牛磺胆酸促进肝硬化发展的机制

乐英彪; 王昆华; 邹雷

doi:10.3969/j.issn.1001-5256.2021.11.037

牛磺胆酸促进肝硬化发展的机制

DOI: 10.3969/j.issn.1001-5256.2021.11.037

1.
昆明医科大学，昆明医科大学第一附属医院胃肠与疝外科，昆明医科大学第一附属医院科研实验中心，国家卫健委毒品依赖和戒治重点实验室，昆明 650032
2.
昆明医科大学第一附属医院肝胆外科，国家卫健委毒品依赖和戒治重点实验室，昆明 650032

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
计量
- 文章访问数: 1111
- HTML全文浏览量: 148
- PDF下载量: 94
- 被引次数: 0
出版历程
- 收稿日期: 2021-04-06
- 录用日期: 2021-05-08
- 出版日期: 2021-11-20

Mechanism of taurocholic acid in promoting the progression of liver cirrhosis

1.
NHC Key Laboratory of Drug Addiction Medicine, Department of Gastrointestinal and Hernia Surgery, The First Affiliated Hospital of Kunming Medical University, Scientific Research Laboratory Center, The First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming 650032, China
2.
NHC Key Laboratory of Drug Addiction Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China

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

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。
- 牛磺胆酸 /
- 肝硬化 /
- 胆汁淤积
Abstract: Bile acid is the main component of bile, and the external secretion of bile acid into the intestine can help with the absorption of lipids and fat-soluble vitamins; in addition, bile acid acts as a signal molecule to regulate bile acid metabolism and help maintain intestinal homeostasis. The process of liver cirrhosis is accompanied by varying degrees of cholestasis, causing bile duct injury, and exposure of liver cells to a high concentration of bile acid will accelerate the progression of liver cirrhosis and form a vicious circle. Among these abnormally elevated bile acids, taurocholic acid (TCA) shows the greatest increase, suggesting that TCA may play an important role in the process of liver cirrhosis. At present, there are relatively few studies on the mechanism of TCA in liver cirrhosis, and current studies in China and globally have shown that TCA at a high concentration (≥50 μmol/L) can promote the progression of liver cirrhosis by acting on liver cells (hepatic stellate cells, hepatocytes, hepatic progenitor cells, and bile duct epithelial cells). This article discusses the detailed mechanism of TCA in promoting liver cirrhosis and points out that TCA has the clinical potential as a biomarker and therapeutic target for liver cirrhosis.
- Taurocholic Acid /
- Liver Cirrhosis /
- Cholestasis

HTML全文

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。

下载: 全尺寸图片幻灯片

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。

下载: 全尺寸图片幻灯片

参考文献(41)

[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.