Mechanism of 1，25（OH）<sub>2</sub>D<sub>3</sub> improving liver inflammation in a rat model of nonalcoholic steatohepatitis induced by choline-deficient L-amino acid-defined diet

Haiyang ZHU; Jingshu CUI; Liu YANG; Mengting ZHOU; Jian TONG; Hongmei HAN

doi:10.12449/JCH250210

Volume 41 Issue 2

Feb. 2025

Turn off MathJax

Article Contents

Abstract

References

Article Navigation > Journal of Clinical Hepatology > 2025 > 41(2): 254-262

PDF( 4284 KB)

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

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.
- Non-alcoholic Steatohepatitis,
- Calcitriol,
- Inflammation,
- PPAR gamma,
- Rats， Wistar

FullText(HTML)

References(30)

References

[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

[1]	Enrui XIA, Gege TIAN, Suyan ZHANG, Shunzhen ZHANG. Effect of Quzhi Ruangan prescription on the farnesoid X receptor-fibroblast growth factor 19 pathway in rats with nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2022, 38(5): 1069-1074. doi: 10.3969/j.issn.1001-5256.2022.05.018
[2]	QIAN ShuaiJie, GU JingYue, GAO JinHang, TONG Huan. Advances in therapeutic drugs for nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2020, 36(12): 2826-2830. doi: 10.3969/j.issn.1001-5256.2020.12.039
[3]	Zhang LiHui, Zhang JianBo, Zhao WenXia. Effect of Huatan Qushi Huoxue prescription on the key proteins of the ADPN/PI3K/Akt signaling pathway in rats with nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2020, 36(4): 835-839. doi: 10.3969/j.issn.1001-5256.2020.04.025
[4]	Song QingLian, Tan YuE, Liu JingJing, Yuan BeiBei, Li Min, He LiQin, Dai GuangRong. Establishment of a rat model of nonalcoholic steatohepatitis and histopathological changes of the pancreas and the kidney[J]. Journal of Clinical Hepatology, 2020, 36(1): 140-144. doi: 10.3969/j.issn.1001-5256.2020.01.031
[5]	Chen Jun, Li LiangPing, Fu WanZhi. Value of microparticles in the diagnosis of nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2019, 35(9): 2026-2031. doi: 10.3969/j.issn.1001-5256.2019.09.028
[6]	Guo Yan, Huang Li, Yang GuoChao, Liu Shan, Du LinNa, Wang MinJuan. Association between nonalcoholic fatty liver disease and dietary inflammation index and its practical significance[J]. Journal of Clinical Hepatology, 2019, 35(10): 2324-2326. doi: 10.3969/j.issn.1001-5256.2019.10.042
[7]	Zhou QingLi, Xu ZhenYuan, Zhang SuYan, Shi AnHua, Zhang ShunZhen. The role of the NOD-like receptor family, pyrin domain-containing protein 3 inflammasome in nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2019, 35(6): 1380-1383. doi: 10.3969/j.issn.1001-5256.2019.06.045
[8]	Zhang ChaoXian, Guo LiKe, Zhang LiLi, Li GuangYan, Chang TingMin. Interaction between Helicobacter pylori infection and polymorphisms of PPAR-γ2 gene Pro12Ala and GPx-1 gene Pro198Leu and its association with nonalcoholic fatty liver disease[J]. Journal of Clinical Hepatology, 2019, 35(7): 1551-1559. doi: 10.3969/j.issn.1001-5256.2019.07.026
[9]	Jiang Yu, Hu JuLong, Ma JiaLi, Li Ping, Zhou YuLing, Liang XiuXia, Ai ZhengLin, Yao ShuKun. Antioxidant effect of berberine in a rat model of nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2018, 34(6): 1273-1276. doi: 10.3969/j.issn.1001-5256.2018.06.028
[10]	Hu MengQi, Xu YouQing, Zhang Tao, Xu HongTuan. Research advances in noninvasive diagnostic methods for nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2017, 33(12): 2288-2291. doi: 10.3969/j.issn.1001-5256.2017.12.006
[11]	Zhao WenXia, Yan Le, Shao MingYi, Zhang LiHui. Effect of Huatan Qushi Huoxue prescription on the ADPN/AMPK/ACC signaling pathway in rats with nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2017, 33(5): 932-936. doi: 10.3969/j.issn.1001-5256.2017.05.029
[12]	Zhu JuanJuan, Cheng MingLiang, Zhao XueKe. Role of liver immunological inflammation in development and progression of nonalcoholic fatty liver disease[J]. Journal of Clinical Hepatology, 2016, 32(3): 570-573. doi: 10.3969/j.issn.1001-5256.2016.03.038
[13]	Ding Jie, Wang Liang, Li Juan, Kong Yin, Zhao Rui, He JingJing, Li GuangMing, Wang JuanXia, Zhang LingYi. Changes in serum asymmetric dimethylarginine levels in progression of liver inflammation in an experimental rat model of nonalcoholic fatty liver disease[J]. Journal of Clinical Hepatology, 2016, 32(1): 148-151. doi: 10.3969/j.issn.1001-5256.2016.01.029
[14]	Xin Xuan, Yan HongZhu, Li WeiQing, Yu HongYu. Studies on PPAR α and γ participating in progression of liver fibrosis by regulating ACSL1[J]. Journal of Clinical Hepatology, 2014, 30(7): 700-702. doi: 10.3969/j.issn.1001-5256.2014.07.034
[15]	Xin Xuan, Yan HongZhu, Li WeiQing, Yu HongYu. Studies on PPAR α and γ participating in progression of liver fibrosis by regulating ACSL1[J]. Journal of Clinical Hepatology, 2014, 30(8): 833-835. doi: 10.3969/j.issn.1001-5256.2014.08.038
[16]	Cheng Rui, Cai XinRan, Zhou HaoHui, Han ShengHua, Zhu JinHai, Chen HuiXing, Chen YanLing. Omega-3 polyunsaturated fatty acids inhibit inflammation during the early stage of acute pancreatitis[J]. Journal of Clinical Hepatology, 2012, 28(8): 598-602.
[17]	Chen Jie, Ceng LingLan, Wang Hua, Liu Chao. Effects of asiatic acid on the expression of mRNA of smad7 and PPARγ in HSC-T6 in vitro[J]. Journal of Clinical Hepatology, 2011, 27(3): 251-253+264.
[18]	Huang Ning, Wu WanChun. The effect of low iron loads on Nonalcoholic Steatohepatitis in rats[J]. Journal of Clinical Hepatology, 2009, 25(6): 427-430.
[19]	Wang HuiChao, Ye HongJun, Wei ShiLiang, Liu XiaoYi, Wan HuiJuan, Du YiPing. Therapeutic effects of compound glycyrrhizin liposome on rats with nonalcoholic steatohepatitis.[J]. Journal of Clinical Hepatology, 2008, 24(3): 199-201.
[20]	Xu Hui, Wen QinSheng, Wang XuXia, Zhang YaFei, Li Jun, Gu BingQuan. The effect of cimetidine on the blood sugar, serum insulin and other indexes in NASH rats[J]. Journal of Clinical Hepatology, 2007, 23(2): 112-114.

Supplements(0)

Cited By

Proportional views

Proportional views

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

Figures(6) / Tables(2)

Get Citation

PDF

XML

Article Metrics

Article views (138) PDF downloads(14)

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

Abstract

References

Relative Articles

Proportional views

Catalog

通讯作者: 陈斌, bchen63@163.com

Article Metrics

Proportional views

Related

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

Abstract

References

Relative Articles

Proportional views

Catalog

通讯作者: 陈斌, bchen63@163.com

Article Metrics

Proportional views

Related

About Journal

Submission Guideline

Journal Online

Hepatobiliary College

Guidelines

Export File

Citation

Format

Content

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