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Autotaxin

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https://www.readbyqxmd.com/read/28425454/association-of-serum-autotaxin-levels-with-liver-fibrosis-in-patients-with-chronic-hepatitis-c
#1
Tomoo Yamazaki, Satoru Joshita, Takeji Umemura, Yoko Usami, Ayumi Sugiura, Naoyuki Fujimori, Soichiro Shibata, Yuki Ichikawa, Michiharu Komatsu, Akihiro Matsumoto, Koji Igarashi, Eiji Tanaka
Metabolized by liver sinusoidal endothelial cells, autotaxin (ATX) is a secreted enzyme considered to be associated with liver damage. We sought to clarify the diagnostic ability of ATX for liver fibrosis in 593 biopsy-confirmed hepatitis C virus (HCV)-infected patients. The diagnostic accuracy of ATX was compared with clinical parameters and the established fibrosis biomarkers Wisteria floribunda agglutinin-positive Mac-2-binding protein, FIB-4 index, AST-to-platelet ratio, and Forn's index. Median ATX levels were consistently higher in female controls and patients than in their male counterparts (P < 0...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28414242/discovery-of-2-2-ethyl-6-4-2-3-hydroxyazetidin-1-yl-2-oxo-ethyl-piperazin-1-yl-8-methyl-imidazo-1-2-a-pyridin-3-yl-methyl-amino-4-4-fluorophenyl-thiazole-5-carbonitrile-glpg1690-a-first-in-class-autotaxin-inhibitor-undergoing-clinical-evaluation-for-the-treatment
#2
Nicolas Desroy, Christopher Housseman, Xavier Bock, Agnès Joncour, Natacha Bienvenu, Laëtitia Cherel, Virginie Labeguere, Emilie Rondet, Christophe Peixoto, Jean-Marie Joël Grassot, Olivier Picolet, Denis Annoot, Nicolas Triballeau, Alain Monjardet, Emanuelle Wakselman, Veronique Roncoroni, Sandrine Le Tallec, Roland Blanque, Celine Cottereaux, Nele Vandervoort, Thierry Christophe, Patrick Mollat, Marieke B A C Lamers, Marielle Auberval, Boska Hrvacic, Jovica Ralic, Line Oste, Ellen Van der Aar, Reginald Brys, Bertrand Heckmann
Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice, and in reducing extra-cellular matrix deposition in the lung whilst also reducing LPA 18:2 content in bronchoalveolar lavage fluid...
April 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28347252/the-critical-role-and-potential-target-of-the-autotaxin-lysophosphatidate-axis-in-pancreatic-cancer
#3
REVIEW
Ming Quan, Jiu-Jie Cui, Xiao Feng, Qian Huang
Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1-6)...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28328321/ultrafast-and-predictive-mass-spectrometry-based-autotaxin-assays-for-label-free-potency-screening
#4
Tom Bretschneider, Andreas Harald Luippold, Helmut Romig, Daniel Bischoff, Klaus Klinder, Paul Nicklin, Wolfgang Rist
Autotaxin (ATX) is a promising drug target for the treatment of several diseases, such as cancer and fibrosis. ATX hydrolyzes lysophosphatidyl choline (LPC) into bioactive lysophosphatidic acid (LPA). The potency of ATX inhibitors can be readily determined by using fluorescence-based LPC derivatives. While such assays are ultra-high throughput, they are prone to false positives compared to assays based on natural LPC. Here we report the development of ultrafast mass spectrometry-based ATX assays enabling the measurement of data points within 13 s, which is 10 times faster than classic liquid chromatography-mass spectrometry...
April 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28324037/autotaxin-is-regulated-by-glucose-and-insulin-in-adipocytes
#5
Kenneth D'Souza, Daniel A Kane, Mohamed Touaibia, Erin E Kershaw, Thomas Pulinilkunnil, Petra C Kienesberger
Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid. Despite recent studies implicating adipose-derived ATX in metabolic disorders including obesity and insulin resistance, the nutritional and hormonal regulation of ATX in adipocytes remains unclear. The current study examined the regulation of ATX in adipocytes by glucose and insulin and the role of ATX in adipocyte metabolism. Induction of insulin resistance in adipocytes with high glucose and insulin concentrations increased ATX secretion, whereas coincubation with the insulin sensitizer, rosiglitazone, prevented this response...
April 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28298439/selective-export-of-autotoxin-from-the-endoplasmic-reticulum
#6
Lin Lyu, Baolu Wang, Chaoyang Xiong, Xiaotian Zhang, Xiaoyan Zhang, Junjie Zhang
Autotaxin (ATX) or ecto-nucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) is a secretory glycoprotein and functions as the key enzyme for lysophosphatidic acid (LPA) generation. The mechanism of ATX protein trafficking is largely unknown. Here we demonstrated that p23, a member of the p24 protein family, was the protein sorting receptor required for ER export of ATX. A di-phenylalanine (F838/F839) motif in human ATX C-terminal region was identified as a transport signal essential for the ATX-p23 interaction...
March 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28240604/autocrine-lysophosphatidic-acid-signaling-activates-%C3%AE-catenin-and-promotes-lung-allograft-fibrosis
#7
Pengxiu Cao, Yoshiro Aoki, Linda Badri, Natalie M Walker, Casey M Manning, Amir Lagstein, Eric R Fearon, Vibha N Lama
Tissue fibrosis is the primary cause of long-term graft failure after organ transplantation. In lung allografts, progressive terminal airway fibrosis leads to an irreversible decline in lung function termed bronchiolitis obliterans syndrome (BOS). Here, we have identified an autocrine pathway linking nuclear factor of activated T cells 2 (NFAT1), autotaxin (ATX), lysophosphatidic acid (LPA), and β-catenin that contributes to progression of fibrosis in lung allografts. Mesenchymal cells (MCs) derived from fibrotic lung allografts (BOS MCs) demonstrated constitutive nuclear β-catenin expression that was dependent on autocrine ATX secretion and LPA signaling...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28205098/enhanced-cellular-functions-through-induction-of-lpa2-by-cisplatin-in-fibrosarcoma-ht1080-cells
#8
Kaede Takahashi, Kaori Fukushima, Nobuyuki Fukushima, Kanya Honoki, Toshifumi Tsujiuchi
Lysophosphatidic acid (LPA) is a simple biophysical lipid which interacts with at least six subtypes of G protein-coupled LPA receptors (LPA1-LPA6). In cancer cells, LPA signaling via LPA receptors is involved in the regulation of malignant properties, such as cell growth, motility, and invasion. The aim of this study was to assess whether LPA receptors regulate cellular functions of fibrosarcoma cells treated with anticancer drug. HT1080 cells were maintained by the stepwise treatment of cisplatin (CDDP) at a range of 0...
February 15, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28170448/genome-wide-analysis-identifies-colonic-genes-differentially-associated-with-serum-leptin-and-insulin-concentrations-in-c57bl-6j-mice-fed-a-high-fat-diet
#9
Sung-Eun Kim, Jinsil Choo, Joon Yoon, Jae Ryang Chu, Yun Jung Bae, Seungyeoun Lee, Taesung Park, Mi-Kyung Sung
Obesity-induced chronic inflammation is known to increase the risk of ulcerative colitis, Crohn's disease, and colorectal cancer. Accumulating evidence suggests that leptin and insulin are key molecules linking obesity with diseases of the lower intestine. Here, we identified serum phenotype-associated genes in the colon of diet-induced obese mice as early biomarkers of obesity-associated colonic diseases. C57BL/6J mice were fed with either normal diet (ND, 15% of fat calories) or high-fat diet (HFD, 45% of fat calories) for 8 weeks...
2017: PloS One
https://www.readbyqxmd.com/read/28165241/rational-design-of-autotaxin-inhibitors-by-structural-evolution-of-endogenous-modulators
#10
Willem-Jan Keune, Frances Potjewyd, Tatjana Heidebrecht, Fernando Salgado-Polo, Simon J F Macdonald, Lakshman Chelvarajan, Ahmed Abdel Latif, Sony Soman, Andrew J Morris, Allan J B Watson, Craig Jamieson, Anastassis Perrakis
Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery...
March 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28143894/analysis-of-glycero-lysophospholipids-in-gastric-cancerous-ascites
#11
Shigenobu Emoto, Makoto Kurano, Kuniyuki Kano, Keisuke Matsusaki, Hiroharu Yamashita, Masako Nishikawa, Koji Igarashi, Hitoshi Ikeda, Junken Aoki, Joji Kitayama, Yutaka Yatomi
Lysophosphatidic acid (LysoPA) has been proposed to be involved in the pathogenesis of various cancers. Moreover, glycero-lysophospholipids (glycero-LysoPLs) other than LysoPA are now emerging as novel lipid mediators. Therefore, we aimed to elucidate the possible involvement of glycero-LysoPLs in the pathogenesis of gastric cancer by measuring glycero-LysoPLs, autotaxin (ATX), and phosphatidylserine-specific phospholipase A1 (PS-PLA1) in ascites obtained from patients with gastric cancer and those with cirrhosis (as a control)...
April 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28126468/autotaxin-lysophosphatidic-acid-receptor-signalling-regulates-hepatitis-c-virus-replication
#12
Michelle J Farquhar, Isla S Humphreys, Simon A Rudge, Garrick K Wilson, Bishnupriya Bhattacharya, Maria Ciaccia, Ke Hu, Qifeng Zhang, Laurent Mailly, Gary M Reynolds, Margaret Ashcroft, Peter Balfe, Thomas F Baumert, Stephanie Roessler, Michael J O Wakelam, Jane A McKeating
BACKGROUND & AIMS: Chronic hepatitis C is a global health problem with an estimated 170 million hepatitis C virus (HCV) infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX, gene name: ENPP2) is a phospholipase with diverse roles in the physiological and pathological processes including inflammation and oncogenesis. Clinical studies have reported increased ATX expression in chronic hepatitis C, however, the pathways regulating ATX and its role in the viral life cycle are not well understood...
January 23, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28112925/highly-potent-non-carboxylic-acid-autotaxin-inhibitors-reduce-melanoma-metastasis-and-chemotherapeutic-resistance-of-breast-cancer-stem-cells
#13
Souvik Banerjee, Derek D Norman, Sue Chin Lee, Abby L Parrill, Truc Chi T Pham, Daniel L Baker, Gabor J Tigyi, Duane D Miller
Autotaxin (ATX, aka. ENPP2) is the main source of the lipid mediator lysophosphatidic acid (LPA) in biological fluids. This study reports on inhibitors of ATX derived by lead optimization of the benzene-sulfonamide in silico hit compound 3. The new analogues provide a comprehensive structure-activity relationship of the benzene-sulfonamide scaffold that yielded a series of highly potent ATX inhibitors. The three most potent analogues (3a, IC50 ∼ 32 nM; 3b, IC50 ∼ 9 nM; and 14, IC50 ∼ 35 nM) inhibit ATX-dependent invasion of A2058 human melanoma cells in vitro...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28111010/blocking-lysophosphatidic-acid-receptor-1-signaling-inhibits-diabetic-nephropathy-in-db-db-mice
#14
Hui Ying Li, Yoon Sin Oh, Ji-Woong Choi, Ji Yong Jung, Hee-Sook Jun
Lysophosphatidic acid (LPA) is known to regulate various biological responses by binding to LPA receptors. The serum level of LPA is elevated in diabetes, but the involvement of LPA in the development of diabetes and its complications remains unknown. Therefore, we studied LPA signaling in diabetic nephropathy and the molecular mechanisms involved. The expression of autotaxin, an LPA synthesis enzyme, and LPA receptor 1 was significantly increased in both mesangial cells (SV40 MES13) maintained in high-glucose media and the kidney cortex of diabetic db/db mice...
January 19, 2017: Kidney International
https://www.readbyqxmd.com/read/28073697/proliferation-of-mouse-endometrial-stromal-cells-in-culture-is-highly-sensitive-to-lysophosphatidic-acid-signaling
#15
Shizu Aikawa, Kuniyuki Kano, Asuka Inoue, Junken Aoki
Endometrial stromal cells (ESCs) proliferate rapidly both in vivo and in vitro. Here we show that proliferation of ESCs in vitro is strongly dependent on lysophosphatidic acid (LPA) signaling. LPA is produced by autotaxin (ATX) and induces various kinds of cellular processes including migration, proliferation and inhibition of cell death possibly through six G protein-coupled receptors (LPA1-6). We found that ESCs proliferated rapidly in vitro in an autocrine manner and that the proliferation was prominently suppressed by either an ATX inhibitor (ONO-8430506) or an LPA1/3 antagonist (Ki16425)...
February 26, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28069607/lysophosphatidic-acid-converts-monocytes-into-macrophages-in-both-mice-and-humans
#16
Rashmi Ray, Vivek Rai
Monocytes and macrophages represent critical arms of the innate immune system and are considered regulators and effectors of inflammation and innate immune response. Monocytes can mobilize from bone marrow, traffic to their required destination and differentiate into effector cells depending on the local tissue environment to perform multiple roles during infection or inflammation, making them an important component of body's immune defense. Macrophages have diverse roles in tissue homeostasis, development as well as tissue repair following injury...
January 9, 2017: Blood
https://www.readbyqxmd.com/read/28052132/association-between-promoter-hypomethylation-and-overexpression-of-autotaxin-with-outcome-parameters-in-biliary-atresia
#17
Wanvisa Udomsinprasert, Nakarin Kitkumthorn, Apiwat Mutirangura, Voranush Chongsrisawat, Yong Poovorawan, Sittisak Honsawek
OBJECTIVE: Biliary atresia (BA) is a progressive fibroinflammatory liver disease. Autotaxin (ATX) has a profibrotic effect resulting from lysophosphatidic acid activity. The purpose of this study was to examine ATX expression and ATX promoter methylation in peripheral blood leukocytes and liver tissues from BA patients and controls and investigate their associations with outcome parameters in BA patients. METHODS: A total of 130 subjects (65 BA patients and 65 age-matched controls) were enrolled...
2017: PloS One
https://www.readbyqxmd.com/read/28028754/alteration-of-lysophosphatidylcholine-related-metabolic-parameters-in-the-plasma-of-mice-with-experimental-sepsis
#18
Won-Gyun Ahn, Jun-Sub Jung, Hyeok Yil Kwon, Dong-Keun Song
Plasma concentration of lysophosphatidylcholine (LPC) was reported to decrease in patients with sepsis. However, the mechanisms of sepsis-induced decrease in plasma LPC levels are not currently well known. In mice subjected to cecal ligation and puncture (CLP), a model of polymicrobial peritoneal sepsis, we examined alterations in LPC-related metabolic parameters in plasma, i.e., the plasma concentration of LPC-related substances (i.e., phosphatidylcholine (PC) and lysophosphatidic acid (LPA)), and activities or levels in the plasma of some enzymes that can be involved in the regulation of plasma LPC concentration (i...
April 2017: Inflammation
https://www.readbyqxmd.com/read/28028180/dissecting-the-process-of-activation-of-cancer-promoting-zinc-requiring-ectoenzymes-by-zinc-metalation-mediated-by-znt-transporters
#19
Tokuji Tsuji, Yayoi Kurokawa, Johanna Chiche, Jacques Pouysségur, Hiroshi Sato, Hideya Fukuzawa, Masaya Nagao, Taiho Kambe
Zinc-requiring ectoenzymes, including both secreted and membrane-bound enzymes, are considered to capture zinc in their active site for their activation in the early secretory pathway. This idea has been confirmed by our studies conducted using tissue-nonspecific alkaline phosphatase (TNAP), which is elaborately activated by means of a two-step mechanism by zinc transporter 5 (ZNT5)-ZNT6 heterodimers and ZNT7 homodimers, through protein stabilization followed by enzyme activation with zinc in the early secretory pathway...
February 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27994727/benzyl-methyl-tetrazole-ligands-of-autotaxin-for-pet-imaging-techniques-and-diagnostic
#20
EDITORIAL
Gerard Rosse
No abstract text is available yet for this article.
December 8, 2016: ACS Medicinal Chemistry Letters
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