{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nN-acyl phosphatidylethanolamine‐phospholipase D (NAPE‐PLD) is an integral enzyme that catalyzes the formation of fatty acid ethanolamides (FAEs)—bioactive lipids such as anandamide, oleoylethanolamide (OEA), and palmitoylethanolamide—that regulate endocannabinoid signaling. In the central nervous system, NAPE‐PLD is expressed in cortical regions where it contributes to the modulation of neurotransmission, while in reproductive tissues its activity helps govern plasma levels of anandamide, thereby influencing processes like implantation and early pregnancy maintenance. Moreover, immunohistochemical studies in human uterine biopsies have revealed that NAPE‐PLD expression fluctuates during the menstrual cycle, with differential localization in the glandular epithelium and stroma that may have implications for endometrial transformation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and mechanistic insights have further underscored the importance of NAPE‐PLD in lipid metabolism. The high‐resolution crystal structure of human NAPE‐PLD has revealed its homodimeric assembly and a distinctive hydrophobic cavity that facilitates substrate access and binding of bile acids—molecules that modulate its activity—thereby opening avenues for the design of small‐molecule modulators to control its function. In addition to generating FAEs from N-acyl phosphatidylethanolamines, NAPE‐PLD can participate in the degradation of aberrantly modified phospholipids, such as isolevuglandin‐modified phosphatidylethanolamine, thus contributing to cellular protection against proinflammatory and cytotoxic lipid adducts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in endocannabinoid synthesis, NAPE‐PLD has emerged as a critical player in metabolic regulation. Genetic analyses have identified common haplotypes within the NAPEPLD gene that are associated with a protective effect against severe obesity, suggesting that natural variation in enzyme function can influence energy homeostasis. Furthermore, targeted deletion of NAPE‐PLD in intestinal epithelial cell models leads to reduced OEA production, altered lipoprotein synthesis, and modified fat uptake, which collectively underscore its involvement in nutrient absorption and systemic lipid balance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anthony H Taylor, Muna S Abbas, Marwan A Habiba, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Histomorphometric evaluation of cannabinoid receptor and anandamide modulating enzyme expression in the human endometrium through the menstrual cycle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Histochem Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00418-010-0695-9"}], "href": "https://doi.org/10.1007/s00418-010-0695-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20369362"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20369362"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hua Zhang, David A Hilton, C Oliver Hanemann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cannabinoid receptor and N-acyl phosphatidylethanolamine phospholipase D--evidence for altered expression in multiple sclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Pathol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1750-3639.2011.00477.x"}], "href": "https://doi.org/10.1111/j.1750-3639.2011.00477.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21251115"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21251115"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Leonora E Long, Jonna Lind, Maree Webster, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Developmental trajectory of the endocannabinoid system in human dorsolateral prefrontal cortex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Neurosci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2202-13-87"}], "href": "https://doi.org/10.1186/1471-2202-13-87"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22827915"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22827915"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "C Abán, G F Leguizamón, M Cella, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential expression of endocannabinoid system in normal and preeclamptic placentas: effects on nitric oxide synthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Placenta (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.placenta.2012.10.009"}], "href": "https://doi.org/10.1016/j.placenta.2012.10.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23122699"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23122699"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Gitte Petersen, Anders H Pedersen, Darryl S Pickering, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effect of synthetic and natural phospholipids on N-acylphosphatidylethanolamine-hydrolyzing phospholipase D activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chem Phys Lipids (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chemphyslip.2009.08.005"}], "href": "https://doi.org/10.1016/j.chemphyslip.2009.08.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19715685"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19715685"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Lilu Guo, Stephen D Gragg, Zhongyi Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Isolevuglandin-modified phosphatidylethanolamine is metabolized by NAPE-hydrolyzing phospholipase D."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Lipid Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1194/jlr.M042556"}], "href": "https://doi.org/10.1194/jlr.M042556"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24018423"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24018423"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Paola Magotti, Inga Bauer, Miki Igarashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2014.12.018"}], "href": "https://doi.org/10.1016/j.str.2014.12.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25684574"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25684574"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Teresia Wangensteen, Hanne Akselsen, Jostein Holmen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A common haplotype in NAPEPLD is associated with severe obesity in a Norwegian population-based cohort (the HUNT study)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Obesity (Silver Spring) (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/oby.2010.219"}], "href": "https://doi.org/10.1038/oby.2010.219"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20885390"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20885390"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Miki Igarashi, Kazuhide Watanabe, Tsuyoshi Tsuduki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NAPE-PLD controls OEA synthesis and fat absorption by regulating lipoprotein synthesis in an in vitro model of intestinal epithelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.201801408R"}], "href": "https://doi.org/10.1096/fj.201801408R"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30399323"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30399323"}]}]}]}