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鞘氨醇激酶信号通路在肝纤维化中的作用机制

孙跃 兰天 郭姣

引用本文:
Citation:

鞘氨醇激酶信号通路在肝纤维化中的作用机制

DOI: 10.3969/j.issn.1001-5256.2017.09.038
基金项目: 

广东省科技厅国际合作项目(2015A050502050); 广东省教育厅创新强校项目(2014GKPT021); 

详细信息
  • 中图分类号: R575.2

Research advances in the sphingosine kinase signaling pathway in liver fibrosis

Research funding: 

 

  • 摘要: 肝纤维化的形成主要体现为肝星状细胞的激活和细胞外基质合成降解的失衡。鞘氨醇激酶-1-磷酸鞘氨醇-1-磷酸鞘氨醇受体(SphK-S1P-S1PRs)信号通路在调控细胞的增殖、迁移以及炎症反应等生命活动中发挥重要作用。介绍了SphK、S1P、S1PRs的分布及生物学功能,简述了SphK-S1P-S1PRs信号通路在肝纤维化中的作用机制及其研究进展。多项研究证实SphK-S1P-S1PRs信号通路在肝纤维化疾病研究中起关键性作用,深入的探索有助于为临床上肝纤维化治理和药物新靶点开发提供新的思路。

     

  • [1]KANG FL, ZHANG YX.Research advances in liver cirrhosis complicated by portal vein thrombosis[J].J Clin Hepatol, 2016, 32 (8) :1608-1612. (in Chinese) 康福来, 张跃新.肝硬化并发门静脉血栓的研究进展[J].临床肝胆病杂志, 2016, 32 (8) :1608-1612.
    [2]GULBINS E.Regulation of death receptor signaling and apoptosis by ceramide[J].Pharmacol Res, 2003, 47 (5) :393-399.
    [3]UEDA N.Sphingolipids in genetic and acquired forms of chronic kidney diseases[J].Curr Med Chem, 2017.[Epub ahead of print]
    [4]SOBEL K, MENYHART K, KILLER N, et al.Sphingosine 1-phosphate (S1P) receptor agonists mediate pro-fibrotic responses in normal human lung fibroblasts via S1P2 and S1P3 receptors and Smad-independent signaling[J].J Biol Chem, 2013, 288 (21) :14839-14851.
    [5]ZHANG J, BANG A, LYE SJ.Analysis of S1P receptor expression by uterine immune cells using standardized multi-parametric flow cytometry[J].Methods Mol Biol, 2017.[Epub ahead of print]
    [6]SHEA BS, TAGER AM.Sphingolipid regulation of tissue fibrosis[J].Open Rheumatol J, 2012, 6 (1) :123-129.
    [7]CHANG HC, HSU C, HSU HK, et al.Functional role of caspases in sphingosine-induced apoptosis in human hepatoma cells[J].IUBMBLife, 2003, 55 (7) :403-407.
    [8]MACEYKA M, SANKALA H, HAIT NC, et al.Sph K1 and Sph K2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism[J].J Biol Chem, 2005, 280 (44) :37118-37129.
    [9]ALEMANY R, van KOPPEN CJ, DANNEBERG K, et al.Regulation and functional roles of sphingosine kinases[J].Naunyn Schmiedebergs Arch Pharmacol, 2007, 374 (5) :413-428.
    [10]LIU H, SUGIURA M, NAVA VE, et al.Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform[J].J Biol Chem, 2000, 275 (26) :19513-19520.
    [11]HANNUN YA, OBEID LM.Principles of bioactive lipid signalling:lessons from sphingolipids[J].Nat Rev Mol Cell Biol, 2008, 9 (2) :139-150.
    [12]SPIEGEL S, MILSTIEN S.Sphingosine-1-phosphate:an enigmatic signalling lipid[J].Nat Rev Mol Cell Biol, 2003, 4 (5) :397-407.
    [13]GELLINGS LN, SWANEY JS, MORENO KM, et al.Sphingosine-1-phosphate and sphingosine kinase are critical for transforming growth factor-beta-stimulated collagen production by cardiac fibroblasts[J].Cardiovasc Res, 2009, 82 (2) :303-312.
    [14]LEE SY, KIM DH, SUNG SA, et al.Sphingosine-1-phosphate reduces hepatic ischaemia/reper-fusion-induced acute kidney injury through attenuation of endothelial injury in mice[J].Nephrology, 2011, 16 (2) :163-173.
    [15]ZHAO Y, GORSHKOVA IA, BERDYSHEV E, et al.Protection of LPS-induced murine acute lung injury by sphingosine-1-phosphate lyase suppression[J].Am J Respir Cell Mol Biol, 2011, 45 (2) :426-435.
    [16]LIU X, YUE S, LI C, et al.Essential roles of sphingosine 1-phosphate receptor types 1 and 3 in human hepatic stellate cells motility and activation[J].J Cell Physiol, 2011, 226 (9) :2370-2377.
    [17]MEYER ZU HERINGDORF D, JAKOBS KH.Lysophospholipid receptors:signalling, pharmacology and regulation by lysophospholipid metabolism[J].Biochim Biophys Acta, 2007, 1768 (4) :923-940.
    [18]XIN C, REN S, KLEUSER B, et al.Sphingosine-1-phosphate cross-activates the Smad signaling cascade and mimics TGF betainduced cell responses[J].J Biol Chem, 2004, 279 (34) :35255-35262.
    [19]PROIA RL, HLA T.Emerging biology of sphingosine-1-phosphate:its role in pathogenesis and therapy[J].J Clin Invest, 2015, 125 (4) :1379-1387.
    [20]MOUSSEAU Y, MOLLARD S, RICHARD L, et al.Fingolimod inhibits PDGF-B-induced migration of vascular smooth muscle cell by down-regulating the S1PR1/S1PR3 pathway.[J].Biochimie, 2012, 94 (12) :2523-2531.
    [21]THOMAS K, SEHR T, PROSCHMANN U, et al.Fingolimod additionally acts as immunomodulator focused on the innate immune system beyond its prominent effects on lymphocyte recirculation[J].JNeuroinflammation, 2017, 14 (1) :41.
    [22]PATMANATHAN SN, WEI W, YAP LF, et al.Mechanisms of sphingosine 1-phosphate receptor signalling in cancer[J].Cell Signal, 2017, 34:66-75.
    [23]YOSHIMURA A, WAKABAYASHI Y, MORI T.Cellular and molecular basis for the regulation of inflammation by TGF-beta[J].JBiochem, 2010, 147 (6) :781-792.
    [24]BONNER JC.Regulation of PDGF and its receptors in fibrotic diseases[J].Cytokine Growth Factor Rev, 2004, 15 (4) :255-273.
    [25]REN S, BABELOVA A, MORETH K, et al.Transforming growth factor-β2 upregulates sphingosine kinase-1 activity, which in turn attenuates the fibrotic response to TGF-β2 by impeding CTGF expression[J].Kidney International, 2009, 76 (8) :857-867.
    [26]XIU L, CHANG N, YANG L, et al.Intracellular sphingosine 1-phosphate contributes to collagen expression of hepatic myofibroblasts in human liver fibrosis independent of its receptors[J].Am J Pathol, 2014, 185 (2) :387-398.
    [27]BORKHAM-KAMPHORST E, WEISKIRCHEN R.The PDGFsystem and its antagonists in liver fibrosis[J].Cytokine Growth Factor Rev, 2016, 28:53-61.
    [28]KATSUMA S, SHIOJIMA S, HIRASAWA A, et al.Genomic analysis of a mouse model of immunoglobulin A nephropathy reveals an enhanced PDGF-EDG5 cascade[J].Pharmacogenomics J, 2001, 1 (3) :211-217.
    [29]KATSUMA S, HADA Y, SHIOJIMA S, et al.Transcriptional profiling of gene expression patterns during sphingosine 1-phosphateinduced mesangial cell proliferation[J].Biochem Biophys Res Commun, 2003, 300 (2) :577-584.
    [30]KING A, HOULIHAN DD, KAVANAGH D, et al.Sphingosine-1-phosphate prevents egress of hematopoietic stem cells from liver to reduce fibrosis[J].Gastroenterology, 2017.[Epub ahead of print]
    [31]ZHANG CH, LI Y, CHEN W, et al.Protective effect of FTY720 on hepatic injury in experimental hepatic fibrosis mice[J].J Jilin Univ:Med Edit, 2015, 41 (6) :1154-1157. (in Chinese) 张宸豪, 李瑶, 陈为, 等.FTY720对实验性肝纤维化小鼠肝损伤的保护作用[J].吉林大学学报:医学版, 2015, 41 (6) :1154-1157.
    [32]OO ML, THANGADA S, WU MT, et al.Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor[J].J Biol Chem, 2007, 282 (12) :9082-9089.
    [33]AL FADEL F, FAYYAZ S, JAPTOK L, et al.Involvement of sphingosine 1-phosphate in palmitate-induced non-alcoholic fatty liver disease[J].Cell Physiol Biochem, 2016, 40 (6) :1637-1645.
    [34]GELLINGS LN, SWANEY JS, MORENO KM, et al.Sphingosine-1-phosphate and sphingosine kinase are critical for transforming growth factor-beta-stimulated collagen production by cardiac fibroblasts[J].Cardiovasc Res, 2009, 82 (2) :303.
    [35]YANG L, HAN Z, TIAN L, et al.Sphingosine 1-phosphate receptor 2 and 3 mediate bone marrow-derived monocyte/macrophage motility in cholestatic liver injury in mice[J].Sci Rep, 2015, 5:13423.
    [36]YANG L, YUE S, YANG L, et al.Sphingosine kinase/sphingosine1-phosphate (S1P) /S1P receptor axis is involved in liver fibrosis-associated angiogenesis[J].J Hepatol, 2013, 59 (1) :114-123.
    [37]LIU R, ZHAO R, ZHOU X, et al.Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2[J].Hepatology, 2014, 60 (3) :908-918.
    [38]KARIMIAN G, BUIST-HOMAN M, SCHMIDT M, et al.Sphingosine kinase-1 inhibition protects primary rat hepatocytes against bile saltinduced apoptosis[J].Biochim Biophys Acta, 2013, 1832 (12) :1922-1929.
    [39]GENG T, SUTTER A, HARLAND MD, et al.Sph K1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes[J].J Lipid Res, 2015, 56 (12) :2359-2371.
    [40]LIU Y, SAIYAN S, MEN T, et al.Hepatopoietin Cn reduces ethanol-induced hepatoxicity via sphingosine kinase 1 and sphingosine1-phosphate receptors[J].J Pathol, 2013, 230 (4) :365-376.
    [41]GONZLEZ FERNNDEZ B, SNCHEZ DI, CRESPO I, et al.Inhibition of the Sph K1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells[J].Biofactors, 2017, 43 (2) :272-282.
    [42]OKAMOTO H, TAKUWA N, YOKOMIZO T, et al.Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5but not EDG1 or EDG3[J].Mol Cell Biol, 2000, 20 (24) :9247-9261.
    [43]WANG Y, AOKI H, YANG J, et al.The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice[J].Hepatology, 2017, 65 (6) :2005-2018.
    [44]DING BS, LIU CH, SUN Y, et al.HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver[J].JCI Insight, 2016, 1 (21) :e87058.
    [45]NAGAHASHI M, TAKABE K, LIU R, et al.Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2and hepatic gene expression[J].Hepatology, 2015, 61 (4) :1216-1226.
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  • 收稿日期:  2017-04-17
  • 出版日期:  2017-09-20
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