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溶血磷脂酸(lysophosphatidic acid,LPA)是一种结构简单的生物活性脂质分子,可通过与细胞膜上的LPA受体(lysophosphatidic acid receptors,LPARs)结合参与调控细胞生命活动,在多种生理和病理过程中发挥作用.分泌型糖蛋白Autotaxin(ATX)具溶血磷脂酶D(l... 相似文献
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Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions and demonstrates medicinal relevance. LPA’s functional roles are driven by extracellular signaling through at least six 7-transmembrane G protein-coupled receptors. These receptors are named LPA1–6 and signal through numerous effector pathways activated by heterotrimeric G proteins, including Gi/o, G12/13, Gq, and Gs. LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity. These studies underscore the potential of LPA receptor subtypes and related signaling mechanisms to provide novel therapeutic targets. 相似文献
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Keigo Inoue Nobutada Tanaka Arayo Haga Kyohei Yamasaki Tomonobu Umeda Yoshio Kusakabe Yasumitsu Sakamoto Takamasa Nonaka Yoshihiro Deyashiki Kazuo T. Nakamura 《Acta Crystallographica. Section F, Structural Biology Communications》2011,67(4):450-453
Autotaxin (ATX), which is also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (NPP2 or ENPP2) or phosphodiesterase Iα (PD‐Iα), is an extracellular lysophospholipase D which generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). ATX stimulates tumour‐cell migration, angiogenesis and metastasis and is an attractive target for cancer therapy. For crystallographic studies, the α isoform of human ATX was overproduced in Escherichia coli, purified and crystallized using the hanging‐drop vapour‐diffusion method. X‐ray diffraction data were collected to 3.0 Å resolution from a monoclinic crystal form belonging to space group C2, with unit‐cell parameters a = 311.4, b = 147.9, c = 176.9 Å, β = 122.6°. 相似文献
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We previously reported that nerve injury‐induced neuropathic pain and its underlying mechanisms are initiated by lysophosphatidic acid. In the present study, by measuring cell‐rounding in a biological assay using lysophosphatidic acid 1 receptor‐expressing B103 cells, we evaluated the molecular mechanism underlying lysophosphatidic acid biosynthesis following intense stimulation of primary afferents. Lysophosphatidic acid production was induced by treatment of spinal cord slices with capsaicin (10 μM), an intense stimulator of primary afferents, in the presence of recombinant autotaxin, but not in its absence. Lysophosphatidic acid was also induced by combination treatment of slices with high doses (10 and 30 μM) of substance P and NMDA, but not by other combinations of substance P, NMDA, calcitonin gene‐related peptide and α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (30 μM each) in the presence of recombinant autotaxin. We also found that following neurokinin 1 and NMDA receptor activation, activation of both cytosolic phospholipase A2 and calcium‐independent intracellular phospholipase A2 signalling pathways through protein kinase C and mitogen‐activated protein/extracellular signal‐regulated kinase activation and intracellular calcium elevation were required for lysophosphatidic acid production. These findings suggest that simultaneous intense stimulation of neurokinin 1 and NMDA receptors in the spinal dorsal horn triggers lysophosphatidic acid production from lysophosphatidylcholine through extracellular autotaxin. 相似文献
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Identification of autotaxin as a neurite retraction-inducing factor of PC12 cells in cerebrospinal fluid and its possible sources 总被引：5，自引：0，他引：5
Sato K Malchinkhuu E Muraki T Ishikawa K Hayashi K Tosaka M Mochiduki A Inoue K Tomura H Mogi C Nochi H Tamoto K Okajima F 《Journal of neurochemistry》2005,92(4):904-914
Abstract Cerebrospinal fluid (CSF) induced neurite retraction of differentiated PC12 cells; the action was observed in 15 min (a rapid response) and the activity further increased until 6 h (a long-acting response) during exposure of CSF to the cells. The CSF action was sensitive to monoglyceride lipase and diminished by homologous desensitization with lysophosphatidic acid (LPA) and by pretreatment with an LPA receptor antagonist Ki16425. Although fresh CSF contains LPA to some extent, the LPA content in the medium was increased during culture of PC12 cells with CSF. The rapid response was mimicked by exogenous LPA, and a long-acting response was duplicated by a recombinant autotaxin, lysophospholipase D (lyso-PLD). Although the lyso-PLD substrate lysophosphatidylcholine (LPC) was not detected in CSF, lyso-PLD activity and an approximately 120-kDa autotaxin protein were detected in CSF. On the other hand, LPC but not lyso-PLD activity was detected in the conditioned medium of a PC12 cell culture without CSF. Among neural cells examined, leptomeningeal cells expressed the highest lyso-PLD activity and autotaxin protein. These results suggest that leptomeningeal cells may work as one of the sources for autotaxin, which may play a critical role in LPA production and thereby regulate axonal and neurite morphological change. 相似文献
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Chen J Chen Y Zhu W Han Y Han B Xu R Deng L Cai Y Cong X Yang Y Hu S Chen X 《Journal of cellular biochemistry》2008,103(6):1718-1731
Lysophosphatidic acid (LPA) is a bioactive phospholipid with diverse functions mediated via G-protein-coupled receptors (GPCRs). In view of the elevated levels of LPA in acute myocardial infarction (MI) patients we have conducted studies aimed at identifying specific LPA receptor subtypes and signaling events that may mediate its actions in hypertrophic remodeling. Experiments were carried out in cultured neonatal rat cardiomyocytes (NRCMs) exposed to LPA and in a rat MI model. In NRCMs, LPA-induced hypertrophic growth was completely abrogated by DGPP, an LPA1/LPA3 antagonist. The LPA3 agonist OMPT, but not the LPA2 agonist dodecylphosphate, promoted hypertrophy as examined by 3[H]-Leucine incorporation, ANF-luciferase expression and cell area. In in vivo experiments, LPA1, LPA2 and LPA3 mRNA levels as well as LPA1 and LPA3 protein levels increased together with left ventricular remodeling (LVRM) after MI. In addition, LPA stimulated the phosphorylation of Akt and p65 protein and activated NF-kappaB-luciferase expression. Inhibitors of PI3K (wortmannin), mTOR (rapamycin), and NF-kappaB (PDTC or SN50) effectively prevented LPA-induced 3[H]-Leucine incorporation and ANF-luciferase expression. Furthermore, ERK inhibitors (U0126 and PD98059) suppressed LPA-stimulated activation of NF-kappaB and p65 phosphorylation whereas wortmannin showed no effect on NF-kappaB activation. Our findings indicate that LPA3 and/or LPA1 mediate LPA-induced hypertrophy of NRCMs and that LPA1 and LPA3 may be involved in LVRM of MI rats. Moreover, Akt and NF-kappaB signaling pathways independently implicate in LPA-stimulated myocardial hypertrophic growth. 相似文献
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溶血磷脂酸受体及下游信号通路在心脏细胞生长中的调节作用 总被引：4，自引：0，他引：4
溶血磷脂酸（1ysophosphatidic acid,LPA）是一种十分活跃的磷脂信号分子,具有广泛的生物学效应,包括诱导神经轴突回缩、应力纤维形成、促进血小板凝集、诱导平滑肌收缩、刺激血管平滑肌细胞增殖等。LPA通过其受体及耦联的G蛋白调节细胞内信号途径,介导各种生物学效应。心脏组织中存在多种LPA受体亚型,尤其受体LPAl亚型在心脏组织中的含量仅次于脑,位居第二,暗示LPA在心脏中有重要的生物学功能。本文着重对LPA的5种受体亚型的组织分布、与G蛋白的耦联和对第二信使的活性调节,以及LPA及其受体亚型对心脏细胞的生长调节作一综述。 相似文献
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Autotaxin–lysophosphatidic acid–LPA3 signaling at the embryo‐epithelial boundary controls decidualization pathways 
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下载免费PDF全文 Asuka Inoue Jiao Wang Daisuke Saigusa Takeshi Nagamatsu Yasushi Hirota Tomoyuki Fujii Soken Tsuchiya Yoshitaka Taketomi Yukihiko Sugimoto Makoto Murakami Makoto Arita Makoto Kurano Hitoshi Ikeda Yutaka Yatomi Jerold Chun Junken Aoki 《The EMBO journal》2017,36(14):2146-2160
During pregnancy, up‐regulation of heparin‐binding (HB‐) EGF and cyclooxygenase‐2 (COX‐2) in the uterine epithelium contributes to decidualization, a series of uterine morphological changes required for placental formation and fetal development. Here, we report a key role for the lipid mediator lysophosphatidic acid (LPA) in decidualization, acting through its G‐protein‐coupled receptor LPA3 in the uterine epithelium. Knockout of Lpar3 or inhibition of the LPA‐producing enzyme autotaxin (ATX) in pregnant mice leads to HB‐EGF and COX‐2 down‐regulation near embryos and attenuates decidual reactions. Conversely, selective pharmacological activation of LPA3 induces decidualization via up‐regulation of HB‐EGF and COX‐2. ATX and its substrate lysophosphatidylcholine can be detected in the uterine epithelium and in pre‐implantation‐stage embryos, respectively. Our results indicate that ATX–LPA–LPA3 signaling at the embryo‐epithelial boundary induces decidualization via the canonical HB‐EGF and COX‐2 pathways. 相似文献
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Hong Wang Urmila Sreenivasan Da-Wei Gong Kelly A. O'Connell Erinne R. Dabkowski Peter A. Hecker Nicoleta Ionica Manige Konig Anup Mahurkar Yezhou Sun William C. Stanley Carole Sztalryd 《Journal of lipid research》2013,54(4):953-965
Presence of ectopic lipid droplets (LDs) in cardiac muscle is associated to lipotoxicity and tissue dysfunction. However, presence of LDs in heart is also observed in physiological conditions, such as when cellular energy needs and energy production from mitochondria fatty acid β-oxidation are high (fasting). This suggests that development of tissue lipotoxicity and dysfunction is not simply due to the presence of LDs in cardiac muscle but due at least in part to alterations in LD function. To examine the function of cardiac LDs, we obtained transgenic mice with heart-specific perilipin 5 (Plin5) overexpression (MHC-Plin5), a member of the perilipin protein family. Hearts from MHC-Plin5 mice expressed at least 4-fold higher levels of plin5 and exhibited a 3.5-fold increase in triglyceride content versus nontransgenic littermates. Chronic cardiac excess of LDs was found to result in mild heart dysfunction with decreased expression of peroxisome proliferator-activated receptor (PPAR)α target genes, decreased mitochondria function, and left ventricular concentric hypertrophia. Lack of more severe heart function complications may have been prevented by a strong increased expression of oxidative-induced genes via NF-E2-related factor 2 antioxidative pathway. Perilipin 5 regulates the formation and stabilization of cardiac LDs, and it promotes cardiac steatosis without major heart function impairment. 相似文献
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本研究用免疫细胞化学荧光双标技术观察了溶血磷脂酸（lysophosphatidic acid,LPA）对大鼠胚胎神经干细胞（neural stem cells,NSCs）分化为少突胶质细胞（galactocerebroside—positive,Gal-C阳性）和星形胶质细胞（grim fibrillary acidic protein-positive,GFAP阳性）的影响,并且用RT-PCR技术对NSCs可能表达的LPA受体进行分析。结果显示：（1）加入不同浓度（0．010．0μmol／L）LPA,第7天进行检测时,少突胶质细胞数量呈明显的剂量依赖性增加,峰值出现在1．0μmol／LLPA组,少突胶质细胞所占百分比从对照组的8．5％增加到32．6％;（2）星形胶质细胞的分化几乎不受LPA的影响,第7天时各LPA处理组星形胶质细胞百分比与对照组相比均无显著性差异;（3）RT-PCR结果显示,大鼠胚胎NSCs的LPA1和LPA3受体表达明显,而LPA3受体表达很弱。以上结果表明,较低浓度的LPA可能作为细胞外信号,通过LPA1和LPA3受体促进大鼠胚胎NSCs向少突胶质细胞分化和生成,但对星形胶质细胞的分化过程无明显影响。 相似文献
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James G. Bollinger Hiromi Ii Martin Sadilek Michael H. Gelb 《Journal of lipid research》2010,51(2):440-447
LC/ESI-MS/MS has been previously demonstrated to be a powerful method to detect and quantify molecular species of glycerophospholipids including lysophospholipids. In this study, we provide an improved pre-mass spectrometry lipid extraction procedure that avoids the acid-catalyzed decomposition of plasmenyl phospholipids that is problematic with previously reported methods. We show that the use of lysophospholipid internal standards with perdeuterated fatty acyl chains avoids isobar problems associated with the use of internal standards containing odd carbon number fatty acyl chains. We also show that LC prior to MS is required to avoid numerous problems associated with isobars and with MS in-source decomposition of lysophosphatidylserine. The reported method of using normal phase chromatography/ESI-MS is used to quantify lysophospholipids in serum and to quantify lysophospholipids produced in mammalian cells by human group X secreted phospholipase A2. The latter shows that group X phospholipase A2 added exogenously to cells generates a different set of lysophospholipids compared with enzyme produced endogenously in cells, which supports earlier studies showing that this phospholipase A2 can act on cell membranes prior to externalization from cells. 相似文献
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皮肤作为人体最大器官覆盖于全身,能阻挡有害物质的侵入,保护人体内环境稳态,参与人体代谢过程。皮肤损伤、炎症和纤维化等,都会导致皮肤屏障功能的减退,影响正常的生命活动。溶血磷脂酸(lysophosphatidic acid,LPA)是十分活跃的磷脂信号分子,参与多种生理和病理生理过程。LPA是维持体内平衡所必需的生物活性脂质介质,在皮肤中通过不同的信号通路发挥多功能磷脂信使作用。本文综述了皮肤中溶血磷脂酸受体(lysophosphatidic acid receptor,LPA1-6)及其细胞信号通路的作用及机制,综述了LPA在皮肤创面愈合、皮肤瘢痕、皮肤黑色素瘤、硬皮病、皮肤瘙痒、过敏性皮炎、皮肤屏障、皮肤疼痛,皮肤毛发生长中的作用及分子机制,有助于了解LPA在皮肤中的生理和病理生理作用。深入研究LPA的作用机制将有助于挖掘其在皮肤治疗中的作用,开发以LPA为靶点的药物。 相似文献
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Lysophosphatidic acid (LPA) is an important bioactive phospholipid involved in cell signaling through Gprotein- coupled receptors pathways. It is also involved in balancing the lipid composition inside the cell, and modulates the function of lipid rafts as an intermediate in phospholipid metabolism. Because of its involvement in these important processes, LPA degradation needs to be regulated as precisely as its production. Lysophosphatidic acid phosphatase type 6 (ACP6) is an LPA-specific acid phosphatase that hydrolyzes LPA to monoacylglycerol (MAG) and phosphate. Here, we report three crystal structures of human ACP6 in complex with malonate, L- (+)-tartrate and tris, respectively. Our analyses revealed that ACP6 possesses a highly conserved Rossmann-foldlike body domain as well as a less conserved cap domain. The vast hydrophobic substrate-binding pocket, which is located between those two domains, is suitable for accommodating LPA, and its shape is different from that of other histidine acid phosphatases, a fact that is consistent with the observed difference in substrate preferences. Our analysis of the binding of three molecules in the active site reveals the involvement of six conserved and crucial residues in binding of the LPA phosphate group and its catalysis. The structure also indicates a water-supplying channel for substrate hydrolysis. Our structural data are consistent with the fact that the enzyme is active as a monomer. In combination with additional mutagenesis and enzyme activity studies, our structural data provide important insights into substrate recognition and the mechanism for catalytic activity of ACP6. 相似文献
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Gbor Tigyi Kuan-Hung Lin Il Ho Jang Sue Chin Lee 《Experimental biology and medicine (Maywood, N.J.)》2021,246(16):1802
Stem cells possess unique biological characteristics such as the ability to self-renew and to undergo multilineage differentiation into specialized cells. Whereas embryonic stem cells (ESC) can differentiate into all cell types of the body, somatic stem cells (SSC) are a population of stem cells located in distinct niches throughout the body that differentiate into the specific cell types of the tissue in which they reside in. SSC function mainly to restore cells as part of normal tissue homeostasis or to replenish cells that are damaged due to injury. Cancer stem-like cells (CSC) are said to be analogous to SSC in this manner where tumor growth and progression as well as metastasis are fueled by a small population of CSC that reside within the corresponding tumor. Moreover, emerging evidence indicates that CSC are inherently resistant to chemo- and radiotherapy that are often the cause of cancer relapse. Hence, major research efforts have been directed at identifying CSC populations in different cancer types and understanding their biology. Many factors are thought to regulate and maintain cell stemness, including bioactive lysophospholipids such as lysophosphatidic acid (LPA). In this review, we discuss some of the newly discovered functions of LPA not only in the regulation of CSC but also normal SSC, the similarities in these regulatory functions, and how these discoveries can pave way to the development of novel therapies in cancer and regenerative medicine. 相似文献
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《Bioscience, biotechnology, and biochemistry》2013,77(8):2052-2056
Polyamines with diamine structures of chain length longer than 3C were essential for the synthesis of phosphatidic acid (PA) from ricinoleoyl-CoA and lysophosphatidic acid (LPA) by the castor LPA acyltransferase reaction, suggesting that polyamines modulate enzyme affinity for the acyl-CoA substrate in vivo. 相似文献