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  • Physiological total plasma LPA levels are normally

    2023-01-19

    Physiological total plasma LPA levels are normally less than 1μM in healthy subjects. LPA levels have been reported to be increased in malignant effusions or plasma in cancer patients [20]. In addition, increasing ATX activity detected in healthy pregnant women in the third trimester of pregnancy exposes them to a higher risk of preterm delivery. LPA is particularly elevated in the plasma of pregnant women with intrahepatic cholestasis of pregnancy [21]. The dynamic regulation of LPA concentration in the blood is established by the balance of ATX activity and lipid phosphate phosphohydrolases [22]. ATX is abundantly present in blood and ATX and LPA levels are strongly correlated [19], [23]. In ATX-depleted serum and plasma, LPA production is completely absent [24], [25].
    The function of the ATX-LPA signaling axis After production by ATX, LPA acts through the 7-transmembrane domain distinct GPCRs, which can be divided into two subfamilies, and show over-lapping and distinct tissue distribution and signaling properties [26], [27]. The classical LPA1-3 receptors belong to the so-called “endothelial differentiation gene” (EDG) family, which includes five other GPCRs specific for the lipid mediator sphingosine 1-phosphate (S1P). LPA4 [28], LPA5 [29], and LPA6 [30] which were discovered later, demonstrate 35% amino TKI258 australia homology to the purinergic (P2Y) family of GPCRs, as compared to less than 20% homology to LPA1, which suggests that LPA4-6 are more closely related to the P2Y receptors [31]. All six LPA receptors can be stimulated by 1-acyl-LPA, albeit with different potencies. Some LPA receptors (LPA-3 and LPA-6) prefer unsaturated 2-acyl-LPA as a ligand, while LPA-5 exhibits a strong preference for ether-linked 1-alkyl-LPA species [32], [33]. The LPA receptors differ in tissue distribution and downstream signaling pathways. In the brain, LPA1, LPA2 and LPA4 are expressed in developing brain, and LPA3 is expressed in the postnatal brain. Expression of LPA1 and LPA2 can also be found in neurons [34]. LPA5 is expressed on sensory or motor neurons in the medulla spinalis and takes part in the processing of pain. For efficient delivery of LPA to LPA receptors, secreted ATX binds to integrins on the cell surface through SMB domains, which function independently of the catalytic domain [31]. Platelet activation requires binding to integrin β3 [35]. Moreover, α4β1 integrins are necessary for ATX binding to activated lymphocytes. T cells are able to interact with ATX in an integrin α4β1-dependent manner, suggesting a model in which secretion of ATX and subsequent localized LPA production promotes lymphocyte motility [36]. Injected enzymatically-inert ATX into mice attenuates the entry of T cells from the blood into peripheral lymphoid organs, presumably by competing with endogenous ATX for binding to integrins [37]. In addition to integrin, binding to heparin sulfate proteoglycans (HSPs) on the cell surface can be another way for ATX to deliver LPA to its cognate receptors. The main LPA-induced signaling pathways and these downstream effects include cytoskeletal remodeling and cell migration, calcium mobilization and PKC activation, cell proliferation, cell survival, changes inducing cAMP and production of growth factors and cytokines [26]. LPA receptor knockout studies have uncovered a part of the normal physiological roles for LPA signaling, including bone development and neurogenesis (LPA 1 receptor), embryo implantation (LPA 3 receptor), and the formation of blood and lymphatic vessels (LPA 4). ATX knockout mice display much more severe phenotypes than LPA receptor knockout. ATX deficient embryos die around day 10.5 because their early blood vessels failed to develop into mature vessels [8], [36], [38], [39], [40].
    The ATX-LPA signaling axis in cholestasis-associated pruritus Pruritus is a common symptom of cholestasis, particularly in primary biliary cholangitis (PBC), a rare autoimmune disease in which biliary epithelial cells are targeted [41]. An internet survey of PBC patients indicated that 69% of patients reported itch, and in 75% of the patients, the itch preceded the diagnosis of PBC [42]. Although less prevalent among recently diagnosed individuals, more than one third of PBC patients develop pruritus [36], [39], [40], [42]. Pruritus associated with PBC impacts quality of life and disturbs sleep, as the itch in 65.2% PBC patients is worse at night [42]. Itching can result in depression, and in extreme cases, suicidal ideation [38]. It may be an indication for liver transplantation even in the absence of liver failure [43], [44].