NAPE-PLD: the healthy intersection of N-acylethanolamines and bile acids in physiology and diseases.

Linking the distinctive structural and functional properties of lipids belonging to different signaling classes is a frontier of physiology. The present minireview focuses on the endocannabinoidome phospholipase NAPE-PLD, which has bile acids (BAs) as structural cofactors at membrane interface and generates bioactive N-acylethanolamines (NAEs) that promote pleiotropic effects. NAPE-PLD is thus at the crossroads of both their physiological functions, an area of ongoing research. The wide internal channel of NAPE-PLD facilitates the transmembrane transport of pyridoxal 5'-phosphate (PLP) and can support the activity of PLP-dependent enzymes in mitochondria, peroxisome and other subcellular compartments. Recent insights demonstrate that drugs and agents that stabilize NAPE-PLD can control blood pressure, vascular resistance and cardiovascular morbidity in clinics, offering new perspectives on the interaction between NAEs and BAs in cardiometabolic and neurological disorders.