中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Menu
Volume 41 Issue 2
Feb.  2025
Turn off MathJax
Article Contents
Abstract
References
Article Navigation >  Journal of Clinical Hepatology  > 2025  >  41(2): 254-262

Mechanism of 1，25（OH）2D3 improving liver inflammation in a rat model of nonalcoholic steatohepatitis induced by choline-deficient L-amino acid-defined diet

DOI: 10.12449/JCH250210
  • a.

    Department of Gastroenterology, The Affiliated Hospital of Yanbian University，Yanji，Jilin 133001，China

  • b.

    Department of Pathology, The Affiliated Hospital of Yanbian University，Yanji，Jilin 133001，China

Research funding:

National Natural Science Foundation of China (81860110)

More Information
  • Corresponding author: HAN Hongmei， hanhm79@126.com （ORCID： 0000-0001-7147-4447）
  • Received Date: 2024-07-01
  • Accepted Date: 2024-09-30
  • Published Date: 2025-02-25
    Abstract
  •   Objective  To investigate the effect of 1，25（OH）2D3 on the level of peroxisome proliferator-activated receptor-γ （PPAR-γ） in the liver， the phenotype of hepatic macrophages， and liver inflammation in a rat model of nonalcoholic steatohepatitis （NASH）， as well as the mechanism of 1，25（OH）2D3 improving liver inflammation.  Methods  After 1 week of adaptive feeding， 24 specific pathogen-free Wistar rats were randomly divided into normal group ［choline-supplemented L-amino acid-defined （CSAA） diet］， normal+1，25（OH）2D3 group ［CSAA diet+1，25（OH）2D3］， model group ［choline-deficient L-amino acid-defined diet （CDAA） diet］， and model+1，25（OH）2D3 group ［CDAA diet+1，25（OH）2D3］， with 6 rats in each group. The dose of 1，25（OH）2D3 was 5 μg/kg for intraperitoneal injection twice a week for 12 weeks. The serum levels of aspartate aminotransferase （AST） and alanine aminotransferase （ALT） were measured， liver histopathology was observed， and SAF score was assessed. M1 hepatic macrophages and M2 hepatic macrophages were measured to analyze in the change in the phenotype of hepatic macrophages， and ELISA was used to measure the levels of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， interleukin-4 （IL-4）， and interleukin-10 （IL-10） in liver tissue， and qPCR was used to measure the mRNA level of PPAR-γ. The two-factor analysis of variance was use for comparison between groups， and the least significant difference t-test was used for further comparison； the Pearson method was used for correlation analysis.  Results  Compared with the normal group， the model rats with CDAA diet-induced NASH had significant increases in the serum levels of AST and ALT （P=0.019 and P<0.001）， the SAF score of liver histopathology （P<0.001）， the level of M1 hepatic macrophages （P<0.001）， and the ratio of M1 and M2 hepatic macrophages （P<0.001）， as well as a significant increase in the level of TNF-α （P<0.001） and a significant reduction in the level of IL-4 in liver tissue （P=0.025）. The 1，25（OH）2D3 group had significant reductions in the serum levels of ALT （P<0.001）， the SAF score of liver histopathology （P<0.001）， the level of M1 hepatic macrophages （P<0.001）， and the ratio of M1 and M2 hepatic macrophages （P=0.001）， the level of IL-1β （P<0.001） and a significant increase in the level of M2 hepatic macrophages （P=0.017）， the level of IL-10 （P=0.039）， the level of IL-4 （P<0.001）， the level of PPAR-γ （P=0.016）. There were significant interactions between CDAA diet-induced NASH model and 1，25（OH）2D3 in serum the levels of AST and ALT （P=0.007 and P=0.008）， the SAF scores of liver histopathology （P<0.001）， the level of M1 hepatic macrophages （P<0.001）， the level of M2 hepatic macrophages （P=0.008）， the ratio of M1 and M2 of hepatic macrophages （P=0.005）， the level of TNF-α （P<0.001）， the level of IL-10 （P=0.038）， the level of IL-4 （P<0.001） and the level of PPAR-γ （P=0.009）. The correlation analysis showed that PPAR-γ was negatively correlated with the ratio of M1 and M2 hepatic macrophages （r=-0.415， P=0.044） and was positively correlated with M2 hepatic macrophages （r=0.435， P=0.033）， IL-10 （r=0.433， P=0.035）， and IL-4 （r=0.532， P=0.007）.  Conclusion  This study shows that 1，25（OH）2D3 improves liver inflammation in NASH by activating PPAR-γ to regulate the phenotypic transformation of hepatic macrophages.

     

    • FullText(HTML)
    • References(30)
  • [1]
    MA KF, CHEN YH, LIANG XG, et al. Inhibition of 5-lipoxygenase inhibitor zileuton in high-fat diet-induced nonalcoholic fatty liver disease progression model[J]. Iran J Basic Med Sci, 2017, 20( 11): 1207- 1212. DOI: 10.22038/IJBMS.2017.9482.
    [2]
    YOUNOSSI ZM, KOENIG AB, ABDELATIF D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology, 2016, 64( 1): 73- 84. DOI: 10.1002/hep.28431.
    [3]
    TAKEGOSHI K, HONDA M, OKADA H, et al. Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model[J]. Oncotarget, 2017, 8( 11): 18191- 18205. DOI: 10.18632/oncotarget.15304.
    [4]
    MIURA K, ISHIOKA M, IIJIMA K. The roles of the gut microbiota and toll-like receptors in obesity and nonalcoholic fatty liver disease[J]. J Obes Metab Syndr, 2017, 26( 2): 86- 96. DOI: 10.7570/jomes.2017.26.2.86.
    [5]
    REMMERIE A, MARTENS L, SCOTT CL. Macrophage subsets in obesity, aligning the liver and adipose tissue[J]. Front Endocrinol(Lausanne), 2020, 11: 259. DOI: 10.3389/fendo.2020.00259.
    [6]
    DUARTE N, COELHO IC, PATARRÃO RS, et al. How inflammation impinges on NAFLD: A role for kupffer cells[J]. Biomed Res Int, 2015, 2015: 984578. DOI: 10.1155/2015/984578.
    [7]
    RANNOU E, FRANÇOIS A, TOULLEC A, et al. In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury[J]. Sci Rep, 2015, 5: 15738. DOI: 10.1038/srep15738.
    [8]
    TANG DS, CAO F, YAN CS, et al. Extracellular vesicle/macrophage axis: Potential targets for inflammatory disease intervention[J]. Front Immunol, 2022, 13: 705472. DOI: 10.3389/fimmu.2022.705472.
    [9]
    NI YH, NAGASHIMADA M, ZHAN LL, et al. Prevention and reversal of lipotoxicity-induced hepatic insulin resistance and steatohepatitis in mice by an antioxidant carotenoid, β-cryptoxanthin[J]. Endocrinology, 2015, 156( 3): 987- 999. DOI: 10.1210/en.2014-1776.
    [10]
    HAN H, CUI M, YOU X, et al. A role of 1, 25(OH)2D3 supplementation in rats with nonalcoholic steatohepatitis induced by choline-deficient diet[J]. Nutr Metab Cardiovasc Dis, 2015, 25( 6): 556- 561. DOI: 10.1016/j.numecd.2015.02.011.
    [11]
    LUO WJ, XU QY, WANG Q, et al. Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease[J]. Sci Rep, 2017, 7: 44612. DOI: 10.1038/srep44612.
    [12]
    ZHANG XL, ZHOU M, GUO YF, et al. 1, 25-dihydroxyvitamin D₃ promotes high glucose-induced M1 macrophage switching to M2 via the VDR-PPARγ signaling pathway[J]. Biomed Res Int, 2015, 2015: 157834. DOI: 10.1155/2015/157834.
    [13]
    European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity. 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.
    [14]
    BEDOSSA P, PATHOLOGY CONSORTIUM FLIP. Utility and appropriateness of the fatty liver inhibition of progression(FLIP) algorithm and steatosis, activity, and fibrosis(SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease[J]. Hepatology, 2014, 60( 2): 565- 575. DOI: 10.1002/hep.27173.
    [15]
    YANG YM, WANG ZJ, MATSUDA M, et al. Inhibition of hyaluronan synthesis by 4-methylumbelliferone ameliorates non-alcoholic steatohepatitis in choline-deficient L-amino acid-defined diet-induced murine model[J]. Arch Pharm Res, 2021, 44( 2): 230- 240. DOI: 10.1007/s12272-021-01309-7.
    [16]
    NAKANISHI K, KAJI K, KITADE M, et al. Exogenous administration of low-dose lipopolysaccharide potentiates liver fibrosis in a choline-deficient l-amino-acid-defined diet-induced murine steatohepatitis model[J]. Int J Mol Sci, 2019, 20( 11): 2724. DOI: 10.3390/ijms20112724.
    [17]
    KUCSERA D, TÓTH VE, GERGŐ D, et al. Characterization of the CDAA diet-induced non-alcoholic steatohepatitis model: Sex-specific differences in inflammation, fibrosis, and cholesterol metabolism in middle-aged mice[J]. Front Physiol, 2021, 12: 609465. DOI: 10.3389/fphys.2021.609465.
    [18]
    POVERO D, EGUCHI A, LI HY, et al. Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease[J]. PLoS One, 2014, 9( 12): e113651. DOI: 10.1371/journal.pone.0113651.
    [19]
    XU L, KITADE H, NI YH, et al. Roles of chemokines and chemokine receptors in obesity-associated insulin resistance and nonalcoholic fatty liver disease[J]. Biomolecules, 2015, 5( 3): 1563- 1579. DOI: 10.3390/biom5031563.
    [20]
    VONGHIA L, MAGRONE T, VERRIJKEN A, et al. Peripheral and hepatic vein cytokine levels in correlation with non-alcoholic fatty liver disease(NAFLD)-related metabolic, histological, and haemodynamic features[J]. PLoS One, 2015, 10( 11): e0143380. DOI: 10.1371/journal.pone.0143380.
    [21]
    CIMINI FA, BARCHETTA I, CAROTTI S, et al. Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease[J]. World J Gastroenterol, 2017, 23( 19): 3407- 3417. DOI: 10.3748/wjg.v23.i19.3407.
    [22]
    NELSON JE, ROTH CL, WILSON LA, et al. Vitamin D deficiency is associated with increased risk of non-alcoholic steatohepatitis in adults with non-alcoholic fatty liver disease: Possible role for MAPK and NF-κB?[J]. Am J Gastroenterol, 2016, 111( 6): 852- 863. DOI: 10.1038/ajg.2016.51.
    [23]
    ZHANG HW, LIU YM, FANG X, et al. Vitamin D3 protects mice from diquat-induced oxidative stress through the NF-κB/Nrf2/HO-1 signaling pathway[J]. Oxid Med Cell Longev, 2021, 2021: 6776956. DOI: 10.1155/2021/6776956.
    [24]
    KHEDER R, HOBKIRK J, SAEED Z, et al. Vitamin D3 supplementation of a high fat high sugar diet ameliorates prediabetic phenotype in female LDLR-/- and LDLR+/+ mice[J]. Immun Inflamm Dis, 2017, 5( 2): 151- 162. DOI: 10.1002/iid3.154.
    [25]
    REDA D, ELSHOPAKEY GE, ALBUKHARI TA, et al. Vitamin D3 alleviates nonalcoholic fatty liver disease in rats by inhibiting hepatic oxidative stress and inflammation via the SREBP-1-c/PPARα-NF-κB/IR-S2 signaling pathway[J]. Front Pharmacol, 2023, 14: 1164512. DOI: 10.3389/fphar.2023.1164512.
    [26]
    YIN Y, YU ZW, XIA M, et al. Vitamin D attenuates high fat diet-induced hepatic steatosis in rats by modulating lipid metabolism[J]. Eur J Clin Invest, 2012, 42( 11): 1189- 1196. DOI: 10.1111/j.1365-2362.2012.02706.x.
    [27]
    ZHANG XL, GUO YF, SONG ZX, et al. Vitamin D prevents podocyte injury via regulation of macrophage M1/M2 phenotype in diabetic nephropathy rats[J]. Endocrinology, 2014, 155( 12): 4939- 4950. DOI: 10.1210/en.2014-1020.
    [28]
    MU YM, LI JT, KANG JH, et al. A lipid-based nanocarrier containing active vitamin D3 ameliorates NASH in mice via direct and intestine-mediated effects on liver inflammation[J]. Biol Pharm Bull, 2020, 43( 9): 1413- 1420. DOI: 10.1248/bpb.b20-00432.
    [29]
    SHAB-BIDAR S, NEYESTANI TR, DJAZAYERY A, et al. Improvement of vitamin D status resulted in amelioration of biomarkers of systemic inflammation in the subjects with type 2 diabetes[J]. Diabetes Metab Res Rev, 2012, 28( 5): 424- 430. DOI: 10.1002/dmrr.2290.
    [30]
    KOMISARENKO YI, BOBRYK MI. Vitamin D deficiency and immune disorders in combined endocrine pathology[J]. Front Endocrinol(Lausanne), 2018, 9: 600. DOI: 10.3389/fendo.2018.00600.
    • 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 (147) PDF downloads(15) 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[2052]YesterdayPV[3500]TodayIP[593]TodayPV[949]Online[106]

    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