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

Black, Katharine E.; Berdyshev, Evgeny; Bain, Gretchen; Castelino, Flavia V.; Shea, Barry S.; Probst, Clemens K.; Fontaine, Benjamin A.; Goulet, Lance; Lagares, David; Ahluwalia, Neil; Knipe, Rachel S.; Natarajan, Viswanathan; Tager, Andrew M.

doi:10.1096/fj.201500197r

Cited by 42 publications

(31 citation statements)

References 47 publications

(85 reference statements)

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“…Chemicals and three reference ATX inhibitors, (Fig. 1C), and PAT-048 (Black et al, 2016) (Fig. 1D) were synthesized at PharmAkea (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

“…In vitro lysoPLD inhibition in human blood or mouse plasma was evaluated by measuring the generation of 20:4 LPA from endogenous LPC. The human blood and mouse plasma assays have been described previously elsewhere (Stein et al, 2015;Black et al, 2016). The concentrations of 20:4 LPA in the baseline sample from each assay were set to 0%, and the concentrations of 20:4 LPA in the vehicletreated 4-hour incubated sample were set to 100%.…”

Section: In Vitro Human Blood/mouse Plasma Lysophospholipase D Assaymentioning

confidence: 99%

“…In one study, conditional genetic deletion of ATX from pulmonary epithelial cells or macrophages resulted in a reduction in fibrosis that was confirmed through pharmacologic inhibition with the uncharacterized ATX inhibitor GWJ-A-23 ([4-(decanoylamino)benzyl]phosphonic acid) (Oikonomou et al, 2012). However, in a more recent study, a well-characterized ATX 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), was ineffective at reducing bleomycin-induced lung fibrosis despite virtually complete inhibition of ATX in plasma and BALF (Black et al, 2016). The lack of effect of PAT-048 was attributed to the fact that local production of LPA in the lung after bleomycin instillation is mediated by an ATX-independent, PLA 1 -dependent pathway.…”

Section: Introductionmentioning

confidence: 99%

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Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis

Bain

Shannon

Huang

et al. 2016

J Pharmacol Exp Ther

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Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH.

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“…Chemicals and three reference ATX inhibitors, (Fig. 1C), and PAT-048 (Black et al, 2016) (Fig. 1D) were synthesized at PharmAkea (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Section: In Vitro Human Blood/mouse Plasma Lysophospholipase D Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis

Bain

Shannon

Huang

et al. 2016

J Pharmacol Exp Ther

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“…Given the large exess of substrate availability in hyperlipidemic mice fed high fat diet, it is very likely that the intended ATX inhibition was not achieved since the substrate was not a limiting factor for ATX-mediated LPA production. Furthermore, the presence of an ATX-independent pathway for LPA formation may lead to some resistance to ATX inhibition [59]. In this pathway, PC and other phospholipids are hydrolyzed by phospholipase D (PLD1 or PLD2) to generate phosphatidic acid (PA).…”

Section: Discussionmentioning

confidence: 99%

Dietary phosphatidylcholine promotes breast cancer in the hyperlipidemic E0771 murine model

Onono¹,

Chelvarajan²,

Yan³

et al. 2020

Preprint

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BackgroundCancer cells are characterized by aberrant phosphatidylcholine (PC) metabolism. PC can be synthesized de novo or absorbed from diet, after digestion, by the intestinal enterocytes. Here, we investigated the association of dietary intake of PC and breast cancer development in mice. MethodsWe used tandem mass spectrometry methods to quantitate PC content of various fat sources used to manufacture rodent diets. Rodent diets were then formulated with either casein or amino acids in place of casein. To test the effects of dietary PC on tumor growth we fed low density lipoprotein receptor-null (LDLR–/–) mice high fat diets formulated with casein (high PC) or amino acids in place of casein (low PC). Endogenous PC biosynthesis and levels of total circulated plasma PC was monitored using stable isotope tracer choline and mass spectrometry analysis. Tumors were induced in mice after 12 weeks of high fat diet feeding. Since PC-derived molecules are important transducers of mitogenic signals, we tested the effects of inhibiting production of lysophosphatidic acid (LPA) using a recently described autotaxin (ATX) inhibitor. Finally, plasma inflammatory cytokine levels were analyzed to determine the effects of diets and ATX inhibition on systemic cytokine milieu. ResultsWe found that casein is the main source of PC when present in rodent diets. Replacing casein with amino acids increased the relative proportion of endogenously biosynthesized PC in mouse plasma. Compared to diets containing casein, amino acid-defined diets decreased primary tumor growth in the hyperlipidemic estrogen-receptor positive E0771 breast cancer mouse model. Inhibition of autotaxin with the potent inhibitor PAT-505 did not attenuate breast cancer development in these hyperlipidemic mice. Further, replacing casein with amino acids or treatment with PAT-505 significantly reduced systemic markers of inflammation. ConclusionOur results show that casein is a significant source of PC when present in rodent diets. Diets formulated with amino acids in place of casein have higher proportion of circulating PC from the endogenous biosynthetic pool. Casein-containing high fat diets promote primary breast tumor development in mice through mechanisms that involve systemic inflammation but is independent of LPA production by autotaxin.

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“…It also contacts with Lys248, Trp254 and Trp260. More recently, the pharmacokinetic properties of two novel compounds, PAT-505 (IC 50 = 2 nM; LPC) and PAT-048 (IC 50 = 1.1 nM; LPC) were assessed (Figure 7) [57][58][59][60]. The crystal structure of PAT-505 bound to ATX showed a very similar binding mode to that of PAT-347, namely by interacting with Lys248, Phe249, His251, Trp254, Trp260, Phe274, but also Ser81 and Val277 (Table 1).…”

Section: Type III Inhibitorsmentioning

confidence: 99%

The potential of different Autotaxin inhibitor types regulating catalysis-dependent and -independent signalling

F¹,

Perrakis²

2019

Preprint

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Autotaxin (ATX) is a secreted lysophospholipase D, catalysing the conversion of lysophosphatidylcholine (LPC) to bioactive lysophosphatidic acid (LPA). LPA acts through two families of G protein-coupled receptors (GPCRs) controlling key cellular responses, and is implicated in many physiological processes and pathologies. ATX has therefore been established as an important drug target in the pharmaceutical industry. Structural and biochemical studies of ATX have shown that it has a bimetallic nucleophilic catalytic site, a substrate-binding (orthosteric) hydrophobic pocket that accommodates the lipid alkyl chain, and an allosteric tunnel that can accommodate various steroids and LPA. Here we first review what is known about ATX-mediated catalysis, crucially in light of allosteric regulation. We then present the known ATX catalysis-independent functions, including binding to cell-surface integrins and proteoglycans. In light of these data we then discuss the four types of ATX inhibitors, as classified depending on their binding to the orthosteric and/or the allosteric site. Finally, we analyse the binding mode of known members of all four types and discuss how mechanistic differences might differentially modulate the activity of the ATX-LPA signalling axis, and clinical applications including cancer.

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

Cited by 42 publications

References 47 publications

Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis

Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis

Dietary phosphatidylcholine promotes breast cancer in the hyperlipidemic E0771 murine model

The potential of different Autotaxin inhibitor types regulating catalysis-dependent and -independent signalling

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