title: An anatomical and temporal portrait of physiological substrates for fatty acid amide hydrolase.
abstract: Fatty acid amide hydrolase (FAAH) regulates amidated lipid transmitters, including the endocannabinoid anandamide and its N-acyl ethanolamine (NAE) congeners and transient receptor potential channel agonists N-acyl taurines (NATs). Using both the FAAH inhibitor PF-3845 and FAAH(-/-) mice, we present a global analysis of changes in NAE and NAT metabolism caused by FAAH disruption in central and peripheral tissues. Elevations in anandamide (and other NAEs) were tissue dependent, with the most dramatic changes occurring in brain, testis, and liver of PF-3845-treated or FAAH(-/-) mice. Polyunsaturated NATs accumulated to very high amounts in the liver, kidney, and plasma of these animals. The NAT profile in brain tissue was markedly different and punctuated by significant increases in long-chain NATs found exclusively in FAAH(-/-), but not in PF-3845-treated animals. Suspecting that this difference might reflect a slow pathway for NAT biosynthesis, we treated mice chronically with PF-3845 for 6 days and observed robust elevations in brain NATs. These studies, taken together, define the anatomical and temporal features of FAAH-mediated NAE and NAT metabolism, which are complemented and probably influenced by kinetically distinguishable biosynthetic pathways that produce these lipids in vivo.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.forename: Melanie
authors.initials: M
authors.lastname: LaCava
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D052436:Adipose Tissue, White / Q000201:enzymology; D000581:Amidohydrolases / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000201:enzymology; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013379:Substrate Specificity; D013654:Taurine / Q000031:analogs & derivatives / Q000378:metabolism; D013737:Testis / Q000201:enzymology; D014018:Tissue Distribution; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011725:Pyridines; D013654:Taurine; D000099252:Fatty Acid Amide Hydrolases; C557973:PF 3845; C078814:anandamide