中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 40 Issue 2
Feb.  2024
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(2): 292-297

Effect of hyodeoxycholic acid on the activity of steatosis hepatocytes and its mechanism

DOI: 10.12449/JCH240212
  • 1a.

    Department of Gastroenterology，Nanhua Hospital Affiliated to University of South China，Hengyang，Hunan 421002，China

  • 1b.

    Department of Hand and Foot Surgery，Nanhua Hospital Affiliated to University of South China，Hengyang，Hunan 421002，China

  • 2.

    Hunan Provincial Clinical Research Center for Metabolic Associated Fatty Liver Disease，Hengyang，Hunan 421002，China

Research funding:

General Project of Hunan Provincial Education Department (20C1586);

Hunan Provincial Science and Technology Innovation Program Project (2020SK51910);

Hunan Provincial Science and Technology Innovation Program Project (2021SK51902)

More Information
  • Corresponding author: YANG Xuefeng， yxf009988@sina.com （ORCID： 0000-0002-3470-0350）
  • Received Date: 2023-05-08
  • Accepted Date: 2023-06-09
  • Published Date: 2024-02-19
    Abstract
  •   Objective  To investigate the role and mechanism of hyodeoxycholic acid （HDCA） in the progression of metabolic associated fatty liver disease （MAFLD）， and to provide a new theoretical basis for further clarifying the pathogenesis of MAFLD.  Methods  L02 hepatocytes were used as experimental cells， and palmitic acid was used to induce steatosis in L02 cells. The farnesoid X receptor （FXR） siRNA interference chain technique was used to construct a hepatocyte cell line with low FXR expression. CCK8 assay was used to observe the effect of HDCA on L02 steatosis hepatocytes at different concentrations （0， 100， 200， 300， and 400 μmol/L） and time points （12， 24， 36， and 48 hours）. The method of qRT-PCR was used to measure the mRNA expression levels of FXR， proliferating cell nuclear antigen （PCNA）， Cyclin D1， phosphatidylinositol 3-kinase （PI3K）， and protein kinase-B （AKT）， and Western blot was used to measure the protein expression levels of FXR， Cyclin D1， PCNA， PI3K， phosphorylated PI3K （p-PI3K）， AKT， and phosphorylated （p-AKT）. A one-way analysis of variance was used for comparison of normally distributed continuous data with homogeneity of variance between multiple groups， and the Tukey HSD test was used for further comparison between two groups； the Welch analysis of variance was used for comparison of normally distributed continuous data with heterogeneity of variance between multiple groups， and the Games-Howell test was used for further comparison between two groups. The independent-samples t test was used for comparison between two groups.  Results  CCK8 assay showed a significant reduction in the viability of L02 cells and steatosis hepatocytes treated by 300 μmol/L HDCA （P<0.05）， and qRT-PCR showed a significant increase in the mRNA expression level of FXR and significant reductions in the mRNA expression levels of PCNA， Cyclin D1， PI3K， and AKT （all P<0.05）. Western blot showed a significant increase in the protein expression level of FRX （P<0.05）， and after interference of FXR expression in L02 cells， there were significant increases in the protein expression levels of PCNA， PI3K， p-PI3K， AKT， and p-AKT （all P<0.05）.  Conclusion  HDCA inhibits the PI3K/AKT signaling pathway by upregulating FXR expression， thereby inducing a reduction in the viability of steatosis hepatocytes.

     

    • FullText(HTML)
  • loading
    • References(30)
  • [1]
    ESLAM M, SANYAL AJ, GEORGE J. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease[J]. Gastroenterology, 2020, 158( 7): 1999- 2014. DOI: 10.1053/j.gastro.2019.11.312.
    [2]
    COBBINA E, AKHLAGHI F. Non-alcoholic fatty liver disease(NAFLD)-pathogenesis, classification, and effect on drug metabolizing enzymes and transporters[J]. Drug Metab Rev, 2017, 49( 2): 197- 211. DOI: 10.1080/03602532.2017.1293683.
    [3]
    DEPRINCE A, HAAS JT, STAELS B. Dysregulated lipid metabolism links NAFLD to cardiovascular disease[J]. Mol Metab, 2020, 42: 101092. DOI: 10.1016/j.molmet.2020.101092.
    [4]
    ALVES-BEZERRA M, COHEN DE. Triglyceride metabolism in the liver[J]. Compr Physiol, 2017, 8( 1): 1- 8. DOI: 10.1002/cphy.c170012.
    [5]
    CHÁVEZ-TALAVERA O, TAILLEUX A, LEFEBVRE P, et al. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease[J]. Gastroenterology, 2017, 152( 7): 1679- 1694. DOI: 10.1053/j.gastro.2017.01.055.
    [6]
    WANG XW, SEED B. A PCR primer bank for quantitative gene expression analysis[J]. Nucleic Acids Res, 2003, 31( 24): e154. DOI: 10.1093/nar/gng154.
    [7]
    O'LEARY NA, WRIGHT MW, BRISTER JR, et al. Reference sequence(RefSeq) database at NCBI: Current status, taxonomic expansion, and functional annotation[J]. Nucleic Acids Res, 2016, 44( D1): D733- D745. DOI: 10.1093/nar/gkv1189.
    [8]
    YOUNOSSI ZM, RINELLA ME, SANYAL AJ, et al. From NAFLD to MAFLD: Implications of a premature change in terminology[J]. Hepatology, 2021, 73( 3): 1194- 1198. DOI: 10.1002/hep.31420.
    [9]
    Italian Association for the Study of the Liver(AISF). AISF position paper on nonalcoholic fatty liver disease(NAFLD): Updates and future directions[J]. Dig Liver Dis, 2017, 49( 5): 471- 483. DOI: 10.1016/j.dld.2017.01.147.
    [10]
    JIANG TT, SUN FF, ZENG Z, et al. Progress on metabolic associated fatty liver disease related liver cancer[J/CD]. Chin J Liver Dis(Electronic Version), 2022, 14( 3): 14- 17. DOI: 10.3969/j.issn.1674-7380.2022.03.004.

    蒋婷婷, 孙芳芳, 曾湛, 等. 代谢相关脂肪性肝病相关肝癌研究进展[J/CD]. 中国肝脏病杂志(电子版), 2022, 14( 3): 14- 17. DOI: 10.3969/j.issn.1674-7380.2022.03.004.
    [11]
    RIZZOLO D, BUCKLEY K, KONG B, et al. Bile acid homeostasis in a cholesterol 7α-hydroxylase and sterol 27-hydroxylase double knockout mouse model[J]. Hepatology, 2019, 70( 1): 389- 402. DOI: 10.1002/hep.30612.
    [12]
    WATANABE S, FUJITA K. Dietary hyodeoxycholic acid exerts hypolipidemic effects by reducing farnesoid X receptor antagonist bile acids in mouse enterohepatic tissues[J]. Lipids, 2014, 49( 10): 963- 973. DOI: 10.1007/s11745-014-3947-y.
    [13]
    SONG M, MA XY, ZHANG FL, et al. Effects of hyodeoxycholic acid on growth performance, energy metabolism and fat digestion and absorption of mice[J]. Chin J Anim Nutr, 2022, 34( 6): 3983- 3990. DOI: 10.3969/j.issn.1006-267x.2022.06.057.

    宋敏, 马现永, 张枫琳, 等. 猪去氧胆酸对小鼠生长性能、能量代谢及脂肪消化吸收的影响[J]. 动物营养学报, 2022, 34( 6): 3983- 3990. DOI: 10.3969/j.issn.1006-267x.2022.06.057.
    [14]
    SEHAYEK E, ONO JG, DUNCAN EM, et al. Hyodeoxycholic acid efficiently suppresses atherosclerosis formation and plasma cholesterol levels in mice[J]. J Lipid Res, 2001, 42( 8): 1250- 1256.
    [15]
    SHIH DM, SHAPOSHNIK Z, MENG YH, et al. Hyodeoxycholic acid improves HDL function and inhibits atherosclerotic lesion formation in LDLR-knockout mice[J]. FASEB J, 2013, 27( 9): 3805- 3817. DOI: 10.1096/fj.12-223008.
    [16]
    FORMAN BM, GOODE E, CHEN J, et al. Identification of a nuclear receptor that is activated by farnesol metabolites[J]. Cell, 1995, 81( 5): 687- 693. DOI: 10.1016/0092-8674(95)90530-8.
    [17]
    PELLICCIARI R, COSTANTINO G, FIORUCCI S. Farnesoid X receptor: From structure to potential clinical applications[J]. J Med Chem, 2005, 48( 17): 5383- 5403. DOI: 10.1021/jm0582221.
    [18]
    PARKS DJ, BLANCHARD SG, BLEDSOE RK, et al. Bile acids: Natural ligands for an orphan nuclear receptor[J]. Science, 1999, 284( 5418): 1365- 1368. DOI: 10.1126/science.284.5418.1365.
    [19]
    DOWNES M, VERDECIA MA, ROECKER AJ, et al. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR[J]. Mol Cell, 2003, 11( 4): 1079- 1092. DOI: 10.1016/s1097-2765(03)00104-7.
    [20]
    PELLICCIARI R, FIORUCCI S, CAMAIONI E, et al. 6alpha-ethyl-chenodeoxycholic acid(6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity[J]. J Med Chem, 2002, 45( 17): 3569- 3572. DOI: 10.1021/jm025529g.
    [21]
    SAYIN S, WAHLSTRÖM A, FELIN J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist[J]. Cell Metab, 2013, 17( 2): 225- 235. DOI: 10.1016/j.cmet.2013.01.003.
    [22]
    SUN LL, XIE C, WANG G, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin[J]. Nat Med, 2018, 24( 12): 1919- 1929. DOI: 10.1038/s41591-018-0222-4.
    [23]
    CHIANG JYL, FERRELL JM. Bile acids as metabolic regulators and nutrient sensors[J]. Annu Rev Nutr, 2019, 39: 175- 200. DOI: 10.1146/annurev-nutr-082018-124344.
    [24]
    MUELLER M, THORELL A, CLAUDEL T, et al. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity[J]. J Hepatol, 2015, 62( 6): 1398- 1404. DOI: 10.1016/j.jhep.2014.12.034.
    [25]
    HARRISON SA, BASHIR MR, LEE KJ, et al. A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis[J]. J Hepatol, 2021, 75( 1): 25- 33. DOI: 10.1016/j.jhep.2021.01.047.
    [26]
    HAN CY, RHO HS, KIM A, et al. FXR inhibits endoplasmic reticulum stress-induced NLRP3 inflammasome in hepatocytes and ameliorates liver injury[J]. Cell Rep, 2018, 24( 11): 2985- 2999. DOI: 10.1016/j.celrep.2018.07.068.
    [27]
    JUNG K, KIM M, SO J, et al. Farnesoid X receptor activation impairs liver progenitor cell-mediated liver regeneration via the PTEN-PI3K-AKT-mTOR axis in zebrafish[J]. Hepatology, 2021, 74( 1): 397- 410. DOI: 10.1002/hep.31679.
    [28]
    FRIEDMAN ES, LI Y, SHEN TC D, et al. FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid[J]. Gastroenterology, 2018, 155( 6): 1741- 1752. DOI: 10.1053/j.gastro.2018.08.022.
    [29]
    MAKRI E, CHOLONGITAS E, TZIOMALOS K. Emerging role of obeticholic acid in the management of nonalcoholic fatty liver disease[J]. World J Gastroenterol, 2016, 22( 41): 9039- 9043. DOI: 10.3748/wjg.v22.i41.9039.
    [30]
    XU J, YAO X, LI X, et al. Farnesoid X receptor regulates PI3K/AKT/mTOR signaling pathway, lipid metabolism, and immune response in hybrid grouper[J]. Fish Physiol Biochem, 2022, 48( 6): 1521- 1538. DOI: 10.1007/s10695-022-01130-z.
    • 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(6)  / Tables(2)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (301) PDF downloads(44) 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