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autotaxin表达调控机制及其生物学功能

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中国科学：生命科学 2022年第8期52卷 1148-1162页

作者：张地张俊杰北京师范大学生命科学学院细胞增殖及调控生物学教育部重点实验室北京100875

autotaxin(ATX)是催化溶血磷脂酸(lysophosphatidic acid,LPA)生成的关键酶,LPA可以与细胞膜上至少6种G蛋白偶联受体(称为LPA受体1-6)结合,激活各种信号转导通路,在多种生理和病理过程中发挥重要作用.ATX的表达在转录、转录后及分泌过... 详细信息

autotaxin(ATX)是催化溶血磷脂酸(lysophosphatidic acid,LPA)生成的关键酶,LPA可以与细胞膜上至少6种G蛋白偶联受体(称为LPA受体1-6)结合,激活各种信号转导通路,在多种生理和病理过程中发挥重要作用.ATX的表达在转录、转录后及分泌过程中受到多水平的调控,近期的研究还发现了ATX表达的表观遗传调控机制.肿瘤微环境中ATX和LPA可以促进肿瘤细胞的增殖和迁移,因此ATX-LPA通路被认为是一种潜在的癌症治疗靶点.目前,人们已经研发了多种ATX抑制剂,并发现具有临床应用潜力.本文重点关注ATX的表达调控机制和生物学功能,阐释ATX-LPA信号轴调控的生理和病理意义.

关键词： autotaxin 溶血磷脂酸溶血磷脂酸受体表达调控生物学功能

Serum autotaxin levels are correlated with hepatic fibrosis and ballooning in patients with non-alcoholic fatty liver disease

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World Journal of Gastroenterology 2018年第11期24卷 1239-1249页

作者： Naoyuki Fujimori Takeji Umemura Takefumi Kimura Naoki Tanaka Ayumi Sugiura Tomoo Yamazaki Satoru Joshita Michiharu Komatsu Yoko Usami Kenji Sano Koji Igarashi Akihiro Matsumoto Eiji Tanaka Department of Internal Medicine Division of GastroenterologyShinshu University School of MedicineMatsumoto 390-8621Japan Department of Metabolic Regulation Shinshu University Graduate School of MedicineMatsumotoJapanand Research Center for Agricultural Food IndustryShinshu UniversityMatsumoto390-8621Japan Department of Laboratory Medicine Shinshu University HospitalMatsumoto 390-8621Japan Bioscience Division TOSOH CorporationKanagawa 252-1123Japan

AIM To examine the relationship between serum autotaxin(ATX) concentrations and clinicopathological findings in non-alcoholic fatty liver disease(NAFLD) patients.METHODS One hundred eighty-six NAFLD patients who had undergone liver biopsy between 2008 and 2017 were retrospectively enrolled.Serum samples were collected at the time of biopsy and ATX was measured by enzyme immunoassays.Sera obtained from 160 healthy,nonobese individuals were used as controls.Histological findings were graded according to an NAFLD scoring system and correlations with serum ATX were calculated by Spearman's test.Diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve(AUC).Cut-off values were identified by the Youden index,and the nearest clinically applicable value to the cutoff was considered the optimal threshold for clinical convenience.RESULTS Serum ATX levels were significantly higher in NAFLD patients than in controls(0.86 mg/L vs 0.76 mg/L,P < 0.001) and correlated significantly with ballooning score and fibrosis stage(r = 0.36,P < 0.001 and r = 0.45,P < 0.001,respectively).Such tendencies were stronger in female patients.There were no remarkable relationships between ATX and serum alanine aminotransferase,lipid profiles,or steatosis scores.The AUC values of ATX for predicting the presence of fibrosis(≥ F1),significant fibrosis(≥ F2),severe fibrosis(≥ F3),and cirrhosis(F4),were all more than 0.70 in respective analyses.CONCLUSION Serum ATX levels may at least partially reflect histological severity in NAFLD.

关键词： autotaxin Non-alcoholic fatty liver disease Fibrosis Ballooning

autotaxin在原发性胆汁性胆管炎和原发性干燥综合征中的意义

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中华风湿病学杂志 2023年第3期27卷 145-150,I0002页

作者：杨怡飞臧博刘秉乾赵晨阳王会芳刘伶伟韩怡冰刘斌青岛大学附属医院风湿免疫科青岛266003

目的本研究旨在探究autotaxin(ATX)在原发性胆汁性胆管炎(PBC)与pSS中的差异与诊断价值。方法取自2020年9月至2021年9月期间237例诊断为PBC、PBC继发SS、pSS以及健康对照组(HC)的血浆,收集各组的临床资料,采用ELISA测定各组ATX的水平,... 详细信息

目的本研究旨在探究autotaxin(ATX)在原发性胆汁性胆管炎(PBC)与pSS中的差异与诊断价值。方法取自2020年9月至2021年9月期间237例诊断为PBC、PBC继发SS、pSS以及健康对照组(HC)的血浆,收集各组的临床资料,采用ELISA测定各组ATX的水平,并统计相应灵敏度、特异度、阳性预测值(PPV)、阴性预测值(NPV)和曲线下面积(AUC)等。正态分布数据以±s表示,非正态分布以中位数M(Q1,Q3)表示。应用Mann-Whitney U检验、Spearman秩相关性分析等,评估ATX和各组生化检查之间的差异性和相关性。P<0.05为差异有统计学意义。结果研究结果显示ATX在PBC、PBC继发SS、和pSS阳性率分别为33.9%、33.3%和53.3%;特异度分别为93.1%,100%和93.2%。并且在pSS中的ATX诊断灵敏度和特异度分别为86.5%和93.2%均明显高于PBC组(灵敏度56.8%,特异度93.1%)。与HC组[32.6(21.8,60.5)ng/ml]相比较,ATX水平在PBC[59.3(48.6,86.3)ng/ml,U=1750.50,P<0.001]、PBC继发SS[73.6(53.3,102.4)ng/ml,U=199.00,P<0.001]、pSS[152.6(97.4,192.1)ng/ml,U=264.00,P<0.001]中均有升高,差异有统计学意义。从中位数水平看ATX浓度从pSS组至HC组呈现递减趋势,且ATX在PBC组[AUC(95%CI)=0.73(0.651,0.812),P<0.001],PBC继发SS组[AUC(95%CI)=0.82(0.730,0.912),P<0.001]和pSS组[AUC(95%CI)=0.94(0.898,0.984),P<0.001]中均有一定预测准确性。pSS组中ATX与白蛋白(r=-0.31,P=0.041)含量和ALT(r=-0.26,P=0.024)含量呈负相关性。结论ATX在PBC和pSS中均有诊断价值,且在pSS中的灵敏度和特异度更高。

关键词：原发性胆汁性胆管炎干燥综合征诊断 autotaxin

Usefulness of autotaxin for the complications of liver cirrhosis

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World Journal of Gastroenterology 2020年第1期26卷 97-108页

作者： Xue Shao Haruki Uojima Toru Setsu Tomomi Okubo Masanori Atsukawa Yoshihiro Furuichi Yoshitaka Arase Hisashi Hidaka Yoshiaki Tanaka Takahide Nakazawa Makoto Kako Tatehiro Kagawa Katsuhiko Iwakiri Shuji Terai Wasaburo Koizumi Department of Gastroenterology Internal MedicineKitasato University School of MedicineSagamiharaKanagawa 252-0375Japan Department of Hepatopancreatobiliary Medic Department of Gastroenterology Shonan Kamakura General HospitalKamakuraKanagawa 247-8533Japan Division of Gastroenterology and Hepatology Graduate School of Medical and Dental SciencesNiigata UniversityNiigata 951-8510Japan Department of Internal Medicine Division of GastroenterologyNippon Medical School Chiba Hokusoh HospitalChiba 270-1694Japan Department of Internal Medicine Division of Gastroenterology and HepatologyNippon Medical SchoolTokyo 113-8603Japan Department of Gastroenterology and Hepatology Tokyo Medical University HospitalShinjukuTokyo 113-8510Japan Division of Gastroenterology and Hepatology Department of Internal MedicineTokai University School of MedicineKanagawa 259-1193Japan

BACKGROUND autotaxin(ATX)has been reported as a direct biomarker for estimating the evaluation of liver fibrosis.But available data on ATX as a useful biomarker for the complications of liver cirrhosis(LC)are scant.AIM To assess the clinical usefulness of ATX for assessing the complications of LC.METHODS This multicenter,retrospective study was conducted at six locations in Japan.We include patients with LC,n=400.The ATX level was evaluated separately in men and women because of its high level in female patients.To assess the clinical usefulness of ATX for the complications of LC,the area under the curve(AUC)of ATX assessing for the severe complications was analyzed in comparison with the model for end-stage liver disease score,albumin-bilirubin(ALBI)score,fibrosis-4 index,and aspartate aminotransferase-to-platelet ratio index.RESULTS The mean age was 68.4±11.4 years,240 patients(60.0%)were male.A total of 213(53.3%)and 187(46.8%)patients were compensated and decompensated,respectively.The numbers of patients with varix rupture,hepatic ascites,and hepatic encephalopathy were 35(8.8%),131(32.8%),and 103(25.8%),respectively.The AUCs of ATX in men for hepatic encephalopathy,hepatic ascites,and varix ruptures were 0.853,0.816,and 0.706,respectively.The AUCs of ATX in women for hepatic encephalopathy,hepatic ascites,and varix rupture were 0.759,0.717,and 0.697,respectively.The AUCs of ATX in men were higher than those in women,as were all the other biomarkers used to detect encephalopathy and varix ruptures.However,for detecting ascites,the AUC of ALBI in men was more effective than using ATX.CONCLUSION ATX in men was more effective than any other biomarkers for detecting hepatic encephalopathy and varix ruptures.

关键词： autotaxin Hepatic encephalopathy Hepatic ascites Liver fibrosis Biomarker

Recent advances in the management of pruritus in chronic liver diseases

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World Journal of Gastroenterology 2017年第19期23卷 3418-3426页

作者： Kazuto Tajiri Yukihiro Shimizu Department of Gastroenterology Toyama University Hospital Gastroenterology Center Nanto Municipal Hospital

Pruritus is a symptom found in patients with chronic liver diseases,especially cholestatic liver diseases such as primary biliary cholangitis.This symptom impairs patient quality of life by disturbing sleep and may lead to consideration of liver transplantation.Mechanisms implicated in pruritus have been associated with the peripheral and central nervous systems,leading to the development of various therapeutic options.Little evidence for the efficacy of most of these treatments is currently available,indicating a need for further investigations.

关键词：瘙痒 Cholestasis autotaxin Opioid 受体对手

production of extracellular lysophosphatidic acid in the regulation of adipocyte functions and liver fibrosis

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World Journal of Gastroenterology 2018年第36期24卷 4132-4151页

作者： Fang Yang Guo-Xun Chen School of Laboratory Medicine Hubei University of Chinese Medicine Department of Nutrition University of Tennessee at Knoxville

Lysophosphatidic acid(LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in submillimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin(ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.

关键词： autotaxin Lysophosphatidic acid receptors Obesity Lysophosphatidic acid Insulin resistance Liver fibrosis

autotaxin and lysophosphatidic acid signalling in lung pathophysiology

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World Journal of Respirology 2013年第3期3卷 77-103页

作者： Christiana Magkrioti Vassilis Aidinis Institute of Immunology Biomedical Sciences Research Center Alexander Fleming

autotaxin(ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid(LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors(LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysi-ological situations in vivo and in human diseases.

关键词： autotaxin Lysophosphatidic acid Lung Acute lung injury Pulmonary fibrosis Asthma Lung cancer

肝细胞癌autotaxin cDNA部分序列测定及其意义

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中华肝脏病杂志 1999年第3期7卷 140-141页

作者：赵志泉徐顺福张国新张红杰南京医科大学第一附属医院消化科 210029

目的进行肝癌Ａｕｔｏｔａｘｉｎ（ＡＴＸ）ｃＤＮＡ部分序列测定，观察ＡＴＸｍＲＮＡ在肝癌组织中的表达程度，以探讨ＡＴＸ在肝癌转移机理中的作用。方法提取肝癌７７２１细胞株、５例正常肝组织、３２例肝癌组织ＲＮＡ，参照黑色素... 详细信息

目的进行肝癌Ａｕｔｏｔａｘｉｎ（ＡＴＸ）ｃＤＮＡ部分序列测定，观察ＡＴＸｍＲＮＡ在肝癌组织中的表达程度，以探讨ＡＴＸ在肝癌转移机理中的作用。方法提取肝癌７７２１细胞株、５例正常肝组织、３２例肝癌组织ＲＮＡ，参照黑色素瘤ＡＴＸｃＤＮＡ序列设计引物，经逆转录聚台酶链反应（ＲＴ－ＰＣＲ）扩增肝癌ＡＴＸ，以卜ａｃｔｉｎ基因为内参照进行ＡＴＸｍＲＮＡ表达程度分析，同时７７２１细胞株ＲＴ－ＰＣＲ产物进行ｃＤＮＡ序列测定。结果肝癌７７２１细胞株３２例肝癌组织５例正常肝组织中均有ＡｕｔｏｔａｘｉｎｍＲＮＡ表达，其ｃＤＮＡ序列测定（３３ｈｐ）显示与黑色素瘤具有９９．７％的同源性；癌组织ＡＴＸｍＲＮＡ表达显著高于正常肝组织（分别为０．６８±０．１和０．３１±０．０８）。结论肝癌及正常肝组织表达ＡＴＸｍＲＮＡ，ＡＴＸ可能参与了肝癌的浸润与转移过程，在其中扮演了重要角色。

关键词： autotaxin 肝细胞癌 cDNA 序列分析

Alkaline sphingomyelinase(NPP7) in hepatobiliary diseases: A field that needs to be closely studied

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World Journal of Hepatology 2018年第2期10卷 246-253页

作者： Rui-Dong Duan Gastroenterology and Nutrition Lab Department of Clinical Sciences Lund University

Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidyl-choline. The enzyme shares no structure similarities with acid or neutral sphingomyelinase but belongs to ectonucleotide pyrophosphatase/phosphodiesterase(NPP) family and therefore is also called NPP7 nowadays. The enzyme is expressed in the intestinal mucosa in many species and additionally in human liver. The enzyme in the intestinal tract has been extensively studied but not that in human liver. Studies on intestinal alkaline sphingomyelinase show that it inhibits colonic tumorigenesis and inflammation, hydrolyses dietary sphingomyelin, and stimulates cholesterol absorption. The review aims to summarize the current knowledge on liver alkaline sphingomyelinase in human and strengthen the necessity for close study on this unique human enzyme in hepatobiliary diseases.

关键词： Sphingomyelin Alkaline sphingomyelinase Nucleotide pyrophosphatase/phosphodiesterase 7 autotaxin Platelet-activating factor Cholangiocarcinoma Liver diseases Gallstone