Autotaxin

Autotaxin (ATX), also known as ectonucleotide pyrophosphatase / phosphodiesterase 2 (NPP2 or ENPP2), is a membrane ectoenzyme that acts as phosphodiesterase and phospholipase. Autotaxin in humans is encoded by the ENPP2 gene located on chromosome 8q24.12. Several alternatively spliced transcript variants have been identified. Autotaxin is important for the formation of the lipid signal molecule lysophosphatidic acid (LPA). Autotaxin has lysophospholipase D activity and cleaves lysophosphatidylcholine into the signal lipid lysophosphatidic acid (LPA). Lysophosphatidic acid induces growth factor-like responses, including stimulation of cell proliferation and chemotaxis.

Originally, autotaxin was identified as a factor that stimulates cell proliferation. Later it was shown that it is indeed lysophosphatidic acid (LPA) catalysed by autotaxin, which releases lysophosphatidylcholine (LPC) from its substrate and signals via lysophospholipid receptors (LPAR). Under physiological conditions, LPA negatively regulates autotaxin transcription.

LPARs are expressed in all known cell types of the CNS, where they mediate basic cellular processes such as proliferation, differentiation, migration, chronic inflammation and cytoskeletal organization. Consequently, dysregulation of the LPA content can lead to a number of CNS and PNS disorders. These include chronic inflammatory or neuropathic pain, glioblastoma multiforme (GBM), hemorrhagic hydrocephalus, schizophrenia, multiple sclerosis, Alzheimer's disease, brain damage induced by the metabolic syndrome, and cerebral oedema induced by hepatic encephalopathy. It also plays a role in macular edema, in severe depressive disorders, in stress-induced psychiatric disorders, in alcohol- and HIV-induced brain damage, in pruritus and peripheral nerve injury. ATX inhibitors are in clinical phase III (Mr. DR et al.2018/2019; Fujino H et al. 2019). Autotaxin is found in all cholestatic liver diseases, including the serum of cholestatic patients with pruritus (Ständer S 2018).

1. Fujino H et al (2019) Pruritus in patients with chronic liver disease and serum autotaxin levels in patients with primary biliary cholangitis. BMC Gastroenterol 24:169. https://www.ncbi.nlm.nih.gov/pubmed/31651244
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6. Robering JW et al (2019) Lysophosphatidic acid activates satellite glia cells and Schwann cells. Glia 67:999-1012.
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