as well as the levels of conjugated BAs, primary BAs and the ratios of conjugated BAs/unconjugated BAs, primary BAs/secondary BAs in colon contents (P < 0.01). In addition, CPT and its association with MET elevated Cyp7a1, Cyp7b1, Cyp27a1, Bacs, Baat, FXR, SHP, Bsep, Ntcp, PPARα, CPT1, LPL, MTTP mRNA expressions and Cyp7a1, Cyp7b1, Cyp27a1, FXR, SHP, PPARα, CPT1, LPL, MTTP protein expressions in hepatic tissues, reduced the mRNA and protein expressions of Cyp8b1, FGFR4, SREBP-1c, SCD1, FASN in hepatic tissues, depressed FXR, FGF15, Asbt, Ibabp, Ost-α, Ost-β mRNA expressions and FXR, FGF15, Asbt protein expressions in ileum tissues (P < 0.01). The combination of CPT and MET showed better efficacy than CPT alone (P < 0.05, 0.01). Conclusion CPT may activate the hepatic FXR/SHP pathway by inhibiting intestinal FXR/FGF15 signaling, facilitating the synthesis of BAs in the hepatic intestinal circulation, repressing their ileal reabsorption, and boosting the excretion of BAs with feces. The activated hepatic FXR/SHP pathway restrains lipid synthesis by suppressing SREBP-1c/SCD1/FASN signaling axis, while activated hepatic FXR promotes lipid oxidation and lipid decomposition through activating the PPARα/CPT1 and LPL/MTTP signaling axes to treat MAFLD.

Key words

total triterpenoid from Cyclocarya paliurus / metabolic-associated fatty liver disease / bile acid / lipid metabolism / farnesoid X receptor

引用本文

张颖, 谈燕清, 刘杰, 孔吉旭, 许杰, 贺海波, 王洪武, 孟子元, 李浩然, 唐海明, 张继红. 青钱柳总三萜通过调节FXR介导的胆汁酸和脂质代谢途径改善高脂饮食诱导的小鼠代谢相关脂肪性肝病. 中草药, 2026 , 57 (3) : 949 -967 . DOI: 10.7501/j.issn.0253-2670.2026.03.014

ZHANG Ying, TAN Yanqing, LIU Jie, KONG Jixu, XU Jie, HE Haibo, WANG Hongwu, MENG Ziyuan, LI Haoran, TANG Haiming, ZHANG Jihong. Total triterpenoid from Cyclocarya paliurus improves high-fat diet-induced metabolic-associated fatty liver disease in mice by regulating FXR-mediated bile acid and lipid metabolism pathways[J]. Chinese Traditional and Herbal Drugs, 2026 , 57 (3) : 949 -967 . DOI: 10.7501/j.issn.0253-2670.2026.03.014

基金

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湖北省科技厅重点研发项目(2025BCB067);宜昌市医疗卫生研究项目(A22-2-059,A23-1-066);湖北省科技厅重点研发大健康计划项目(2022BCE017);湖北省卫生健康委员会中医药重点项目(ZY2023Z015);湖北省卫生健康委员会中医药面上项目(ZY2025M038);湖北省科技厅自然科学基金项目(2025AFB805,2025AFB839,2025AFD301,2025AFD294,2023AFB600,2022CFB357,2022CFB427);湖北省卫生健康委员会科研资助项目(WJ2023M153);湖北省功能性消化系统疾病中医临床医学研究中心开放基金项目(SXZ202303,SXZ202308,SXZ202311)

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2026年第57卷第3期

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doi: 10.7501/j.issn.0253-2670.2026.03.014

接收时间：2025-10-12
首发时间：2026-09-08

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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