Enpp2, also known as Autotaxin, is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine into Lysophosphatidic acid (LPA). LPA, the bioactive product, triggers diverse signaling pathways via six LPA-G-protein coupled receptors. Enpp2 is essential for normal development, and its altered expression is linked to various diseases. Genetic models, like gene knockout, are valuable for studying its functions [3].

In AOM/DSS-induced colorectal cancer mice, knockdown of Enpp2 or use of its inhibitor GLPG1690 decreased CRC proliferation. GLPG1690 restored gut-barrier function, attenuated M2 tumor-associated macrophage polarization and colonic inflammation, and alleviated gut dysbiosis [1]. In endothelial cells, tamoxifen-induced EC-specific Enpp2 knockout in Apoe -/- mice decreased atherosclerosis, lesional macrophages, monocyte adhesion, and endothelial CXCL1 expression. In vitro, Enpp2 mediated mildly oxidized LDL-induced CXCL1 expression in aortic ECs by generating LPAs [2]. In diet-induced obesity, Enpp2(+/-) mice and adipocyte-specific Enpp2 knockout mice had smaller body weight gains, less insulin resistance, more active BAT, and increased energy expenditure [4].

In conclusion, Enpp2 plays crucial roles in multiple biological processes. Its knockout or inhibition in mouse models has revealed its significance in diseases such as colorectal cancer, atherosclerosis, and diet-induced obesity, providing potential therapeutic targets for these conditions.

References:

1. Yan, Junling, Duan, Wenting, Gao, Qinhan, Duan, Jialin, Li, Jiankang. 2023. ENPP2 inhibitor improves proliferation in AOM/DSS-induced colorectal cancer mice via remodeling the gut barrier function and gut microbiota composition. In Pharmacological research, 195, 106877. doi:10.1016/j.phrs.2023.106877. https://pubmed.ncbi.nlm.nih.gov/37524154/

2. Karshovska, Ela, Mohibullah, Rokia, Zhu, Mengyu, Aidinis, Vassilis, Schober, Andreas. 2022. Endothelial ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) Increases Atherosclerosis in Female and Male Mice. In Arteriosclerosis, thrombosis, and vascular biology, 42, 1023-1036. doi:10.1161/ATVBAHA.122.317682. https://pubmed.ncbi.nlm.nih.gov/35708027/

3. Cholia, R P, Nayyar, H, Kumar, R, Mantha, A K. . Understanding the Multifaceted Role of Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) and its Altered Behaviour in Human Diseases. In Current molecular medicine, 15, 932-43. doi:. https://pubmed.ncbi.nlm.nih.gov/26391552/

4. Nishimura, Satoshi, Nagasaki, Mika, Okudaira, Shinichi, Yatomi, Yutaka, Nagai, Ryozo. 2014. ENPP2 contributes to adipose tissue expansion and insulin resistance in diet-induced obesity. In Diabetes, 63, 4154-64. doi:10.2337/db13-1694. https://pubmed.ncbi.nlm.nih.gov/24969110/