Autotaxin as a novel serum marker of liver fibrosis

Nakagawa, Hayato; Ikeda, Hitoshi; Nakamura, Kazuhiro; Ohkawa, Ryunosuke; Masuzaki, Ryota; Tateishi, Ryosuke; Yoshida, Haruhiko; Watanabe, Naoko; Tejima, Kazuaki; Kume, Yukio; Iwai, Tomohiro; Suzuki, Atsushi; Tomiya, Tomoaki; Inoue, Yukiko; Nishikawa, Tatsuya; Ohtomo, Natsuko; Tanoue, Yasushi; Omata, Masao; Igarashi, Koji; Aoki, Junken; Koike, Kazuhiko; Yatomi, Yutaka

doi:10.1016/j.cca.2011.03.014

Cited by 97 publications

(102 citation statements)

References 44 publications

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“…Metabolism and adipogenesis studies in mice indicate that ATX and its product, LPA, participate in energy homeostasis and obesity control ( 56-59, 104, 124, 125 ), which when dysregulated can lead to infl ammation and cancerogenesis. In addition to data showing association of ATX activity with rheumatoid arthritis ( 134 ), liver infl ammation ( 135,136 ), fi brosis development (137)(138)(139)(140)(141), and infl ammatory bowel disease ( 142 ), it has been proposed that ATX is mechanistically involved in linking both hepatitis C to hepatocellular carcinoma ( 143 ) and Epstein-Barr virus positivity to anaplastic large-cell and Hodgkin lymphoma development ( 107 ). MMTV-driven transgenic overexpression of either ATX or each of the three major LPA receptors (LPA1, -2, and -3) causes late-onset, invasive, and metastatic breast cancer development in mammary glands of mice ( 144 ).…”

Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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a 125 kDa glycoprotein composed of 915 amino acids ( 1 ). Because it promoted chemotaxis on melanoma cells in an autocrine fashion, the protein was aptly named auto-taxin. Four years after the discovery of the fi rst variant, now commonly referred to as ATX ␣ , or melanoma ATX, a second isoform was cloned by the same team from the teratocarcinoma cell line, Ntera2D1. This polypeptide shared 94% identity with the melanoma protein and was immediately recognized as the alternatively spliced product of the same gene ( 2 ).The initial characterization of the fi rst isoform revealed that ATX biological activity was sensitive to pertussis toxin treatment. Furthermore, not only did the polypeptide share close homology with the murine pyrophosphatase/ type I phosphodiesterase (PDE) PC-1, including a threonine residue crucial for PDE enzymatic activity, but it was also able to hydrolyze PDE substrates in vitro ( 3 ). The confi rmation that ATX was an enzyme came when a new PDE, the PDE1/nucleotide pyrophosphatase (PD-1 ␣ /PDNP 2), was cloned from a cDNA library of human retina and found to be identical to the sequence of melanoma ATX ␣ with the exception of a missing stretch of 52 amino acids encoded by exon 12 in the central region of the open reading frame. The transcript of this variant, now frequently referred to as ATX ␤ , or teratoma ATX, produced a 863 amino acid polypeptide chain with a mass of 99,034 Da ( 4 ), and was independently isolated a few years later in mouse tissues ( 5 ). The third ATX isoform was detected for the fi rst time in rat brain, but was originally designated as PD-I ␣ , a brain-specifi c PDE I/nucleotide pyrophosphatase ( 6 ). Further research showed that PD-I ␣ was identical to ATX ␤ teratoma protein, except for the presence of an additional stretch of 25 amino acids encoded by an alternatively Abstract The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, infl ammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. ( Fig. 1 ). In 1992, the fi rst alternatively spliced isoform was cloned from the melanoma cell line, A2058, and characterized as STRUCTURE AND ENZYMATIC ACTIVITY ATX belongs to the nuc...

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Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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“…Several prior investigations have also suggested a role for ATX in fibrotic diseases. In patients with hepatic fibrosis secondary to hepatitis C, serum ATX levels correlate with the severity of fibrosis (27), and ATX has been shown to be up-regulated in synovial fibroblasts in patients with rheumatoid arthritis (28). We have recently found that ATX expression is increased in the fibrotic skin of patients with scleroderma and that pharmacologic inhibition of ATX with a small molecule inhibitor, PAT-048 [3-[6-chloro-7-fluoro-2-methyl-1-(1-propyl)-1H-pyrazol-4-yl-1H-indol-3-ylsulfanyl]-2-fluoro-benzoic sodium salt], markedly attenuates dermal fibrosis in the bleomycin mouse model of dermal fibrosis (unpublished data).…”

Section: Autotaxin-dependentmentioning

confidence: 99%

Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis

et al. 2016

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Lysophosphatidic acid (LPA) is an important mediator of pulmonary fibrosis. In blood and multiple tumor types, autotaxin produces LPA from lysophosphatidylcholine (LPC) via lysophospholipase D activity, but alternative enzymatic pathways also exist for LPA production. We examined the role of autotaxin (ATX) in pulmonary LPA production during fibrogenesis in a bleomycin mouse model. We found that bleomycin injury increases the bronchoalveolar lavage (BAL) fluid levels of ATX protein 17-fold. However, the LPA and LPC species that increase in BAL of bleomycin-injured mice were discordant, inconsistent with a substrate-product relationship between LPC and LPA in pulmonary fibrosis. LPA species with longer chain polyunsaturated acyl groups predominated in BAL fluid after bleomycin injury, with 22:5 and 22:6 species accounting for 55 and 16% of the total, whereas the predominant BAL LPC species contained shorter chain, saturated acyl groups, with 16:0 and 18:0 species accounting for 56 and 14% of the total. Further, administration of the potent ATX inhibitor PAT-048 to bleomycinchallenged mice markedly decreased ATX activity systemically and in the lung, without effect on pulmonary LPA or fibrosis. Therefore, alternative ATX-independent pathways are likely responsible for local generation of LPA in the injured lung. These pathways will require identification to therapeutically target LPA production in pulmonary

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“…According to the multivariate regression analysis, urinary protein excretion was identified as the only statistically significant independent predictor of the serum ATX levels. Although an inverse correlation between the serum ATX levels and eGFR was shown in the univariate regression analysis, we speculated that a decreased eGFR was unlikely to be a convincing explanation for the association between the serum ATX levels and urinary protein excretion for the following reasons: First, circulating ATX is cleared by liver sinusoidal endothelial cells according to the findings of prior studies (24)(25)(26)39). Second, the molecular weight of ATX, a 125-kDa protein, is not small enough to be filtered through the glomerular filtration barrier (5).…”

Section: Discussionmentioning

confidence: 99%

“…Patients with other glomerular diseases concomitant with diabetic nephropathy were excluded from this study. In addition, patients with liver diseases were not enrolled in this study, because the serum ATX levels are known to be elevated in patients with hepatic fibrosis (24)(25)(26). Renal biopsy was performed to make a precise diagnosis of kidney lesions with the written consent of each patient.…”

Section: Patientsmentioning

confidence: 99%

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Serum Autotaxin Levels Are Associated with Proteinuria and Kidney Lesions in Japanese Type 2 Diabetic Patients with Biopsy-proven Diabetic Nephropathy

et al. 2016

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Objective We evaluated the relationships between the serum autotaxin (ATX) levels and the clinical and pathological parameters, as well as the long-term renal outcome, in type 2 diabetic patients with biopsyproven diabetic nephropathy. Methods In this retrospective single-center cohort study, serum samples were collected from 38 Japanese type 2 diabetic patients with biopsy-proven diabetic nephropathy at the time of renal biopsy. The serum ATX levels were measured using a specific sandwich enzyme immunoassay. Results A multivariate linear regression analysis revealed the urinary protein excretion to be independently associated with the serum ATX levels. In addition, patients with serum ATX levels above the median showed more advanced diffuse lesions, nodular lesions and arteriolar hyalinosis compared to those with serum ATX levels below the median. However, high serum ATX levels were not associated with any increase in the number of renal composite events [a need for dialysis or a 50% decline in the estimated glomerular filtration rate (eGFR) from baseline]. Conclusion The serum ATX levels in type 2 diabetic patients with diabetic nephropathy were associated with proteinuria and diabetic kidney lesions, although the serum ATX levels were not identified to be a predictive indicator for the renal outcome.

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Autotaxin as a novel serum marker of liver fibrosis

Cited by 97 publications

References 44 publications

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis

Serum Autotaxin Levels Are Associated with Proteinuria and Kidney Lesions in Japanese Type 2 Diabetic Patients with Biopsy-proven Diabetic Nephropathy

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