br Conclusion br List of

Conclusion
List of abbreviations
Acknowledgment The studies performed by our laboratory and presented in this review were supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan, (KAKENHI 17590618 [to H.I.] and KAKENHI 22249017 [to Y.Y.]), and the Japanese Society of Laboratory Medicine Fund for the Promotion of Scientific Research (to H.I.).
Introduction Pruritus is a major issue in a number of autoimmune diseases, including, in particular, primary biliary cholangitis (PBC) [1], [2], [3], [4], [5]. Autotaxin (ATX) is a 125-kD type II ectonucleotide pyrophosphatase/phosphodiesterase (ENPP2 or NPP2) originally discovered as an unknown “autocrine motility factor” in human melanoma cells [6], [7]. In addition to its pyrophosphatase/phosphodiesterase activities ATX has lysophospholipase D (lysoPLD) activity, catalyzing the conversion of lysophosphatidylcholine (LPC) into lysophosphatidic T 705 (LPA). ATX is the only ENPP family member with lysoPLD activity and it produces most of the LPA in circulation. In support of this, ATX heterozygous mice have 50% of normal LPA plasma levels [8]. ATX is a secreted glycoprotein comprising a N-terminal signal peptide sequence with a furin cleavage site. ATX contains four domains, including two N-terminal somatomedin B-like (SMB) domains, a central catalytic phosphodiesterase (PDE) domain and a C-terminal nuclease-like (NUC) domain [6]. The crystal structures of mouse [6] and rat [9] ATX indicate loop regions located on both sides of the catalytic domain, which determine the binding specificity. A short loop (L1 linker region) connects the SMB and PDE domains and a long “lasso loop” (L2 linker region), wrapped around the NUC domain, connects the PDE and NUC domains (Fig. 1) [6]. It has been suggested that sequences in these domains together constitute a lysophospholipid (LPL)-binding pocket with preference for unsaturated acyl chains. When LPLs occupy this site nucleotides are unable to bind and since there are high quantities of LPC in circulation the major role of ATX in vivo is as a lysoPLD. The ATX gene has a complex structure, and is located on chromosome 15 in mouse and on chromosome 8q24.1 in the human. There are five alternatively-spliced isoforms of ATX that are catalytically active (ATX α- δ) and expressed in different tissues. ATX β and ATX δ are the major and stable isoforms [8]. The ATX gene is conserved through evolution and the genes are nearly identical in humans and mice [9].
Pathways of LPA production LPA (1- or 2-acyl-sn-glycerol 3-phosphate) is a lipid made up of phosphate, glycerol, and fatty acid moiety [10], [11], [12], [13]. LPA and its major precursor LPC comprise molecular species that vary in length and degree of saturation of their fatty acid chain, which is esterified at the sn-1 (or, less common, sn-2) position of the glycerol backbone. LPA, through activation of at least 6 specific G protein coupled receptors (GPCRs), participates in many cellular processes including cellular proliferation, blood vessel formation, lymphocyte entry into secondary lymphoid organs, prevention of apoptosis, cell migration, cytokine and chemokine secretion, platelet aggregation, smooth muscle contraction, cytoskeletal reorganization and neurite retraction [14], [15] (Fig. 2). LPA is produced both extracellularly and intracellularly. Significant amounts of LPA have been detected extracellularly in biological fluids, including serum, plasma, follicular fluid, saliva, and seminal fluid [15], [16], [17]. LPA can be released from activated platelets and is an abundant active albumin-bound constituent in serum [14]. There are two major pathways for LPA production, the PLA1/PLA2-ATX and the PLD-PLA1/PLA2 pathway. In the first pathway, LPLs generated by phospholipase A 1 (PLA 1) or PLA 2 are converted to LPA by ATX. This pathway accounts for the majority of circulating LPA. The second pathway is the PLD-PLA1/PLA2 pathway, in which phosphatidic acid (PA) is generated by phospholipase D (PLD) and diacylglycerol kinase (DGK) activities. Then, PA is deacylated to LPA by either a PLA 1 or a PLA2 reaction [18]. This pathway may be more important in specific tissues with expression of DGK such as brain and skin [19].