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慢性肝病女性患者绝经后雌激素抗肝纤维化的作用机制

徐文倩 吴瑶麒 张近远 杨天闯 李合国 郭敏

引用本文:
Citation:

慢性肝病女性患者绝经后雌激素抗肝纤维化的作用机制

DOI: 10.3969/j.issn.1001-5256.2021.10.035
基金项目: 

国家自然科学基金 (81904161)

详细信息
    通信作者:

    郭敏,hbguomin@sina.com

  • 中图分类号: R575.2

Mechanism of estrogen against liver fibrosis in postmenopausal women with chronic liver disease

Research funding: 

National Natural Science Foundation of China (81904161)

  • 摘要: 女性绝经后机体代谢水平紊乱,患有慢性肝病的女性进展为肝纤维化的风险增加,且风险高于同龄男性患者。这可能与女性绝经后卵巢功能衰退、体内雌激素水平下降有关。主要从雌激素与氧化应激、肝星状细胞的活化、细胞外基质的堆积、免疫调节的关系等方面归纳了患有慢性肝病的女性患者进展为肝纤维化的分子机制研究进展。从而提出给予围绝经期和绝经初期女性患者补充适量的雌激素可以降低肝纤维化的风险,延缓甚至逆转肝纤维化的进程,从而改善老年女性患者的生存质量、延长生存时间。

     

  • 图  1  雌激素在肝纤维化中的作用机制

    注: E2,雌激素受体; ERα, α型雌二醇; ERβ, β型雌二醇; MERs,雌激素受体; GPERs, G蛋白偶联受体; UCP-2, 解偶联蛋白2;ATP,三磷酸腺苷; SOD,超氧化物歧化酶; TCAcycle,三羧酸循环。

  • [1] Liver Disease Committee, Chinese Association of Integrative Medicine. Guidelines for the diagnosis and treatment of liver fibrosis in integrative medicine practice (2019)[J]. J Clin Hepatol, 2019, 35(7): 1444-1449. DOI: 10.3969/j.issn.1001-5256.2019.07.007.

    中国中西医结合学会肝病专业委员会. 肝纤维化中西医结合诊疗指南(2019年版)[J]. 临床肝胆病杂志, 2019, 35(7): 1444-1449. DOI: 10.3969/j.issn.1001-5256.2019.07.007.
    [2] SARKAR M, DODGE JL, GREENBLATT RM, et al. Reproductive aging and hepatic fibrosis progression in human immunodeficiency virus/hepatitis C virus-coinfected women[J]. Clin Infect Dis, 2017, 65(10): 1695-1702. DOI: 10.1093/cid/cix643.
    [3] YANG JD, ABDELMALEK MF, PANG H, et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis[J]. Hepatology, 2014, 59(4): 1406-1414. DOI: 10.1002/hep.26761.
    [4] KLAIR JS, YANG JD, ABDELMALEK MF, et al. A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease[J]. Hepatology, 2016, 64(1): 85-91. DOI: 10.1002/hep.28514.
    [5] JIA M, DAHLMAN-WRIGHT K, GUSTAFSSON JÅ. Estrogen receptor alpha and beta in health and disease[J]. Best Pract Res Clin Endocrinol Metab, 2015, 29(4): 557-568. DOI: 10.1016/j.beem.2015.04.008.
    [6] BONDER A, TAPPER EB, AFDHAL NH. Contemporary assessment of hepatic fibrosis[J]. Clin Liver Dis, 2015, 19(1): 123-134. DOI: 10.1016/j.cld.2014.09.007.
    [7] PARK SH, PARK YE, LEE J, et al. Lack of association between early menopause and non-alcoholic fatty liver disease in postmenopausal women[J]. Climacteric, 2020, 23(2): 173-177. DOI: 10.1080/13697137.2019.1650018.
    [8] ROBSON SC, NEUBERGER JM, WILLIAMS R. The influence of cyclosporine A therapy on sex hormone levels in pre- and post-menopausal women with primary biliary cirrhosis[J]. J Hepatol, 1994, 21(3): 412-416. DOI: 10.1016/s0168-8278(05)80321-6.
    [9] RINALDI M, CAGNACCI A, PANSINI FE, et al. Neutral effect of prolonged transdermal hormone therapy on liver function of postmenopausal women with chronic active hepatitis[J]. Menopause, 2005, 12(5): 619-622. DOI: 10.1097/01.gme.0000172271.78314.6d.
    [10] PADUA MA, FONSECA AM, DEGUTI MM, et al. Hormone therapy in Brazilian postmenopausal women with chronic hepatitis C: A pilot study[J]. Climacteric, 2010, 13(2): 179-186. DOI: 10.3109/13697130902952577.
    [11] EZHILARASAN D, SOKAL E, NAJIMI M. Hepatic fibrosis: It is time to go with hepatic stellate cell-specific therapeutic targets[J]. Hepatobiliary Pancreat Dis Int, 2018, 17(3): 192-197. DOI: 10.1016/j.hbpd.2018.04.003.
    [12] XU MC, ZHANG F, ZHUGE YZ. Current research status of mechanisms of the development and progression of liver fibrosis[J]. J Clin Hepatol, 2016, 32(9): 1806-1809. DOI: 10.3969/j.issn.1001-5256.2016.09.039.

    徐明翠, 张峰, 诸葛宇征. 肝纤维化发生发展机制的研究现状[J]. 临床肝胆病杂志, 2016, 32(9): 1806-1809. DOI: 10.3969/j.issn.1001-5256.2016.09.039.
    [13] BLANER WS, LI Y, BRUN PJ, et al. Vitamin A absorption, storage and mobilization[J]. Subcell Biochem, 2016, 81: 95-125. DOI: 10.1007/978-94-024-0945-1_4.
    [14] SENOO H, MEZAKI Y, FUJIWARA M. The stellate cell system (vitamin A-storing cell system)[J]. Anat Sci Int, 2017, 92(4): 387-455. DOI: 10.1007/s12565-017-0395-9.
    [15] CAI X, LI Z, ZHANG Q, et al. CXCL6-EGFR-induced Kupffer cells secrete TGF-β1 promoting hepatic stellate cell activation via the SMAD2/BRD4/C-MYC/EZH2 pathway in liver fibrosis[J]. J Cell Mol Med, 2018, 22(10): 5050-5061. DOI: 10.1111/jcmm.13787.
    [16] SUTTI S, TACKE F. Liver inflammation and regeneration in drug-induced liver injury: Sex matters![J]. Clin Sci (Lond), 2018, 132(5): 609-613. DOI: 10.1042/CS20171313.
    [17] QUE R, SHEN Y, REN J, et al. Estrogen receptor-β-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation[J]. Int J Mol Med, 2018, 41(3): 1357-1364. DOI: 10.3892/ijmm.2017.3349.
    [18] GE S, XIE J, LIU F, et al. MicroRNA-19b reduces hepatic stellate cell proliferation by targeting GRB2 in hepatic fibrosis models in vivo and in vitro as part of the inhibitory effect of estradiol[J]. J Cell Biochem, 2015, 116(11): 2455-2464. DOI: 10.1002/jcb.25116.
    [19] PAROLA M, PINZANI M. Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues[J]. Mol Aspects Med, 2019, 65: 37-55. DOI: 10.1016/j.mam.2018.09.002.
    [20] ZHANG M, WANG Y, ZHU G, et al. Hepatoprotective effect and possible mechanism of phytoestrogen calycosin on carbon tetrachloride-induced liver fibrosis in mice[J]. Naunyn Schmiedebergs Arch Pharmacol, 2021, 394(1): 189-204. DOI: 10.1007/s00210-020-01891-5.
    [21] EZHILARASAN D. Critical role of estrogen in the progression of chronic liver diseases[J]. Hepatobiliary Pancreat Dis Int, 2020, 19(5): 429-434. DOI: 10.1016/j.hbpd.2020.03.011.
    [22] DENG YY, GE SF, YU YQ, et al. Cell signaling pathways associated with liver fibrosis and potential therapeutic strategie[J]. J Clin Hepatol, 2020, 36(5): 114. DOI: 10.3969/j.issn.1001-5256.2020.05.043.

    邓羊羊, 葛善飞, 余燕青, 等. 肝纤维化相关细胞信号转导通路及潜在治疗策略[J]. 临床肝胆病杂志, 2020, 36(5): 114. DOI: 10.3969/j.issn.1001-5256.2020.05.043.
    [23] HAN R, HU M, ZHONG Q, et al. Perfluorooctane sulphonate induces oxidative hepatic damage via mitochondria-dependent and NF-κB/TNF-α-mediated pathway[J]. Chemosphere, 2018, 191: 1056-1064. DOI: 10.1016/j.chemosphere.2017.08.070.
    [24] KAZANKOV K, JØRGENSEN S, THOMSEN KL, et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(3): 145-159. DOI: 10.1038/s41575-018-0082-x.
    [25] OISHI Y, MANABE I. Macrophages in inflammation, repair and regeneration[J]. Int Immunol, 2018, 30(11): 511-528. DOI: 10.1093/intimm/dxy054.
    [26] YU Y, LIU Y, AN W, et al. STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis[J]. J Clin Invest, 2019, 129(2): 546-555. DOI: 10.1172/JCI121842.
    [27] SU L, LI N, TANG H, et al. Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells[J]. Cell Death Dis, 2018, 9(3): 323. DOI: 10.1038/s41419-018-0377-4.
    [28] TONELLI C, CHIO I, TUVESON DA. Transcriptional regulation by Nrf2[J]. Antioxid Redox Signal, 2018, 29(17): 1727-1745. DOI: 10.1089/ars.2017.7342.
    [29] BONNARDEL J, T'JONCK W, GAUBLOMME D, et al. Stellate cells, hepatocytes, and endothelial cells imprint the kupffer cell identity on monocytes colonizing the liver macrophage niche[J]. Immunity, 2019, 51(4): 638-654. e9. DOI: 10.1016/j.immuni.2019.08.017.
    [30] ANNESLEY SJ, FISHER PR. Mitochondria in health and disease[J]. Cells, 2019, 8(7). DOI: 10.3390/cells8070680.
    [31] ZHANG L, WANG X, CUETO R, et al. Biochemical basis and metabolic interplay of redox regulation[J]. Redox Biol, 2019, 26: 101284. DOI: 10.1016/j.redox.2019.101284.
    [32] ZHAO Y, WANG Z, FENG D, et al. p66Shc contributes to liver fibrosis through the regulation of mitochondrial reactive oxygen species[J]. Theranostics, 2019, 9(5): 1510-1522. DOI: 10.7150/thno.29620.
    [33] JIA M, DAHLMAN-WRIGHT K, GUSTAFSSON JÅ. Estrogen receptor alpha and beta in health and disease[J]. Best Pract Res Clin Endocrinol Metab, 2015, 29(4): 557-568. DOI: 10.1016/j.beem.2015.04.008.
    [34] KLINGE CM. Estrogens regulate life and death in mitochondria[J]. J Bioenerg Biomembr, 2017, 49(4): 307-324. DOI: 10.1007/s10863-017-9704-1.
    [35] BESSE-PATIN A, LÉVEILLÉ M, OROPEZA D, et al. Estrogen signals through peroxisome proliferator-activated receptor-γ coactivator 1α to reduce oxidative damage associated with diet-induced fatty liver disease[J]. Gastroenterology, 2017, 152(1): 243-256. DOI: 10.1053/j.gastro.2016.09.017.
    [36] LI N, HUA J. Immune cells in liver regeneration[J]. Oncotarget, 2017, 8(2): 3628-3639. DOI: 10.18632/oncotarget.12275.
    [37] VILLALBA M, ALEXIA C, BELLIN-ROBERT A, et al. Non-genetically improving the natural cytotoxicity of Natural Killer (NK) cells[J]. Front Immunol, 2019, 10: 3026. DOI: 10.3389/fimmu.2019.03026.
    [38] LI T, YANG Y, SONG H, et al. Activated NK cells kill hepatic stellate cells via p38/PI3K signaling in a TRAIL-involved degranulation manner[J]. J Leukoc Biol, 2019, 105(4): 695-704. DOI: 10.1002/JLB.2A0118-031RR.
    [39] MACEK JILKOVA Z, DECAENS T, MARLU A, et al. Sex differences in spontaneous degranulation activity of intrahepatic natural killer cells during chronic hepatitis B: Association with estradiol levels[J]. Mediators Inflamm, 2017, 2017: 3214917. DOI: 10.1155/2017/3214917.
    [40] JIAO J, OOKA K, FEY H, et al. Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice[J]. J Hepatol, 2016, 65(2): 344-353. DOI: 10.1016/j.jhep.2016.04.020.
    [41] SHEN H, SHENG L, XIONG Y, et al. Thymic NF-κB-inducing kinase regulates CD4(+) T cell-elicited liver injury and fibrosis in mice[J]. J Hepatol, 2017, 67(1): 100-109. DOI: 10.1016/j.jhep.2017.02.025.
    [42] CHENG LS, LIU Y, JIANG W. Restoring homeostasis of CD4+ T cells in hepatitis-B-virus-related liver fibrosis[J]. World J Gastroenterol, 2015, 21(38): 10721-10731. DOI: 10.3748/wjg.v21.i38.10721.
    [43] MILETTE S, HASHIMOTO M, PERRINO S, et al. Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases[J]. Nat Commun, 2019, 10(1): 5745. DOI: 10.1038/s41467-019-13571-x.
    [44] STUBELIUS A, ERLANDSSON MC, ISLANDER U, et al. Immunomodulation by the estrogen metabolite 2-methoxyestradiol[J]. Clin Immunol, 2014, 153(1): 40-48. DOI: 10.1016/j.clim.2014.03.011.
    [45] CHESTER RC, KLING JM, MANSON JE. What the women's health initiative has taught us about menopausal hormone therapy[J]. Clin Cardiol, 2018, 41(2): 247-252. DOI: 10.1002/clc.22891.
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  • 收稿日期:  2021-03-11
  • 录用日期:  2021-04-22
  • 出版日期:  2021-10-20
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