中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 41 Issue 6
Jun.  2025
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2025  >  41(6): 1097-1104

Effect of prolyl endopeptidase expression inhibition on a mouse model of non-alcoholic steatohepatitis and its mechanism

DOI: 10.12449/JCH250615
  • 1.

    Department of Gastroenterology，The Seventh Affiliated Hospital of Xinjiang Medical University，Urumqi 830028，China

  • 2.

    Infectious Disease Center of The First Affiliated Hospital of Xinjiang Medical University，Urumqi 830054，China

Research funding:

Natural Science Foundation of Xinjiang Uygur Autonomous Region (2022D01A139)

More Information
  • Corresponding author: XIONG Jingping， 469993008@qq.com （ORCID： 0009-0005-0654-9920）
  • Received Date: 2024-11-19
  • Accepted Date: 2025-03-03
  • Published Date: 2025-06-25
    Abstract
  •   Objective  To investigate the effect and possible mechanism of prolyl endopeptidase （PREP） on a mouse model of non-alcoholic steatohepatitis （NASH） induced by high-fat diet.  Methods  A total of 18 healthy male C57BL/6J mice， aged 6‍ ‍—‍ ‍8 weeks， were randomly divided into normal control group， NASH group， and NASH+rosmarinic acid （RA） group， with 6 mice in each group. The mice in the control group were fed with normal diet for 16 weeks， and those in the NASH group and the NASH+RA group were fed with high-fat diet for 16 weeks； the mice in the NASH+RA group were given the PREP inhibitor RA by gavage since week 9 at a dose of 100 mg/kg， once a day for 8 weeks. The mice were sacrificed after modeling and intervention， and each group of mice was observed in terms of serum inflammatory indicators， the concentration of triglyceride in the liver， and the changes in liver lipids/inflammation/liver fibrosis； NAFLD activity score （NAS） was calculated. Western blot and quantitative real-time PCR were used to measure the protein and mRNA expression levels of PREP， peroxisome proliferator-activated receptor-γ （PPAR-γ）， fibroblast growth factor 21 （FGF21）， and silent information regulator 1 （SIRT1） in liver tissue. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups， while the least significant difference t-test and the Dunnett’s-T3 test were used for further comparison between two groups. The Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups and further comparison between two groups.  Results  Compared with the NASH group， the NASH+RA group had significant reductions in the serum levels of interleukin-6， tumor necrosis factor-α， and triglyceride （all P<0.05）， as well as significant improvements in hepatic steatosis， hepatocyte edema， inflammatory cell infiltration， and liver tissue lesion. The NASH+RA group had a significant reduction in NAS compared with the NASH group （P<0.05）， and the NASH group had an increase in perivascular collagen fiber with occasional fiber bridging， while the NASH+RA group had a slight reduction in perivascular collagen fiber compared with the NASH group. Compared with the normal control group， the NASH group had a significant increase in collagen area percentage in the liver （P<0.05）， while the NASH+RA group had no significant reduction in collagen area percentage compared with the NASH group. Compared with the NASH group， the NASH+RA group had significant increases in the relative protein expression levels of PPAR-γ， FGF21， and SIRT1 （all P<0.05） and a significant reduction in the relative protein expression level of PREP （P<0.05）. Compared with the NASH group， the NASH+RA group had significant increases in the relative mRNA expression levels of PPAR-γ， FGF21， and SIRT1 （P<0.05） and a significant reduction in the relative mRNA expression level of PREP （P<0.05）.  Conclusion  PREP reduces the level of inflammation and improves NASH in mice by regulating the PPAR-γ/FGF21/SIRT1 signaling pathway.

     

    • FullText(HTML)
  • loading
    • References(24)
  • [1]
    RONG L, ZOU JY, RAN W, et al. Advancements in the treatment of non-alcoholic fatty liver disease(NAFLD)[J]. Front Endocrinol(Lausanne), 2023, 13: 1087260. DOI: 10.3389/fendo.2022.1087260.
    [2]
    ALMOMANI A, KUMAR P, ONWUZO S, et al. Epidemiology and prevalence of lean nonalcoholic fatty liver disease and associated cirrhosis, hepatocellular carcinoma, and cardiovascular outcomes in the United States: A population-based study and review of literature[J]. J Gastroenterol Hepatol, 2023, 38( 2): 269- 273. DOI: 10.1111/jgh.16049.
    [3]
    TANG HY, LV FR, ZHANG P, et al. The impact of obstructive sleep apnea on nonalcoholic fatty liver disease[J]. Front Endocrinol(Lausanne), 2023, 14: 1254459. DOI: 10.3389/fendo.2023.1254459.
    [4]
    IBRAHIM MK, SIMON TG, RINELLA ME. Extrahepatic outcomes of nonalcoholic fatty liver disease: Nonhepatocellular cancers[J]. Clin Liver Dis, 2023, 27( 2): 251- 273. DOI: 10.1016/j.cld.2023.01.004.
    [5]
    PAIK JM, HENRY L, YOUNOSSI Y, et al. The burden of nonalcoholic fatty liver disease(NAFLD) is rapidly growing in every region of the world from 1990 to 2019[J]. Hepatol Commun, 2023, 7( 10): e0251. DOI: 10.1097/HC9.0000000000000251.
    [6]
    YOUNOSSI ZM, GOLABI P, PAIK JM, et al. The global epidemiology of nonalcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis(NASH): A systematic review[J]. Hepatology, 2023, 77( 4): 1335- 1347. DOI: 10.1097/HEP.0000000000000004.
    [7]
    LU R, LIU Y, HONG TP. Epidemiological characteristics and management of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in China: A narrative review[J]. Diabetes Obes Metab, 2023, 25( Suppl 1): 13- 26. DOI: 10.1111/dom.15014.
    [8]
    NI WJ, GENG N, BAI X, et al. An excerpt of EASL-EASD-EASO clinical practice guidelines on the management of metabolic dysfunctionassociated steatotic liver disease in 2024[J]. J Clin Hepatol, 2024, 40( 8): 1567- 1574. DOI: 10.12449/JCH240810.

    倪文婧, 耿楠, 白雪, 等.《2024年欧洲肝病学会/欧洲糖尿病学会/欧洲肥胖症学会临床实践指南: 代谢相关脂肪性肝病的管理》摘译[J]. 临床肝胆病杂志, 2024, 40( 8): 1567- 1574. DOI: 10.12449/JCH240810.
    [9]
    BABKOVA K, KORABECNY J, SOUKUP O, et al. Prolyl oligopeptidase and its role in the organism: Attention to the most promising and clinically relevant inhibitors[J]. Future Med Chem, 2017, 9( 10): 1015- 1038. DOI: 10.4155/fmc-2017-0030.
    [10]
    LI MT, JIANG DX, ZHANG JB, et al. Effects of sodium valproate on the progression of non-alcoholic fatty liver disease by inhibiting prolyl endopeptidase activity[J]. J Wenzhou Med Univ, 2022, 52( 8): 657- 662. DOI: 10.3969/j.issn.2095-9400.2022.08.009.

    李梦婷, 蒋黛西, 张建斌, 等. 丙戊酸钠抑制脯氨酰内肽酶活性对非酒精性脂肪性肝病进展的影响[J]. 温州医科大学学报, 2022, 52( 8): 657- 662. DOI: 10.3969/j.issn.2095-9400.2022.08.009.
    [11]
    JIANG DX, ZHANG JB, LI MT, et al. Prolyl endopeptidase gene disruption attenuates high fat diet-induced nonalcoholic fatty liver disease in mice by improving hepatic steatosis and inflammation[J]. Ann Transl Med, 2020, 8( 5): 218. DOI: 10.21037/atm.2020.01.14.
    [12]
    ZHOU D, LI BH, WANG J, et al. Prolyl oligopeptidase inhibition attenuates steatosis in the L02 human liver cell line[J]. PLoS One, 2016, 11( 10): e0165224. DOI: 10.1371/journal.pone.0165224.
    [13]
    SAMUEL VT, SHULMAN GI. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases[J]. Cell Metab, 2018, 27( 1): 22- 41. DOI: 10.1016/j.cmet.2017.08.002.
    [14]
    WANG ZY, SUN TT, YU JJ, et al. FGF21: A sharp weapon in the process of exercise to improve NAFLD[J]. Front Biosci(Landmark Ed), 2023, 28( 12): 351. DOI: 10.31083/j.fbl2812351.
    [15]
    BARROSO LN, SALARINI J, LEITE NC, et al. Effect of fish oil supplementation on the concentration of miRNA-122, FGF-21 and liver fibrosis in patients with NAFLD: Study protocol for a randomized, double-blind and placebo-controlled clinical trial[J]. Clin Nutr ESPEN, 2023, 57: 117- 125. DOI: 10.1016/j.clnesp.2023.06.027.
    [16]
    NAN Y, XIANGLI W, ZHANG W, et al. FGF21 inhibits lipid accumulation and inflammation induced by palmitate in human hepatocytes via SIRT1 pathway[J]. Chin J Cell Mol Immunol, 2019, 35( 7): 606- 612. DOI: 10.13423/j.cnki.cjcmi.008839.

    南瑛, 相里伟, 张薇, 等. 成纤维细胞生长因子21(FGF21)通过SIRT1通路抑制棕榈酸酯诱导的人肝细胞脂肪堆积和炎症反应[J]. 细胞与分子免疫学杂志, 2019, 35( 7): 606- 612. DOI: 10.13423/j.cnki.cjcmi.008839.
    [17]
    WU YS. Exosomes derived from lipotoxic hepatocytes in inducing LSEC capillarization and promoting the progression of non-alcoholic fatty liver disease[D]. Zhenjiang: Jiangsu University, 2022.

    武艳霜. 脂毒性损伤肝细胞分泌外泌体诱导LSEC毛细血管化促进NAFLD进展[D]. 镇江: 江苏大学, 2022.
    [18]
    LI YQ, TANG WJ, ZHOU YJ. Role of intestinal microbiota and metabolites in the development, progression, and treatment of nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2023, 39( 8): 1805- 1810. DOI: 10.3969/j.issn.1001-5256.2023.08.006.

    李永强, 唐文娟, 周永健. 肠道菌群及其代谢产物在非酒精性脂肪性肝病发生发展及治疗中的作用[J]. 临床肝胆病杂志, 2023, 39( 8): 1805- 1810. DOI: 10.3969/j.issn.1001-5256.2023.08.006.
    [19]
    YIN JY, WANG Q. Progress on adipokines in non-alcoholic fatty liver disease[J/CD]. Chin J Liver Dis(Electronic Version), 2023, 15( 1): 1- 5. DOI: 10.3969/j.issn.1674-7380.2023.01.001.

    尹静亚, 王琦. 脂肪因子在非酒精性脂肪性肝病中研究进展[J/CD]. 中国肝脏病杂志(电子版), 2023, 15( 1): 1- 5. DOI: 10.3969/j.issn.1674-7380.2023.01.001.
    [20]
    HÖFLING C, KULESSKAYA N, JAAKO K, et al. Deficiency of prolyl oligopeptidase in mice disturbs synaptic plasticity and reduces anxiety-like behaviour, body weight, and brain volume[J]. Eur Neuropsychopharmacol, 2016, 26( 6): 1048- 1061. DOI: 10.1016/j.euroneuro.2016.02.015.
    [21]
    RAPTIS DD, MANTZOROS CS, POLYZOS SA. Fibroblast growth factor-21 as a potential therapeutic target of nonalcoholic fatty liver disease[J]. Ther Clin Risk Manag, 2023, 19: 77- 96. DOI: 10.2147/TCRM.S352008.
    [22]
    YANG XN, JIN ZQ, LIN DF, et al. FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway[J]. J Cell Mol Med, 2022, 26( 3): 868- 879. DOI: 10.1111/jcmm.17144.
    [23]
    HAN JX, LI SW, WANG WZ, et al. SIRT1 activator E1231 alleviates nonalcoholic fatty liver disease by regulating lipid metabolism[J]. Curr Issues Mol Biol, 2023, 45( 6): 5052- 5070. DOI: 10.3390/cimb45060321.
    [24]
    CHEN H, TAN HB, WAN J, et al. PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets[J]. Pharmacol Ther, 2023, 245: 108391. DOI: 10.1016/j.pharmthera.2023.108391.
    • 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(4)  / Tables(5)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (597) PDF downloads(20) 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