中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 41 Issue 4
Apr.  2025
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2025  >  41(4): 661-669

Changes in hepatic bile acid profile in a mouse model of metabolic-associated steatohepatitis induced by a high-fat， high-sugar， and high-cholesterol diet combined with carbon tetrachloride

DOI: 10.12449/JCH250410
  • 1.

    Institute of Liver Diseases，Key Laboratory of Liver and Kidney Diseases，Ministry of Education，Shanghai Key Laboratory of Traditional Chinese Medicine，Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine，Shanghai 201203，China

  • 2.

    Department of Traditional Chinese Medicine，Changzheng Hospital，Navy Medical University，Shanghai 200003，China

  • 3.

    Department of Hepatology，Shanghai Municipal Hospital of Traditional Chinese Medicine，Shanghai University of Traditional Chinese Medicine，Shanghai 200071，China

Research funding:

National Natural Science Foundation of China (82130120);

National Natural Science Foundation of China (82474045);

Shanghai Natural Science Foundation (24ZR1467100);

Open Fund of the Key Laboratory of Compound Traditional Chinese Medicine （Shanghai University of Traditional Chinese Medicine） (21DZ2270500);

Traditional Chinese Medicine Science and Technology Development Project of Shanghai Medical lnnovation & Development Foundation (WL-YPXM-2022002K)

More Information
  • Corresponding author: YANG Hailin， yanghailin95@163.com （ORCID： 0000-0003-1670-868X）; LIU Ping， liuliver@vip.sina.com （ORCID： 0000-0002-6152-4508）
  • Received Date: 2024-11-12
  • Accepted Date: 2024-12-30
  • Published Date: 2025-04-25
    Abstract
  •   Objective  To compare the hepatic bile acid profile between a mouse model of metabolic-associated steatohepatitis （MASH） induced by a high-fat， high-sugar， and high-cholesterol diet combined with intraperitoneal injection of 10% carbon tetrachloride （CCl4） and MASH cases in clinical practice， and to investigate the feasibility of this model in studying drug interventions on bile acid profile in MASH.  Methods  A total of 30 male C57BL/6J mice were randomly divided into control group and model group， with 15 mice in each group. The mice in the control group were given normal diet and drinking water and weekly injections of olive oil， and those in the model group were given a high-fat， high-sugar， and high-cholesterol diet， high-sugar drinking water， and weekly injections of CCl4+olive oil. At the end of weeks 8， 12， and 16， 5 mice were selected from each group to collect samples. Behavioral assessments were performed， and body weight and liver wet weight were measured； liver pathology and lipid deposition were evaluated by HE staining， SAF scoring， oil Red O staining， the semi-quantitative analysis of stained area， the serum levels of alanine aminotransferase （ALT） and aspartate aminotransferase （AST）， and liver triglyceride （TG） content； Sirius Red staining was performed for liver tissue to assess liver fibrosis； ultra-performance liquid chromatography-tandem mass spectrometry and targeted metabolomics were used to measure the hepatic bile acid profile， including cholic acid （CA）， glycocholic acid （GCA）， chenodeoxycholic acid （CDCA）， glycochenodeoxycholic acid （GCDCA）， ursodeoxycholic acid （UDCA）， tauroursodeoxycholic acid （TUDCA）， hyodeoxycholic acid （HDCA）， and glycodeoxycholic acid （GDCA）. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between two groups.  Results  Compared with the control group at the same time point， the model group had disheveled and dull fur， reduced activity， and relatively slow reactions at weeks 8， 12， and 16， as well as significant increases in liver wet weight （P<0.05）， the serum level of ALT （P<0.05）， the content of TG in the liver （P<0.05）， and SAF score （P<0.05）. As for the differentially expressed bile acids in liver tissue， compared with the control group at week 8， the model group had significantly higher levels of CA and CDCA and significantly lower levels of UDCA， TUDCA， HDCA， and GDCA （all P<0.05）； compared with the control group at week 12， the model group had significantly higher levels of CA， GCA， CDCA， and GCDCA and significantly lower levels of UDCA and HDCA （all P<0.05）； compared with the control group at week 16， the model group had significantly higher levels of CA， GCA， CDCA， GCDCA， and TUDCA and significantly lower levels of UDCA， HDCA， and GDCA （all P<0.05）. As for the differentially expressed bile acids in the bile acid pool of liver tissue， compared with the control group at week 8， the model group had significantly higher levels of CA and CDCA and significantly lower levels of UDCA， TUDCA， GDCA， and HDCA （all P<0.05）； compared with the control group at weeks 12 and 16， the model group had significantly higher levels of GCA and GCDCA and significantly lower levels of UDCA， GDCA， and HDCA （all P<0.05）.  Conclusion  There are significant changes in the hepatic bile acid profile in a mouse model of MASH induced by a high-fat， high-sugar， and high-cholesterol diet combined with CCl4， which are similar to the changes in bile acids in MASH cases in clinical practice， suggesting that this model can be used to explore the interventional effect of drugs on the bile acid profile in MASH.

     

    • FullText(HTML)
  • loading
    • References(28)
  • [1]
    TARGHER G, BYRNE CD, TILG H. MASLD: A systemic metabolic disorder with cardiovascular and malignant complications[J]. Gut, 2024, 73( 4): 691- 702. DOI: 10.1136/gutjnl-2023-330595.
    [2]
    YOUNOSSI Z, TACKE F, ARRESE M, et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis[J]. Hepatology, 2019, 69( 6): 2672- 2682. DOI: 10.1002/hep.30251.
    [3]
    PETTA S, TARGHER G, ROMEO S, et al. The first MASH drug therapy on the horizon: Current perspectives of resmetirom[J]. Liver Int, 2024, 44( 7): 1526- 1536. DOI: 10.1111/liv.15930.
    [4]
    RINELLA ME, NEUSCHWANDER-TETRI BA, SIDDIQUI MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease[J]. Hepatology, 2023, 77( 5): 1797- 1835. DOI: 10.1097/HEP.0000000000000323.
    [5]
    SHI L, JIN L, HUANG W. Bile acids, intestinal barrier dysfunction, and related diseases[J]. Cells, 2023, 12( 14): 1888. DOI: 10.3390/cells12141888.
    [6]
    WANG JJ, CAI XB, LU LG. Association between bile acids and nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2023, 39( 5): 1166- 1171. DOI: 10.3969/j.issn.1001-5256.2023.05.026.

    王俊俊, 蔡晓波, 陆伦根. 胆汁酸与非酒精性脂肪性肝病的关系[J]. 临床肝胆病杂志, 2023, 39( 5): 1166- 1171. DOI: 10.3969/j.issn.1001-5256.2023.05.026.
    [7]
    CHÁVEZ-TALAVERA O, HAAS J, GRZYCH G, et al. Bile acid alterations in nonalcoholic fatty liver disease, obesity, insulin resistance and type 2 diabetes: What do the human studies tell?[J]. Curr Opin Lipidol, 2019, 30( 3): 244- 254. DOI: 10.1097/MOL.0000000000000597.
    [8]
    POUPON R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: An overview of their mechanisms of action[J]. Clin Res Hepatol Gastroenterol, 2012, 36( Suppl 1): S3- S12. DOI: 10.1016/S2210-7401(12)70015-3.
    [9]
    ALKHOURI N, LACERTE C, EDWARDS J, et al. Safety, pharmacokinetics and pharmacodynamics of obeticholic acid in subjects with fibrosis or cirrhosis from NASH[J]. Liver Int, 2024, 44( 4): 966- 978. DOI: 10.1111/liv.15816.
    [10]
    DENK H, ABUJA PM, ZATLOUKAL K. Animal models of NAFLD from the pathologist’s point of view[J]. Biochim Biophys Acta BBA Mol Basis Dis, 2019, 1865( 5): 929- 942. DOI: 10.1016/j.bbadis.2018.04.024.
    [11]
    TSUCHIDA T, LEE YA, FUJIWARA N, et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer[J]. J Hepatol, 2018, 69( 2): 385- 395. DOI: 10.1016/j.jhep.2018.03.011.
    [12]
    TSOUKA S, KUMAR P, SEUBNOOCH P, et al. Transcriptomics-driven metabolic pathway analysis reveals similar alterations in lipid metabolism in mouse MASH model and human[J]. Commun Med(Lond), 2024, 4( 1): 39. DOI: 10.1038/s43856-024-00465-3.
    [13]
    ZHANG LZ, SHI JW, SHEN Q, et al. Astragalus saponins protect against extrahepatic and intrahepatic cholestatic liver fibrosis models by activation of farnesoid X receptor[J]. J Ethnopharmacol, 2024, 318( Pt A): 116833. DOI: 10.1016/j.jep.2023.116833.
    [14]
    ZHANG LZ, JIANG XY, SHI JW, et al. Isoastragaloside I attenuates cholestatic liver diseases by ameliorating liver injury, regulating bile acid metabolism and restoring intestinal barrier[J]. J Ethnopharmacol, 2024, 335: 118649. DOI: 10.1016/j.jep.2024.118649.
    [15]
    European Association for the Study of the Liver(EASL), European Association for the Study of Diabetes(EASD), European Association for the Study of Obesity(EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease[J]. J Hepatol, 2016, 64( 6): 1388- 1402. DOI: 10.1016/j.jhep.2015.11.004.
    [16]
    Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of metabolic dysfunction-associated(non-alcoholic)fatty liver disease(Version 2024)[J]. J Pract Hepatol, 2024, 27( 4): 494- 510. DOI: 10.3760/cma.j.cn501113-20240327-00163.

    中华医学会肝病学分会. 代谢相关(非酒精性)脂肪性肝病防治指南(2024年版)[J]. 实用肝脏病杂志, 2024, 27( 4): 494- 510. DOI: 10.3760/cma.j.cn501113-20240327-00163.
    [17]
    ANGULO P, KLEINER DE, DAM-LARSEN S, et al. Liver fibrosis, but No other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease[J]. Gastroenterology, 2015, 149( 2): 389- 397. e 10. DOI: 10.1053/j.gastro.2015.04.043.
    [18]
    KLEINER DE, MAKHLOUF HR. Histology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children[J]. Clin Liver Dis, 2016, 20( 2): 293- 312. DOI: 10.1016/j.cld.2015.10.011.
    [19]
    BERGER D, DESAI V, JANARDHAN S. Con: Liver biopsy remains the gold standard to evaluate fibrosis in patients with nonalcoholic fatty liver disease[J]. Clin Liver Dis(Hoboken), 2019, 13( 4): 114- 116. DOI: 10.1002/cld.740.
    [20]
    YANG HL, ZHANG DQ, CHEN GF, et al. Changes of serum and liver bile acid profiles in a mouse model of metabolic associated fatty liver disease induced by a methionine-choline-deficient diet[J]. Chin J Tissue Eng Res, 2021, 25( 26): 4137- 4144.

    杨海琳, 张定棋, 陈高峰, 等. 蛋氨酸-胆碱缺乏饮食诱导代谢相关脂肪肝模型小鼠血清和肝脏胆汁酸谱的变化[J]. 中国组织工程研究, 2021, 25( 26): 4137- 4144.
    [21]
    BRUNT EM, KLEINER DE, WILSON LA, et al. Improvements in histologic features and diagnosis associated with improvement in fibrosis in nonalcoholic steatohepatitis: Results from the nonalcoholic steatohepatitis clinical research network treatment trials[J]. Hepatology, 2019, 70( 2): 522- 531. DOI: 10.1002/hep.30418.
    [22]
    KANG JH, LI MJ, LUAN PP, et al. Establishment of non-alcoholic steatohepatitis mouse model induced by Western diet combined with low-dose carbon tetrachloride[J]. J Shanghai Jiao Tong Univ Med Sci, 2020, 40( 5): 590- 597. DOI: 10.3969/j.issn.1674-8115.2020.05.005.

    康建华, 李明杰, 栾培培, 等. 西方饮食联合小剂量四氯化碳构建非酒精性脂肪性肝炎小鼠模型研究[J]. 上海交通大学学报(医学版), 2020, 40( 5): 590- 597. DOI: 10.3969/j.issn.1674-8115.2020.05.005.
    [23]
    BASUNI AA, SWEED D, ELGAZZAR MF, et al. Exploring serum bile acids as potential noninvasive biomarkers for nonalcoholic fatty liver disease[J]. Egypt Liver J, 2024, 14( 1): 70. DOI: 10.1186/s43066-024-00378-9.
    [24]
    FENG S, XIE XM, LI JC, et al. Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation[J]. Hepatol Int, 2024, 18( 3): 1040- 1052. DOI: 10.1007/s12072-023-10610-0.
    [25]
    LIN XZ, MAI MQ, HE TP, et al. Efficiency of ursodeoxycholic acid for the treatment of nonalcoholic steatohepatitis: A systematic review and meta-analysis[J]. Expert Rev Gastroenterol Hepatol, 2022, 16( 6): 537- 545. DOI: 10.1080/17474124.2022.2083605.
    [26]
    KUANG JL, WANG JY, LI YT, et al. Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis[J]. Cell Metab, 2023, 35( 10): 1752- 1766. e 8. DOI: 10.1016/j.cmet.2023.07.011.
    [27]
    NIE QX, LUO X, WANG K, et al. Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway[J]. Cell, 2024, 187( 11): 2717- 2734. e 33. DOI: 10.1016/j.cell.2024.03.034.
    [28]
    ZHENG LT, WANG Z, CHEN YC, et al. Role of Akkermansia muciniphila in nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2024, 40( 3): 594- 599. DOI: 10.12449/JCH240326.

    郑立婷, 汪哲, 陈玉春, 等. 嗜黏蛋白阿克曼菌在非酒精性脂肪性肝病中的作用[J]. 临床肝胆病杂志, 2024, 40( 3): 594- 599. DOI: 10.12449/JCH240326.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(7)  / Tables(1)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (857) PDF downloads(41) Cited by()
    Proportional views
    Related
        

    The first journal specializing in hepatobiliary and pancreatic diseases in China

    Supervisor：Ministry of Education of the People's Republic of China

    Sponsor：Jilin University

    Academic Support: Chinese Society of Hepatology，Chinese Medical Association

    Address: 461 Xinjiang Road, Changchun

    Submit：0431-88782044

    Peer review：0431-88783542

    Email：lcgdb@vip.163.com

    About Journal

    Submission Guideline

    Journal Online

    Hepatobiliary College

    Guidelines

    YesterdayIP[]YesterdayPV[]TodayIP[]TodayPV[]Online[]

    Website Design © 2020 Editorial Board of Journal of Clinical Hepatology 吉ICP备10000617号-1 Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return