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ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 37 Issue 4
Apr.  2021
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Article Navigation >  Journal of Clinical Hepatology  > 2021  >  37(4): 857-862

Role of STAT3 in hepatocyte regeneration after acetaminophen-induced hepatocellular injury in mice

DOI: 10.3969/j.issn.1001-5256.2021.04.026

  • Department of Gastroenterology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China

  • Received Date: 2020-09-08
  • Accepted Date: 2020-10-26
  • Published Date: 2021-04-20
    Abstract
  •   Objective  To investigate the role of STAT3 in hepatocyte proliferation after acetaminophen (APAP)-induced hepatocellular injury in mice.  Methods  Normal mouse AML12 hepatocytes were cultured in vitro and were stimulated by APAP (1, 2.5, 5, 10, and 20 mmol/L) for 12, 24 or 48 hours, and the hepatocytes treated with an equal volume of phosphate buffered saline were established as control group. After the optimal stimulation concentration and duration of action were screened out, AML12 hepatocytes were treated with AG490 (10, 50, and 100 μmol/L). The CCK-8 assay was used to measure the viability of AML12 hepatocytes; RT-PCR was used to measure the mRNA expression levels of PCNA, CyclinD1, and Ki67 in AML12 hepatocytes, and Western blot was used to measure the protein expression levels of STAT3, p-STAT3, PCNA, and CyclinD1. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups.  Results  After 24 and 48 hours of APAP treatment, compared with the control group, all concentration groups had a significant reduction in the viability of AML12 hepatocytes (all P < 0.05), with a viability of 0.717±0.0271 and 0.752±0.0141, respectively, when the concentration of APAP was 2.5 mmol/L, which was significantly different from that in the control group (all P < 0.05) and met the conditions of subsequent experiment. Compared with the control group, the 24-hour APAP (2.5 mmol/L) group had significant reductions in the mRNA expression of PCNA, CyclinD1, and Ki67 (all P < 0.01); compared with the 24-hour APAP group, the 48-hour APAP (2.5 mmol/L) group had significant increases in the mRNA expression of PCNA, CyclinD1, and Ki67 (all P < 0.01); therefore, a model of hepatocyte regeneration after in vitro AML12 hepatocyte injury was established by stimulation with APAP 2.5 mmol/L for 48 hours. After the addition of AG490, there was no significant difference in viability between the control group and the 10 and 50 μmol/L AG490 groups, and the other groups had a significant reduction in viability (all P < 0.01); compared with the APAP group, the AG490 (50 μmol/L)+APAP group and the AG490 (100 μmol/L)+APAP group had a significant reduction in viability (P < 0.01); therefore, 50 μmol/L AG490 was selected as the concentration for subsequent experiment. Compared with the control group, the APAP group had a significant increase in the protein expression level of p-STAT3 (P < 0.01), while the AG490 group and the APAP+AG490 group had a significant reduction (both P < 0.05); compared with the APAP group, the APAP+AG490 group had significant reductions in the protein expression levels of PCNA and CyclinD1 and the mRNA expression levels of PCNA, CyclinD1, and Ki67 (all P < 0.05).  Conclusion  STAT3 participates in hepatocyte proliferation after APAP-induced hepatocyte injury in mice, while AG490, as an STAT3 inhibitor, can inhibit hepatocyte proliferation after APAP-induced hepatocyte injury by inhibiting the phosphorylation of STAT3.

     

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    • References(19)
  • [1]
    KIM M, YUN JW, SHIN K, et al. Expression levels of GABA-A receptor subunit alpha 3, gabra3 and lipoprotein lipase, lpl are associated with the susceptibility to acetaminophen-induced hepatotoxicity[J]. Biomol Ther (Seoul), 2017, 25(2): 112-121. DOI: 10.4062/biomolther.2016.076
    [2]
    XU LN, LI Y, PENG JY. microRNA and drug-induced liver injury[J]. Chin J Clin Pharmacol Ther, 2020, 25(7): 803-809. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-YLZL202007015.htm

    许丽娜, 李月, 彭金咏. microRNA与药物性肝损伤[J]. 中国临床药理学与治疗学, 2020, 25(7): 803-809. https://www.cnki.com.cn/Article/CJFDTOTAL-YLZL202007015.htm
    [3]
    YAN M, HUO Y, YIN S, et al. Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions[J]. Redox Biol, 2018, 17: 274-283. DOI: 10.1016/j.redox.2018.04.019
    [4]
    XIE Y, MCGILL MR, DU K, et al. Mitochondrial protein adducts formation and mitochondrial dysfunction during N-acetyl-m-aminophenol (AMAP)-induced hepatotoxicity in primary human hepatocytes[J]. Toxicol Appl Pharmacol, 2015, 289(2): 213-222. DOI: 10.1016/j.taap.2015.09.022
    [5]
    LIU FC, LEE HC, LIAO CC, et al. Tropisetron protects against acetaminophen-induced liver injury via suppressing hepatic oxidative stress and modulating the activation of JNK/ERK MAPK pathways[J]. Biomed Res Int, 2016, 2016: 1952947. http://pubmedcentralcanada.ca/pmcc/articles/PMC5116490/
    [6]
    ABDULKHALEQ FM, ALHUSSAINY TM, BADR MM, et al. Antioxidative stress effects of vitamins C, E, and B12, and their combination can protect the liver against acetaminophen-induced hepatotoxicity in rats[J]. Drug Des Devel Ther, 2018, 12: 3525-3533. DOI: 10.2147/DDDT.S172487
    [7]
    YU PF, WU Q, DUAN ZP, et al. Research progress in the mechanism of drug-induced liver injury due to paracetamol[J]. J Clin Hepatol, 2019, 35(9): 2108-2112. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2019.09.050

    余朋飞, 吴桥, 段钟平, 等. 对乙酰氨基酚致药物性肝损伤的机制研究进展[J]. 临床肝胆病杂志, 2019, 35(9): 2108-2112. DOI: 10.3969/j.issn.1001-5256.2019.09.050
    [8]
    BREU AC, PATWARDHAN VR, NAYOR J, et al. A multicenter study into causes of severe acute liver injury[J]. Clin Gastroenterol Hepatol, 2019, 17(6): 1201-1203. DOI: 10.1016/j.cgh.2018.08.016
    [9]
    MOH A, IWAMOTO Y, CHAI GX, et al. Role of STAT3 in liver regeneration: Survival, DNA synthesis, inflammatory reaction and liver mass recovery[J]. Lab Invest, 2007, 87(10): 1018-1028. DOI: 10.1038/labinvest.3700630
    [10]
    ABE M, YOSHIDA T, AKIBA J, et al. STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury[J]. World J Gastroenterol, 2017, 23(37): 6833-6844. DOI: 10.3748/wjg.v23.i37.6833
    [11]
    JUNG J, MOON JW, CHOI JH, et al. Epigenetic alterations of IL-6/STAT3 signaling by placental stem cells promote hepatic regeneration in a rat model with CCl4-induced Liver Injury[J]. Int J Stem Cells, 2015, 8(1): 79-89. DOI: 10.15283/ijsc.2015.8.1.79
    [12]
    RÍO A, GASSULL MA, ALDEGUER X, et al. Reduced liver injury in the interleukin-6 knockout mice by chronic carbon tetrachloride administration[J]. Eur J Clin Invest, 2008, 38(5): 306-316. DOI: 10.1111/j.1365-2362.2008.01939.x
    [13]
    HU Z, HAN Y, LIU Y, et al. CREBZF as a key regulator of STAT3 pathway in the control of liver regeneration in mice[J]. Hepatology, 2020, 71(4): 1421-1436. DOI: 10.1002/hep.30919
    [14]
    SIVEEN KS, SIKKA S, SURANA R, et al. Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors[J]. Biochim Biophys Acta, 2014, 1845(2): 136-154. http://europepmc.org/abstract/med/24388873
    [15]
    BHUSHAN B, APTE U. Liver regeneration after acetaminophen hepatotoxicity: Mechanisms and therapeutic opportunities[J]. Am J Pathol, 2019, 189(4): 719-729. DOI: 10.1016/j.ajpath.2018.12.006
    [16]
    DENG Y, SHI WH, TONG JD, et al. Effects of epigailocatechin-3-gallate on the proliferation and migration of vascular smooth muscle cells induced by platelet-derived growth factor BB in rats[J]. J Fudan Univ(Med Sci), 2018, 45(4): 503-508. (in Chinese) DOI: 10.3969/j.issn.1672-8467.2018.04.011

    邓颖, 史伟浩, 童进东, 等. EGCG对血小板源性生长因子-BB诱导的大鼠血管平滑肌细胞增殖和迁移的影响[J]. 复旦学报(医学版), 2018, 45(4): 503-508. DOI: 10.3969/j.issn.1672-8467.2018.04.011
    [17]
    HUANG J, LIU FR, WEN T, et al. Salidroside affects proliferation, invasion and apoptosis of cervical squamous cell carcinoma C33A cells through JAK2/STAT3 pathway[J]. J Chin Cancer Biother, 2020, 27(5): 522 -527. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-ZLSW202005008.htm

    黄进, 刘福蓉, 温婷, 等. 红景天苷通过JAK2/STAT3通路影响宫颈鳞癌C33A细胞的增殖、侵袭和凋亡[J]. 中国肿瘤生物治疗杂志, 2020, 27(5): 522-527. https://www.cnki.com.cn/Article/CJFDTOTAL-ZLSW202005008.htm
    [18]
    KOWALSKA E, BARTNICKI F, FUJISAWA R, et al. Inhibition of DNA replication by an anti-PCNA aptamer/PCNA complex[J]. Nucleic Acids Res, 2018, 46(1): 25-41. DOI: 10.1093/nar/gkx1184
    [19]
    PATEL H, ABDULJABBAR R, LAI CF, et al. Expression of CDK7, Cyclin H, and MAT1 Is elevated in breast cancer and is prognostic in estrogen receptor-positive breast cancer[J]. Clin Cancer Res, 2016, 22(23): 5929-5938. DOI: 10.1158/1078-0432.CCR-15-1104
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