法尼醇X受体在溃疡性结肠炎中的作用
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摘要
溃疡性结肠炎是一种慢性、非特异性肠病,其发病机制尚不明确。法尼醇X受体(Farnesoid X receptor,FXR)是胆汁酸的生理性受体,除了调节胆汁酸代谢及转运外,FXR在调节脂质和葡萄糖稳态、炎症反应、屏障功能和预防肠道细菌移位等方面起着关键作用。而FXR的这些调控机制可能会为溃疡性结肠炎的治疗带来新的靶点。该文综述FXR以及其在溃疡性结肠炎中的作用机制。
Ulcerative colitis is a chronic,non-specific enteropathy,and its pathogenesis is still unclear. Farnesoid X receptor(FXR) is a physiological receptor for bile acids. In addition to regulating bile acid metabolism and transport,FXR plays a key role on lipid and glucose homeostasis,inflammatory response,barrier function,and prevention of intestinal bacterial translocation. These regulatory mechanisms of FXR may bring new targets for the treatment of ulcerative colitis. This article reviews the general information of FXR receptors and their mechanisms of action in ulcerative colitis.
Ulcerative colitis is a chronic,non-specific enteropathy,and its pathogenesis is still unclear. Farnesoid X receptor(FXR) is a physiological receptor for bile acids. In addition to regulating bile acid metabolism and transport,FXR plays a key role on lipid and glucose homeostasis,inflammatory response,barrier function,and prevention of intestinal bacterial translocation. These regulatory mechanisms of FXR may bring new targets for the treatment of ulcerative colitis. This article reviews the general information of FXR receptors and their mechanisms of action in ulcerative colitis.
引文
[1]高旭东,谭静范,张莉.溃疡性结肠炎的中医治疗进展[J].当代医学,2017,23(33):175-177.
[2]赵曼,高峰.溃疡性结肠炎发病机制研究进展[J].现代生物医学进展,2010,10(16):3160-3165.
[3]张声生.溃疡性结肠炎中医诊疗共识意见[J].中华中医药杂志,2010,25(6):891-895.
[4]ZHANG Z C,LI Y X,SHEN P.Administration of geniposide ameliorates dextran sulfate sodium-induced colitis in mice via inhibition of in ammation and mucosal damage[J].Journal of Ethnopharmacology,2017,49:168-177.
[5]XU Z Z,HUANG G,GONG W,et al.FXR ligands protect against hepatocellular inflammation via SOCS3 induction[J].Cellular Signalling,2012,24(8):58-64.
[6]ZHU Y,LI F,GUO G L.Tissue-specific function of farnesoid Xreceptor in liver and intestine[J].Pharmacol Res,2011,63,259-265.
[7]FORMAN B M,GOODE E,CHEN J,et al.Identification of a nuclear receptor that is actvated by farnesol metabolities[J].Cell,1995,81(5):687-693.
[8]LEFEBVRE P,CARIOU B,LIEN F,et al.Role of bile acids and bile acid receptors in metabolic regulation[J].Physiol Rev,2009,89(1):147-191.
[9]LI Y,JADHAV K,ZHANG Y.Bile acid receptors in non-alcoholic fatty liver disease[J].Biochem Pharmacol,2013,86:1517-1524.
[10]李卫华,付静,郑明月,等.核受体FXR的配体及复合物结构研究进展[J].药学学报,2012,47(6):704-715.
[11]艾国,颜耀东,黄正明.基于调控法尼醇X受体的中药治疗肝内胆汁瘀积的研究进展[J].中草药,2017,48(19):4077-4088.
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[13]VAVASSOR P,MENCARELLI A,RENGA B,et al.The bile acid receptor FXR is amodulator of intestinal innate immunity[J].JImmunol,2009,183(10):6251-6261.
[14]魏敏,程文芳,平晶,等.胆汁酸受体FXR和TGR5在溃疡性结肠炎中的表达[J].胃肠病学,2017,22(8):465-468.
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[16]林睿.肠肝轴在慢性肝病发生发展中的作用[J].当代医学,2015,3(21):9-10.
[17]罗艺徽.基于“肠-肝”轴研究天然牛磺酸复方对肝硬化门静脉高压症患者肠道菌群的影响[D].南宁:广西中医药大学,2018.
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[26]KURDI P,KAWANISHI K,MIZUTANI K,et al.Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria[J].Journal of Bacteriology,2006,188(5):1979-1986.
[27]INAGAKI T,MOSCHETTA A,LEE Y K,et al.Regulation of anti bacterial defense in the small intestine by the nuclear bile acid receptor[J].Proc Natl Acad Sci USA,2006,103(10):3920-3925.
[28]UBEDA M,LARIO M,MUOZ L,et al.Obeticholic acid reducesbacterial translocation and inhibits intestinal inflammation in cirrhotic rats[J].J Hepatol,2016,64(5):1049-1057.
[29]NIJMEIJER R M,SCHAAP F G,SMITS A J J,et al.Impact of global FXR deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis[J].PLoS One,2014,9(12):e114393.
[30]袁榴翼,李小锦,尹清晟,等.中药干预肠道菌群改善肠黏膜屏障功能的研究进展[J].中草药,2018,49(8):1932-1938.
[31]张超贤,郭李柯,郭晓凤.三硝基苯磺酸/乙醇灌肠液诱导大鼠溃疡性结肠炎TLR4/NF-κB和PI3K/AKT/NF-κB信号通路的表达及电针的干预作用[J].西安交通大学学报(医学版),2015,36(2):263-270.
[32]DURAND J K,BALDWIN A S.Targeting IKK and NF-κB for therapy[J].Adv Protein Chem Struct Biol,2017,107:77-115.
[33]王鹏程,赵珊,冯健,等.基于NF-κB信号通路的中药抗溃疡性结肠炎研究进展[J].中草药,2015,46(10):1556-1561.
[34]MODICA S,MURZILLI S,SALVATORE L,et al.Nuclear bile acid receptor FXR protects against intestinal tumorigenesis[J].Cancer Research,2008,68(23):9589-9594.
[35]RAFFAELLA M,GADAlLET A,OLDENBURG B,et al.Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine[J].BBA-Molecular Basis of Disease,2011,1812(8):851-858.
[36]商晓源,刘杰民.TLR4/MyD88/NF-κB信号通路与溃疡性结肠炎[J].胃肠病学,2013,8(4):244-246.
[37]RACHMILEWITZ D,SIMON P L,SCHWARTZ L W,et al.Inflammatory mediators of experimental colitis in rats[J].Gastroenterology,1989,97(2):326.
[38]YU Z H,HUANG F,XU N,et al.Expression of Toll-like receptor 4,CD14,and NF-κB in Chinese patients with ulcerative colitis[J].Immunoass lmmunochem,2011,32(1):47-56.
[39]STACK W A,MANN S D,Roy A J,et al.Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn’s disease[J].Lancet,1997,349:521-524.
[40]DANESE S,FIOCCHI C.Ulcerative colitis[J].N Engl J Med,2011,365(18):1713-1725.
[41]POPE J L,BHAT A A,SHARMA A,et al.Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notchsignalling[J].Gut,2014,63(4):622-634.
[42]SAITOH Y,SUZUKI H,TANI K,et al.Tight junctions.Structural insight into tight junction disassembly by clostridium perfringens enterotoxin[J].Science,2015,347:775-778.
[43]王希,廖吕钊,江荣林.肠上皮细胞紧密连接蛋白的结构功能及其调节[J].浙江医学,2018,40(8):895-898.
[44]MATTER K,BALDA M S.Snap shot:Epithelial tight junctions[J].Cell,2014,157(4):992-992.
[45]高安定,林宝顺,兰小鹏.STAT3与肿瘤[J].中国生物化学与分子生物学报,2013,29(5):397-403.
[46]张霆.溃疡性结肠炎肠道屏障与STAT3信号转导通路关系的研究[D].天津:天津医科大学,2013.
[47]ZHAO C G,LI H M,LIN H J,et al.Feedback activation of STAT3 as a cancer drug-resistance mechanism[J].Trends in Pharmacological Sciences,2016,37(1):1283.
[48]FIORUCCI S,CIPRIANI S,MENCARELLI A,et al.Counterregulatory role of bile acid activated receptors in immunity and inflammation[J].Curr Mol Med,2010,10:579-595.
[49]储勤军.SOCS3介导的IL6/STAT3炎症通路在结直肠癌发生发展中的作用及机制研究[D].郑州:郑州大学,2016.
[50]涂飞霞,阮菲,吴瑞瑾,等.STAT3和SOCS3与子宫内膜异位症的相关性研究[J].中国病理生理杂志,2012,28(1):152-154,158.
[51]XU Z Z,HUANG G,GONG W,et al.FXR ligands protect against hepatocellular inflammation via SOCS3 induction[J].Cellular Signalling,2012,24(8):1658-1664.
[52]卫江鹏,刘刚,张霆等.溃疡性结肠炎患者肠道机械屏障变化与STAT3信号通路关系的研究[J].胃肠病学和肝病学杂志,2016,25(1):47-50.
[53]PUTOCZKI T L,THIEM S,LOVING A,et al.Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically[J].Cancer Cell,2013,24(2):257-271.
[54]GRIVENNIKOV S I.IL-11:A prominent pro-tumorigenic member of the IL-6 family[J].Cancer Cell,2013,24(2):145-147.
[55]GUO S H,NIGHOT M,AL-SADI R,et al.Lipopolysaccharide regulation of intestinal tight junction permeability is mediated by TLR4 signal transduction pathway activation of FAK and MyD88[J].The Journal of Immunology,2015,195(10):4999-5010.
[56]LENDEMANS S,KREUZFELDER E,RANI M,et al.Toll-like recepor 2 and 4 expression after severe injury is not involved in he dysregulation of the innate immune system[J].J Trauma,2007,63(4):740-746.
[57]杨如会,刘丙进,吴松泉.淫羊藿苷通过FXR降低LPS/TLR4诱导的肝星状细胞自噬和活化[J].中国药学杂志,2016,51(9):708-714.
[58]CARIO E,GERKEN G,PODOLSKY D K.Toll-like receptor 2controls mucosal inflammation by regulating epithelial barrier function[J].Gastroenterology,2007,132(4):1359-1374.
[59]RENGA B,MENCARELLI A,CIPRIAIN S,et al.The bile acid sensor FXR is required for immune-regulatory activities of TLR-9in intestinal inflammation[J].PLoS One,2013,8(1):e54472.
[60]LIU H M,LIAO J F,LEE T Y.Farnesoid X receptor agonist GW4064 ameliorates lipopolysaccharide-induced ileocolitis through TLR4、MyD88 pathway related mitochondrial dysfunction in mice[J].Biochemical and Biophysical Research Communications,2017,490(3):841-848.
[61]徐俐洁,蒋思达,季晖,等.胆汁酸核受体FXR在胆汁淤积及其药物治疗中的研究进展[J].药学研究,2018,37(3):169-173.
[2]赵曼,高峰.溃疡性结肠炎发病机制研究进展[J].现代生物医学进展,2010,10(16):3160-3165.
[3]张声生.溃疡性结肠炎中医诊疗共识意见[J].中华中医药杂志,2010,25(6):891-895.
[4]ZHANG Z C,LI Y X,SHEN P.Administration of geniposide ameliorates dextran sulfate sodium-induced colitis in mice via inhibition of in ammation and mucosal damage[J].Journal of Ethnopharmacology,2017,49:168-177.
[5]XU Z Z,HUANG G,GONG W,et al.FXR ligands protect against hepatocellular inflammation via SOCS3 induction[J].Cellular Signalling,2012,24(8):58-64.
[6]ZHU Y,LI F,GUO G L.Tissue-specific function of farnesoid Xreceptor in liver and intestine[J].Pharmacol Res,2011,63,259-265.
[7]FORMAN B M,GOODE E,CHEN J,et al.Identification of a nuclear receptor that is actvated by farnesol metabolities[J].Cell,1995,81(5):687-693.
[8]LEFEBVRE P,CARIOU B,LIEN F,et al.Role of bile acids and bile acid receptors in metabolic regulation[J].Physiol Rev,2009,89(1):147-191.
[9]LI Y,JADHAV K,ZHANG Y.Bile acid receptors in non-alcoholic fatty liver disease[J].Biochem Pharmacol,2013,86:1517-1524.
[10]李卫华,付静,郑明月,等.核受体FXR的配体及复合物结构研究进展[J].药学学报,2012,47(6):704-715.
[11]艾国,颜耀东,黄正明.基于调控法尼醇X受体的中药治疗肝内胆汁瘀积的研究进展[J].中草药,2017,48(19):4077-4088.
[12]LEE F Y,LEE H,HUBBERT M L,et al.FXR,amulti purpose nuclear receptor[J].Trends Biochem Sci,2006,31(10):572-580.
[13]VAVASSOR P,MENCARELLI A,RENGA B,et al.The bile acid receptor FXR is amodulator of intestinal innate immunity[J].JImmunol,2009,183(10):6251-6261.
[14]魏敏,程文芳,平晶,等.胆汁酸受体FXR和TGR5在溃疡性结肠炎中的表达[J].胃肠病学,2017,22(8):465-468.
[15]MIURA K,OHNISH H.Role of gut microbiota and Toll like receplors in nonalcoholic fatty liver disease[J].World J Gastroenterol,2014,20(23):7381-7391.
[16]林睿.肠肝轴在慢性肝病发生发展中的作用[J].当代医学,2015,3(21):9-10.
[17]罗艺徽.基于“肠-肝”轴研究天然牛磺酸复方对肝硬化门静脉高压症患者肠道菌群的影响[D].南宁:广西中医药大学,2018.
[18]左晓.结肠炎性肝内胆汁淤积的发病机制初探[D].兰州:兰州大学,2018.
[19]LOTTA K,REETTA H.High-fat-induced intestinal permeability dysfunction associated with altered fecal bile acids[J].World Journal of Gastroenterology,2012,18(9):923-929.
[20]DEGIROLAMO C,MODICA S,PALASCIANO G,et al.Bile acids and colon cancer:Solving the puzzle with nuclear receptor[J].Trends Mol Med,2011,17(10):564-572.
[21]CHEN F,MA L,DAWSON P A,et al.Liver receptor homologue-1 mediates species-and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transport[J].J Biol Chem,2003,278(22):19909-19916.
[22]INAGAKI T,CHOI M,MODCHETTA A,et al.Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis[J].Cell Metab,2005,2(4):217-225.
[23]GADALETA R M,ERPECUM K J,OLDENBURG B,et al.Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease[J].Gut,2011,60(4):463-472.
[24]JONES B V,BEGLEY M,HILL C,et al.Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome[J].Proc Nat Acad of Sci USA,2008,105(36):13580-13585.
[25]BEGLEY M,GAHAN C G,HILL C.The interaction between bacteria and bile[J].FEMS Microbiol Rev,2004,29:625-651.
[26]KURDI P,KAWANISHI K,MIZUTANI K,et al.Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria[J].Journal of Bacteriology,2006,188(5):1979-1986.
[27]INAGAKI T,MOSCHETTA A,LEE Y K,et al.Regulation of anti bacterial defense in the small intestine by the nuclear bile acid receptor[J].Proc Natl Acad Sci USA,2006,103(10):3920-3925.
[28]UBEDA M,LARIO M,MUOZ L,et al.Obeticholic acid reducesbacterial translocation and inhibits intestinal inflammation in cirrhotic rats[J].J Hepatol,2016,64(5):1049-1057.
[29]NIJMEIJER R M,SCHAAP F G,SMITS A J J,et al.Impact of global FXR deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis[J].PLoS One,2014,9(12):e114393.
[30]袁榴翼,李小锦,尹清晟,等.中药干预肠道菌群改善肠黏膜屏障功能的研究进展[J].中草药,2018,49(8):1932-1938.
[31]张超贤,郭李柯,郭晓凤.三硝基苯磺酸/乙醇灌肠液诱导大鼠溃疡性结肠炎TLR4/NF-κB和PI3K/AKT/NF-κB信号通路的表达及电针的干预作用[J].西安交通大学学报(医学版),2015,36(2):263-270.
[32]DURAND J K,BALDWIN A S.Targeting IKK and NF-κB for therapy[J].Adv Protein Chem Struct Biol,2017,107:77-115.
[33]王鹏程,赵珊,冯健,等.基于NF-κB信号通路的中药抗溃疡性结肠炎研究进展[J].中草药,2015,46(10):1556-1561.
[34]MODICA S,MURZILLI S,SALVATORE L,et al.Nuclear bile acid receptor FXR protects against intestinal tumorigenesis[J].Cancer Research,2008,68(23):9589-9594.
[35]RAFFAELLA M,GADAlLET A,OLDENBURG B,et al.Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine[J].BBA-Molecular Basis of Disease,2011,1812(8):851-858.
[36]商晓源,刘杰民.TLR4/MyD88/NF-κB信号通路与溃疡性结肠炎[J].胃肠病学,2013,8(4):244-246.
[37]RACHMILEWITZ D,SIMON P L,SCHWARTZ L W,et al.Inflammatory mediators of experimental colitis in rats[J].Gastroenterology,1989,97(2):326.
[38]YU Z H,HUANG F,XU N,et al.Expression of Toll-like receptor 4,CD14,and NF-κB in Chinese patients with ulcerative colitis[J].Immunoass lmmunochem,2011,32(1):47-56.
[39]STACK W A,MANN S D,Roy A J,et al.Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn’s disease[J].Lancet,1997,349:521-524.
[40]DANESE S,FIOCCHI C.Ulcerative colitis[J].N Engl J Med,2011,365(18):1713-1725.
[41]POPE J L,BHAT A A,SHARMA A,et al.Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notchsignalling[J].Gut,2014,63(4):622-634.
[42]SAITOH Y,SUZUKI H,TANI K,et al.Tight junctions.Structural insight into tight junction disassembly by clostridium perfringens enterotoxin[J].Science,2015,347:775-778.
[43]王希,廖吕钊,江荣林.肠上皮细胞紧密连接蛋白的结构功能及其调节[J].浙江医学,2018,40(8):895-898.
[44]MATTER K,BALDA M S.Snap shot:Epithelial tight junctions[J].Cell,2014,157(4):992-992.
[45]高安定,林宝顺,兰小鹏.STAT3与肿瘤[J].中国生物化学与分子生物学报,2013,29(5):397-403.
[46]张霆.溃疡性结肠炎肠道屏障与STAT3信号转导通路关系的研究[D].天津:天津医科大学,2013.
[47]ZHAO C G,LI H M,LIN H J,et al.Feedback activation of STAT3 as a cancer drug-resistance mechanism[J].Trends in Pharmacological Sciences,2016,37(1):1283.
[48]FIORUCCI S,CIPRIANI S,MENCARELLI A,et al.Counterregulatory role of bile acid activated receptors in immunity and inflammation[J].Curr Mol Med,2010,10:579-595.
[49]储勤军.SOCS3介导的IL6/STAT3炎症通路在结直肠癌发生发展中的作用及机制研究[D].郑州:郑州大学,2016.
[50]涂飞霞,阮菲,吴瑞瑾,等.STAT3和SOCS3与子宫内膜异位症的相关性研究[J].中国病理生理杂志,2012,28(1):152-154,158.
[51]XU Z Z,HUANG G,GONG W,et al.FXR ligands protect against hepatocellular inflammation via SOCS3 induction[J].Cellular Signalling,2012,24(8):1658-1664.
[52]卫江鹏,刘刚,张霆等.溃疡性结肠炎患者肠道机械屏障变化与STAT3信号通路关系的研究[J].胃肠病学和肝病学杂志,2016,25(1):47-50.
[53]PUTOCZKI T L,THIEM S,LOVING A,et al.Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically[J].Cancer Cell,2013,24(2):257-271.
[54]GRIVENNIKOV S I.IL-11:A prominent pro-tumorigenic member of the IL-6 family[J].Cancer Cell,2013,24(2):145-147.
[55]GUO S H,NIGHOT M,AL-SADI R,et al.Lipopolysaccharide regulation of intestinal tight junction permeability is mediated by TLR4 signal transduction pathway activation of FAK and MyD88[J].The Journal of Immunology,2015,195(10):4999-5010.
[56]LENDEMANS S,KREUZFELDER E,RANI M,et al.Toll-like recepor 2 and 4 expression after severe injury is not involved in he dysregulation of the innate immune system[J].J Trauma,2007,63(4):740-746.
[57]杨如会,刘丙进,吴松泉.淫羊藿苷通过FXR降低LPS/TLR4诱导的肝星状细胞自噬和活化[J].中国药学杂志,2016,51(9):708-714.
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