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牛磺胆酸促进肝硬化发展的机制

乐英彪 王昆华 邹雷

引用本文:
Citation:

牛磺胆酸促进肝硬化发展的机制

DOI: 10.3969/j.issn.1001-5256.2021.11.037
基金项目: 

国家自然科学基金 (81870458)

云南省科技厅项目 (2018DH006)

云南省科技厅项目 (ZX2019-03-03)

云南省云岭学者项目 (YLXL20170002)

详细信息
    通信作者:

    邹雷,zl_8082@126.com

  • 中图分类号: R575.2

Mechanism of taurocholic acid in promoting the progression of liver cirrhosis

Research funding: 

The National Natural Science Foundation of China (81870458);

Yunnan Engineering Technology Center of Digestive Disease (2018DH006);

Yunnan Engineering Technology Center of Digestive Disease (ZX2019-03-03);

Yunling Scholar (YLXL20170002)

  • 摘要: 胆汁酸是胆汁的主要成分,其外分泌入肠道帮助脂质和脂溶性维生素的吸收,也可作为信号分子调节胆汁酸代谢,帮助维持肠道稳态。而肝硬化过程中伴有不同程度的胆汁淤积,造成胆管损伤,肝脏细胞暴露于高水平胆汁酸会加速肝硬化进展从而形成恶性循环。在这些异常升高的胆汁酸中,以牛磺胆酸(TCA)水平升高最为显著,提示TCA在肝硬化过程中可能发挥重要作用。而目前对于TCA在肝硬化中的作用机制的研究相对较少,现有国内外相关研究表明,高水平TCA(≥50 μmol/L)可以通过作用于肝脏细胞(肝星状细胞、肝细胞、肝祖细胞、胆管上皮细胞)从而促进肝硬化进展。探讨了TCA促进肝硬化的详细机制,提示TCA具有作为肝硬化生物标志物与治疗靶点的临床潜力。

     

  • 图  1  TCA的合成示意图

    注:C1,7α-羟基-4-胆甾烯-3-酮;C2,7α,12α-羟基-4-胆甾烯-3-酮;C3,5β-胆甾烷-3α,7α,12α-三醇;CYP7A1,胆固醇7α-羟化酶;HSD3B7,3β-羟基-Δ5-C27-类固醇脱氢酶;CYP8B1,甾醇12α-羟化酶;AKR1D1,Δ4-3-氧类固醇-5β还原酶;AKR1C4,3α-羟基类固醇脱氢酶;CYP27A1,甾醇27-羟化酶;THCA,3α,7α,12α-三羟基胆甾酸;BACS,胆脂酰CoA合成酶;VLCS,超长链脂酰CoA合成酶;AMACR,α-甲基酰基辅酶A消旋酶;DBP,D-双功能蛋白;SCPx,甾醇载体蛋白x;BAAT,氨基酸N-酰基转移酶;ASBT,钠依赖回肠尖端胆汁转运体;NTCP,牛磺胆酸钠转运蛋白;OATP,有机阴离子转运蛋白。

    图  2  TCA促纤维化作用

    注:Erk1/2,细胞外调节蛋白激酶;EGR-1,早期生长反应蛋白-1。

  • [1] BARNETT R. Liver cirrhosis[J]. Lancet, 2018, 392(10144): 275. DOI: 10.1016/S0140-6736(18)31659-3.
    [2] 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.
    [3] TROTTIER J, BIAŁEK A, CARON P, et al. Profiling circulating and urinary bile acids in patients with biliary obstruction before and after biliary stenting[J]. PLoS One, 2011, 6(7): e22094. DOI: 10.1371/journal.pone.0022094.
    [4] JIA W, WEI M, RAJANI C, et al. Targeting the alternative bile acid synthetic pathway for metabolic diseases[J]. Protein Cell, 2021, 12(5): 411-425. DOI: 10.1007/s13238-020-00804-9.
    [5] KIRIYAMA Y, NOCHI H. The biosynthesis, signaling, and neurological functions of bile acids[J]. Biomolecules, 2019, 9(6): 232. DOI: 10.3390/biom9060232.
    [6] TICHO AL, MALHOTRA P, DUDEJA PK, et al. Intestinal absorption of bile acids in health and disease[J]. Compr Physiol, 2019, 10(1): 21-56. DOI: 10.1002/cphy.c190007.
    [7] KOK B, ABRALDES JG. Child-Pugh classification: Time to abandon?[J]. Semin Liver Dis, 2019, 39(1): 96-103. DOI: 10.1055/s-0038-1676805.
    [8] RIMINI M, ROVESTI G, CASADEI-GARDINI A. Child Pugh and ALBI grade: Past, present or future?[J]. Ann Transl Med, 2020, 8(17): 1044. DOI: 10.21037/atm-20-3709.
    [9] WANG X, XIE G, ZHAO A, et al. Serum bile acids are associated with pathological progression of hepatitis B-induced cirrhosis[J]. J Proteome Res, 2016, 15(4): 1126-1134. DOI: 10.1021/acs.jproteome.5b00217.
    [10] LIU Z, ZHANG Z, HUANG M, et al. Taurocholic acid is an active promoting factor, not just a biomarker of progression of liver cirrhosis: Evidence from a human metabolomic study and in vitro experiments[J]. BMC Gastroenterol, 2018, 18(1): 112. DOI: 10.1186/s12876-018-0842-7.
    [11] HORVATITS T, DROLZ A, ROEDL K, et al. Serum bile acids as marker for acute decompensation and acute-on-chronic liver failure in patients with non-cholestatic cirrhosis[J]. Liver Int, 2017, 37(2): 224-231. DOI: 10.1111/liv.13201.
    [12] KHOMICH O, IVANOV AV, BARTOSCH B. Metabolic hallmarks of hepatic stellate cells in liver fibrosis[J]. Cells, 2019, 9(1): 24. DOI: 10.3390/cells9010024.
    [13] MU M, ZUO S, WU RM, et al. Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signaling pathway[J]. Drug Des Devel Ther, 2018, 12: 4107-4115. DOI: 10.2147/DDDT.S186726.
    [14] FAN Y, LI Y, CHU Y, et al. Toll-like receptors recognize intestinal microbes in liver cirrhosis[J]. Front Immunol, 2021, 12: 608498. DOI: 10.3389/fimmu.2021.608498.
    [15] SEKI E, de MINICIS S, OSTERREICHER CH, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis[J]. Nat Med, 2007, 13(11): 1324-1332. DOI: 10.1038/nm1663.
    [16] FABREGAT I, CABALLERO-DíAZ D. Transforming growth factor-β-induced cell plasticity in liver fibrosis and hepatocarcinogenesis[J]. Front Oncol, 2018, 8: 357.
    [17] CAJA L, DITURI F, MANCARELLA S, et al. TGF-β and the tissue microenvironment: Relevance in fibrosis and cancer[J]. Int J Mol Sci, 2018, 19(5): 1294. DOI: 10.3390/ijms19051294.
    [18] GHAFOORY S, VARSHNEY R, ROBISON T, et al. Platelet TGF-β1 deficiency decreases liver fibrosis in a mouse model of liver injury[J]. Blood Adv, 2018, 2(5): 470-480. DOI: 10.1182/bloodadvances.2017010868.
    [19] PAIK YH, SCHWABE RF, BATALLER R, et al. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells[J]. Hepatology, 2003, 37(5): 1043-1055. DOI: 10.1053/jhep.2003.50182.
    [20] WEI S, MA X, ZHAO Y. Mechanism of hydrophobic bile acid-induced hepatocyte injury and drug discovery[J]. Front Pharmacol, 2020, 11: 1084. DOI: 10.3389/fphar.2020.01084.
    [21] ALLEN K, JAESCHKE H, COPPLE BL. Bile acids induce inflammatory genes in hepatocytes: A novel mechanism of inflammation during obstructive cholestasis[J]. Am J Pathol, 2011, 178(1): 175-186. DOI: 10.1016/j.ajpath.2010.11.026.
    [22] ALLEN K, KIM ND, MOON JO, et al. Upregulation of early growth response factor-1 by bile acids requires mitogen-activated protein kinase signaling[J]. Toxicol Appl Pharmacol, 2010, 243(1): 63-67. DOI: 10.1016/j.taap.2009.11.013.
    [23] GUJRAL JS, LIU J, FARHOOD A, et al. Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice[J]. Am J Physiol Gastrointest Liver Physiol, 2004, 286(3): G499-507. DOI: 10.1152/ajpgi.00318.2003.
    [24] 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.
    [25] KIM ND, MOON JO, SLITT AL, et al. Early growth response factor-1 is critical for cholestatic liver injury[J]. Toxicol Sci, 2006, 90(2): 586-595. DOI: 10.1093/toxsci/kfj111.
    [26] MARRA F, ROMANELLI RG, GIANNINI C, et al. Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells[J]. Hepatology, 1999, 29(1): 140-148. DOI: 10.1002/hep.510290107.
    [27] QUECK A, BODE H, USCHNER FE, et al. Systemic MCP-1 levels derive mainly from injured liver and are associated with complications in cirrhosis[J]. Front Immunol, 2020, 11: 354. DOI: 10.3389/fimmu.2020.00354.
    [28] RAMM GA, SHEPHERD RW, HOSKINS AC, et al. Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment[J]. Hepatology, 2009, 49(2): 533-544. DOI: 10.1002/hep.22637.
    [29] LI L, WEI W, LI Z, et al. The spleen promotes the secretion of CCL2 and supports an M1 dominant phenotype in hepatic macrophages during liver fibrosis[J]. Cell Physiol Biochem, 2018, 51(2): 557-574. DOI: 10.1159/000495276.
    [30] SUN T, ANNUNZIATO S, TCHORZ JS. Hepatic ductular reaction: A double-edged sword[J]. Aging (Albany NY), 2019, 11(21): 9223-9224. DOI: 10.18632/aging.102386.
    [31] SATO K, MARZIONI M, MENG F, et al. Ductular reaction in liver diseases: pathological mechanisms and translational significances[J]. Hepatology, 2019, 69(1): 420-430. DOI: 10.1002/hep.30150.
    [32] POZNIAK KN, PEAREN MA, PEREIRA TN, et al. Taurocholate induces biliary differentiation of liver progenitor cells causing hepatic stellate cell chemotaxis in the ductular reaction: Role in pediatric cystic fibrosis liver disease[J]. Am J Pathol, 2017, 187(12): 2744-2757. DOI: 10.1016/j.ajpath.2017.08.024.
    [33] RUDDELL RG, KNIGHT B, TIRNITZ-PARKER JE, et al. Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury[J]. Hepatology, 2009, 49(1): 227-239. DOI: 10.1002/hep.22597.
    [34] TIRNITZ-PARKER JE, OLYNYK JK, RAMM GA. Role of TWEAK in coregulating liver progenitor cell and fibrogenic responses[J]. Hepatology, 2014, 59(3): 1198-1201. DOI: 10.1002/hep.26701.
    [35] LAMIREAU T, ZOLTOWSKA M, LEVY E, et al. Effects of bile acids on biliary epithelial cells: Proliferation, cytotoxicity, and cytokine secretion[J]. Life Sci, 2003, 72(12): 1401-1411. DOI: 10.1016/s0024-3205(02)02408-6.
    [36] XIANG DM, SUN W, NING BF, et al. The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis[J]. Gut, 2018, 67(9): 1704-1715. DOI: 10.1136/gutjnl-2016-313392.
    [37] REMMLER J, SCHNEIDER C, TREUNER-KAUEROFF T, et al. Increased level of interleukin 6 associates with increased 90-day and 1-year mortality in patients with end-stage liver disease[J]. Clin Gastroenterol Hepatol, 2018, 16(5): 730-737. DOI: 10.1016/j.cgh.2017.09.017.
    [38] LABENZ C, TOENGES G, HUBER Y, et al. Raised serum Interleukin-6 identifies patients with liver cirrhosis at high risk for overt hepatic encephalopathy[J]. Aliment Pharmacol Ther, 2019, 50(10): 1112-1119. DOI: 10.1111/apt.15515.
    [39] DU PLESSIS J, VANHEEL H, JANSSEN CE, et al. Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function[J]. J Hepatol, 2013, 58(6): 1125-1132. DOI: 10.1016/j.jhep.2013.01.038.
    [40] MANCINELLI R, ONORI P, GAUDIO E, et al. Taurocholate feeding to bile duct ligated rats prevents caffeic acid-induced bile duct damage by changes in cholangiocyte VEGF expression[J]. Exp Biol Med (Maywood), 2009, 234(4): 462-474. DOI: 10.3181/0808-RM-255.
    [41] GAUDIO E, BARBARO B, ALVARO D, et al. Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism[J]. Gastroenterology, 2006, 130(4): 1270-1282. DOI: 10.1053/j.gastro.2005.12.034.
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  • 收稿日期:  2021-04-06
  • 录用日期:  2021-05-08
  • 出版日期:  2021-11-20
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