Enpp2, also known as Autotaxin, is a secreted lysophospholipase D. It hydrolyzes lysophosphatidylcholine (LPC) into Lysophosphatidic acid (LPA), which activates diverse signalling pathways via six LPA-G-protein coupled receptors (GPCRs). ENPP2 is essential for normal development and its altered expression is associated with various human diseases. It is involved in processes like embryonic and neural development, migration, invasion, differentiation, proliferation, angiogenesis, and survival [4].

In various disease models, the role of Enpp2 has been investigated. In AOM/DSS-induced colorectal cancer mice, knockdown of Enpp2 or use of its inhibitor GLPG1690 decreased cancer cell proliferation, restored gut-barrier function, attenuated M2 tumor-associated macrophage polarization and colonic inflammation, and alleviated gut dysbiosis [1]. In alcoholic liver disease, Mendelian randomization analysis identified genetically proxied ENPP2/Autotaxin as causally associated with the disease risk [2]. In atherosclerosis mouse models, endothelial Enpp2 knockout decreased atherosclerosis, lesional macrophages accumulation, monocyte adhesion, and expression of endothelial CXCL1, suggesting that endothelial Enpp2 promotes atherosclerosis and endothelial inflammation [3]. In diet-induced obesity, Enpp2(+/-) mice and adipocyte-specific Enpp2 knockout mice had smaller body weight gains and less insulin resistance, with increased brown adipose tissue function and energy expenditure [5].

In conclusion, Enpp2 is crucial in regulating lipid-related signalling pathways and has significant impacts on multiple biological processes and disease conditions. Gene knockout mouse models, including global and tissue-specific knockout, have been instrumental in revealing its role in diseases such as colorectal cancer, alcoholic liver disease, atherosclerosis, and diet-induced obesity, providing potential therapeutic targets for these diseases.