Serum autotaxin measurement in haematological malignancies: a promising marker for follicular lymphoma

Masuda, Akiko; Nakamura, Kazuhiro; Izutsu, Koji; Igarashi, Koji; Ohkawa, Ryunosuke; Jona, Masahiro; Higashi, Katsumi; Yokota, Hiromitsu; Okudaira, Shinichi; Kishimoto, Tatsuya; Watanabe, Takuro; Koike, Yukako; Ikeda, Hitoshi; Kozai, Yasuji; Kurokawa, Mineo; Aoki, Junken; Yatomi, Yutaka

doi:10.1111/j.1365-2141.2008.07325.x

Cited by 107 publications

(98 citation statements)

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“…LPA is mainly produced via an autotaxin -mediated pathway, and in healthy subjects and patients with several diseases, the plasma LPA level is closely correlated with the serum autotaxin level. [18][19][20] In patients with ACS, however, the serum autotaxin level was not elevated, compared with the LPA level.In this study, we aimed to reveal the sources of LPA elevation in patients with ACS and to determine the species of LPA using LC-MS/MS. We found that compared with the normal coronary arteries and SAP patients, the levels of 22:6 LPA, 18:2 LPA, 20:4 LPA, 18:1 LPA, and 22:5 LPA were increased in patients with ACS in the order shown (Figure 1A-1E; Figure IA-IC in the online-only Data Supplement).…”

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confidence: 91%

Possible Involvement of Minor Lysophospholipids in the Increase in Plasma Lysophosphatidic Acid in Acute Coronary Syndrome

Kurano

Suzuki

Inoue

et al. 2015

ATVB

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Objective-Lysophosphatidic acids (LPA) have important roles in the field of vascular biology and are derived mainly from lysophosphatidylcholine via autotaxin. However, in our previous study, only the plasma LPA levels, and not the serum autotaxin levels, increased in patients with acute coronary syndrome (ACS). The aim of this study was to elucidate the pathway by which LPA is increased in patients with ACS. Approach and Results-We measured the plasma lysophospholipids species in 141 consecutive patients undergoing coronary angiography (ACS, n=38; stable angina pectoris, n=71; angiographically normal coronary arteries, n=32) using a liquid chromatography-tandem mass spectrometry analysis. Among the ACS subjects, notable increases in the 22:6 LPA, 18:2 LPA, and 20:4 LPA levels were observed. The in vitro experiments revealed that serum incubation mainly increased the 18:2 LPA level, whereas platelet activation increased the 20:4 LPA level. Minor lysophospholipids other than LPA were also elevated in ACS subjects and were well correlated with the corresponding LPA species, including 22:6 LPA. A multiple regression analysis also revealed that lysophosphatidylinositol, lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylglycerol were independent explanatory variables for several LPA species. Conclusions-Specific LPA species, especially long-chain unsaturated LPA, were elevated in ACS patients, along with the corresponding minor lysophospholipids. The elevation of these LPA species might be mainly caused by presently unidentified LPA-producing pathway(s). Minor lysophospholipids might be involved in the generation of LPA, especially 22:6 LPA, and in the pathogenesis of ACS. LPA levels were elevated in patients with ACS but not in those with stable angina pectoris (SAP). 16 This result suggested that LPA might be involved in plaque instability and platelet activation in human subjects. In addition, we also found that serum autotaxin levels were not elevated in patients with ACS; LPA is hydrolyzed from lysophosphatidylcholine (LPC) by autotaxin/lysophospholipase D. 17 This discrepancy between LPA and autotaxin interested us greatly because autotaxin is a key enzyme in the production of LPA. Actually, we previously reported a strong positive correlation between LPA and autotaxin in healthy subjects, 18 patients with chronic hepatitis, 19 and patients with follicular lymphoma.20 Therefore, the discordance between ACS subjects and other subjects prompted us to investigate the origins of the elevation in LPA in patients with ACS.LPA is structurally composed of a fatty acid linked to snglycerol-3 phosphate, and the molecular species of the fatty acid chain are varied and determine the molecular species of LPA. In a previous report, 16 we measured the total LPA and LPC levels using previously described enzymatic methods. 21 Using these methods, we could not obtain any information concerning which molecular species of LPA were elevated in patients with ACS. To overcome this limitation, we determined th...

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Possible Involvement of Minor Lysophospholipids in the Increase in Plasma Lysophosphatidic Acid in Acute Coronary Syndrome

Kurano

Suzuki

Inoue

et al. 2015

ATVB

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“…LPA stimulates multiple cell signaling pathways through the activation of at least six cell surface G protein-coupled receptors, and the ATX-LPA pathway has been implicated in a number of physiologic and pathologic processes (Yung et al, 2014). Serum LPA and ATX lysoPLD activity are elevated in many disease settings, including renal cancer (Su et al, 2013), glioblastoma , follicular lymphoma (Masuda et al, 2008), liver cirrhosis (Kondo et al, 2014), primary biliary cirrhosis (Kremer et al, 2010), and atopic dermatitis (Shimizu et al, 2014), so it is of great interest to the pharmaceutical and medical community to delineate the therapeutic benefit of LPA receptor antagonism or ATX enzyme inhibition.…”

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confidence: 99%

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding

et al. 2015

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Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors.

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“…LPA is generated via hydrolysis of lysophosphatidylcholine by a secretory protein, autotaxin (ATX) (10), which exerts lysophospholipase D activity (11)(12)(13). In a bleomycininduced lung injury/fibrosis model, mice lacking LPA 1 have been shown to have decreased fibroblast recruitment and vascular leak, and LPA 1 has been noted to be a therapeutic target for interstitial pneumonia (14).…”

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Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

Miyabe

Iwai

et al. 2013

Arthritis & Rheumatism

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Objective. Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA 1-6 ]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA 1 on the development of arthritis.Methods. Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The effects of abrogation of LPA 1 on collageninduced arthritis (CIA) were evaluated using LPA 1 -deficient mice or LPA 1 antagonist. Migrating fluorescence-labeled CD11b؉ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4؉ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined.Results. LPA 1 was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA 1 -deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA 1 antagonist also ameliorated murine CIA. Abrogation of LPA 1 was associated with reductions in cell infiltration, bone destruction in the joints, and interleukin-17 production from CII-stimulated splenocytes. Infiltration of transferred CD11b؉ macrophages from LPA 1 -deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA 1 antagonist inhibited the infiltration of macrophages from wild-type mice. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed under conditions of LPA 1 deficiency or LPA 1 inhibition in vitro.Conclusion. Collectively, these results indicate that LPA/LPA 1 signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA 1 may be a promising target molecule for RA therapy.Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammatory cell infiltration and bone destruction at multiple joints. The inflammation process in RA leads to synovial hyperplasia with proliferation of fibroblast-like synoviocytes (FLS), angiogenesis, and infiltration of inflammatory cells, including lymphocytes and macrophages (1,2).

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Serum autotaxin measurement in haematological malignancies: a promising marker for follicular lymphoma

Cited by 107 publications

References 51 publications

Possible Involvement of Minor Lysophospholipids in the Increase in Plasma Lysophosphatidic Acid in Acute Coronary Syndrome

Possible Involvement of Minor Lysophospholipids in the Increase in Plasma Lysophosphatidic Acid in Acute Coronary Syndrome

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding

Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

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