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Gene Review

FAAH  -  fatty acid amide hydrolase

Homo sapiens

Synonyms: Anandamide amidohydrolase 1, FAAH-1, FAAH1, Fatty-acid amide hydrolase 1, Oleamide hydrolase 1, ...
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Disease relevance of FAAH

  • A clinical study performed on 100 healthy women showed that a low FAAH activity in lymphocytes correlates with spontaneous abortion, whereas anandamide transporter and cannabinoid receptors in these cells remain unchanged [1].
  • An FAAH activity sharing several biochemical properties with the human brain enzyme was demonstrated in human neuroblastoma CHP100 and lymphoma U937 cells [2].
  • Recombinant forms of WT- and DeltaTM-FAAH expressed and purified from Escherichia coli exhibited essentially identical enzymatic properties which were also similar to those of the native enzyme from rat liver [3].
  • Previous research has described the impact of cannabis consumption on pregnancy, potential roles of endocannabinoids and abnormalities of FAAH expression in recurrent miscarriage and pregnancy [4].
  • The cannabinergic proteins currently being explored, which include the CB1 and CB2 receptors, FAAH and the anandamide transporter, are excellent targets for the development of therapeutically useful drugs for a range of conditions including pain, loss of appetite, immunosuppression, peripheral vascular disease and motor disorders [5].

Psychiatry related information on FAAH

  • Collectively, these results suggest that genetic mutations in FAAH may constitute important risk factors for problem drug use and support a potential link between functional abnormalities in the endogenous cannabinoid system and drug abuse and dependence [6].
  • This SNP, which converts a conserved proline residue in FAAH to threonine (P129T), suggests a potential role for the FAAH-endocannabinoid system in regulating addictive behavior [7].
  • As systemic administration of TRPV1 ligands reduces locomotor activity in normal rodents, we hypothesised that activation of TRPV1 by endocannabinoids could play a role in the control of voluntary movement and that such actions could be regulated by AMT and FAAH [8].
  • Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains [9].

High impact information on FAAH

  • Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy [10].
  • CaCo-2 cell differentiation into noninvasive cells results in increased FAAH expression, lower endocannabinoid levels, and no responsiveness to cannabinoids [11].
  • RESULTS: CB1r and FAAH were localized in the dorsal vagal complex, consisting of the area postrema, nucleus of the solitary tract, and the dorsal motor nucleus of the vagus in the brainstem [12].
  • Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC50 7.27 +/- 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K(d) = 7.62 +/- 1.18 nM, B(max) = 31.6 +/- 1.80 fmol/mg protein) that is distinct from fatty acid amide hydrolase [13].
  • Moreover, systemic administration of AM404 to either wild-type or FAAH(-/-) mice enhanced the hypothermic effects of exogenous anandamide, a response that was prevented by the CB(1) cannabinoid antagonist rimonabant (SR141716A) [14].

Chemical compound and disease context of FAAH

  • These data: (a) provide the first evidence that cisplatin causes a selective increase in 2-AG levels in the brain, and (b) support the established notion that 2-AG may produce some of its effects, including emesis, via downstream metabolites produced independently of FAAH [15].
  • Since the anti-apoptotic activity of leptin and progesterone parallels their effect on FAAH, it can be suggested that enhanced degradation of AEA is the means to protect U937 cells against the toxicity of this compound [16].
  • Here, we review recent literature on the role of endocannabinoids in endotoxic shock and inflammation, and report our recent research on the effects of LPS on the production of AEA and 2-AG in human lymphocytes, and on AEA degradation by a specific AEA membrane transporter (AMT) and an AEA-degrading enzyme (fatty acid amide hydrolase, FAAH) [17].

Biological context of FAAH


Anatomical context of FAAH


Associations of FAAH with chemical compounds

  • Adverse effects of elevated levels of anandamide on these processes resulting from FAAH inactivation are mimicked by administration of (-)-Delta9-tetrahydrocannabinol (THC; the major psychoactive constituent of marijuana), due to enhanced signaling via CB1 [21].
  • Good FAAH substrates such as anandamide and 2-arachidonoylglycerol inhibited the release of leukemia-inhibitory factor from human lymphocytes, but N-palmitoylethanolamine, a poor substrate, did not [1].
  • Human chorionic gonadotropin or cortisol had no effect on FAAH activity [1].
  • Thus, FAAH inhibition in mouse brain does not appear to be a primary target for organophosphorus pesticide-induced neurotoxic action (cholinergic or intermediate syndrome or delayed neurotoxicity) [22].
  • Ovariectomy prevented the decrease in FAAH, and both progesterone and estrogen further reduced its basal levels, suggesting hormonal control of the enzyme [23].
  • Yet it has been suggested that FAAH functions in vivo only as an anandamide-degrading enzyme because its pharmacological and genetic inactivation is usually accompanied by elevation of anandamide, but not 2-AG, levels [24].

Enzymatic interactions of FAAH

  • The characterization, cloning, and neuronal distribution of FAAH have been detailed and the enzyme was found to possess the ability to hydrolyze a range of fatty acid amides including anandamide which serves as the endogenous ligand for the cannabinoid receptor [25].

Other interactions of FAAH

  • Analysis of the FAAH promoter showed a cAMP-response element-like site, which is a transcriptional target of STAT3 [19].
  • Our observations demonstrate that genetic variations in TRPA1, COMT, and FAAH contribute gender specifically to individual variations in short duration cold pain sensitivity in a European American cohort [26].
  • Further study in European American subjects found significant associations between short duration cold pain sensitivity and variations in TRPA1, COMT, and FAAH in a gender dependent manner [26].
  • We show that, unlike CB1R and PLD, the activity of AMT and the activity and expression of FAAH increase while the endogenous levels of AEA decrease in HaCaT and NHEK cells induced to differentiate in vitro by 12-O-tetradecanoylphorbol 13-acetate (TPA) plus calcium [27].
  • The activation of FAAH by progesterone was paralleled by a decrease (down to 60%) of the cellular levels of anandamide and involved increased nuclear levels of the transcription factor Ikaros [18].

Analytical, diagnostic and therapeutic context of FAAH

  • Analysis of the oligomerization states of WT- and DeltaTM-FAAH by chemical cross-linking, sedimentation velocity analytical ultracentrifugation, and size exclusion chromatography indicated that both enzymes were oligomeric when membrane-bound and after solubilization [3].
  • Additionally, SDS-PAGE analysis of the recombinant proteins identified the presence of SDS-resistant oligomers for WT-FAAH, but not for DeltaTM-FAAH [3].
  • The human FAAH gene was mapped to region 1p34-p35, closely linked to D1S197 and D1S443, by using PCR analysis of somatic cell hybrid (SCH) and radiation hybrid mapping panels [28].
  • We have examined CB1 receptor and FAAH expression in human term placenta by immunohistochemistry [4].
  • These data, corroborated by transient expression and electrophoretic mobility-shift assays, demonstrate an unprecedented cell-specific regulation of the FAAH gene, which has important implications for the control of tone and activity of AEA along the neuroimmune axis [29].


  1. Progesterone up-regulates anandamide hydrolase in human lymphocytes: role of cytokines and implications for fertility. Maccarrone, M., Valensise, H., Bari, M., Lazzarin, N., Romanini, C., Finazzi-Agrò, A. J. Immunol. (2001) [Pubmed]
  2. Anandamide hydrolysis by human cells in culture and brain. Maccarrone, M., van der Stelt, M., Rossi, A., Veldink, G.A., Vliegenthart, J.F., Agrò, A.F. J. Biol. Chem. (1998) [Pubmed]
  3. Comparative characterization of a wild type and transmembrane domain-deleted fatty acid amide hydrolase: identification of the transmembrane domain as a site for oligomerization. Patricelli, M.P., Lashuel, H.A., Giang, D.K., Kelly, J.W., Cravatt, B.F. Biochemistry (1998) [Pubmed]
  4. Identification of the CB1 cannabinoid receptor and fatty acid amide hydrolase (FAAH) in the human placenta. Park, B., Gibbons, H.M., Mitchell, M.D., Glass, M. Placenta (2003) [Pubmed]
  5. Cannabinergic ligands. Palmer, S.L., Thakur, G.A., Makriyannis, A. Chem. Phys. Lipids (2002) [Pubmed]
  6. A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Sipe, J.C., Chiang, K., Gerber, A.L., Beutler, E., Cravatt, B.F. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Chiang, K.P., Gerber, A.L., Sipe, J.C., Cravatt, B.F. Hum. Mol. Genet. (2004) [Pubmed]
  8. A role for vanilloid receptor 1 (TRPV1) and endocannabinnoid signalling in the regulation of spontaneous and L-DOPA induced locomotion in normal and reserpine-treated rats. Lee, J., Di Marzo, V., Brotchie, J.M. Neuropharmacology (2006) [Pubmed]
  9. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains. Benito, C., Núñez, E., Tolón, R.M., Carrier, E.J., Rábano, A., Hillard, C.J., Romero, J. J. Neurosci. (2003) [Pubmed]
  10. Modulation of anxiety through blockade of anandamide hydrolysis. Kathuria, S., Gaetani, S., Fegley, D., Valiño, F., Duranti, A., Tontini, A., Mor, M., Tarzia, G., La Rana, G., Calignano, A., Giustino, A., Tattoli, M., Palmery, M., Cuomo, V., Piomelli, D. Nat. Med. (2003) [Pubmed]
  11. Possible endocannabinoid control of colorectal cancer growth. Ligresti, A., Bisogno, T., Matias, I., De Petrocellis, L., Cascio, M.G., Cosenza, V., D'argenio, G., Scaglione, G., Bifulco, M., Sorrentini, I., Di Marzo, V. Gastroenterology (2003) [Pubmed]
  12. Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Van Sickle, M.D., Oland, L.D., Ho, W., Hillard, C.J., Mackie, K., Davison, J.S., Sharkey, K.A. Gastroenterology (2001) [Pubmed]
  13. Identification of a high-affinity binding site involved in the transport of endocannabinoids. Moore, S.A., Nomikos, G.G., Dickason-Chesterfield, A.K., Schober, D.A., Schaus, J.M., Ying, B.P., Xu, Y.C., Phebus, L., Simmons, R.M., Li, D., Iyengar, S., Felder, C.C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  14. Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. Fegley, D., Kathuria, S., Mercier, R., Li, C., Goutopoulos, A., Makriyannis, A., Piomelli, D. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  15. Cisplatin increases brain 2-arachidonoylglycerol (2-AG) and concomitantly reduces intestinal 2-AG and anandamide levels in the least shrew. Darmani, N.A., McClanahan, B.A., Trinh, C., Petrosino, S., Valenti, M., Di Marzo, V. Neuropharmacology (2005) [Pubmed]
  16. Further insights into the regulation of human FAAH by progesterone and leptin implications for endogenous levels of anandamide and apoptosis of immune and neuronal cells. Gasperi, V., Fezza, F., Spagnuolo, P., Pasquariello, N., Maccarrone, M. Neurotoxicology (2005) [Pubmed]
  17. Endocannabinoid degradation, endotoxic shock and inflammation. Maccarrone, M., Bari, M., Battista, N., Finazzi-Agrò, A. Current drug targets. Inflammation and allergy. (2002) [Pubmed]
  18. Progesterone activates fatty acid amide hydrolase (FAAH) promoter in human T lymphocytes through the transcription factor Ikaros. Evidence for a synergistic effect of leptin. Maccarrone, M., Bari, M., Di Rienzo, M., Finazzi-Agrò, A., Rossi, A. J. Biol. Chem. (2003) [Pubmed]
  19. Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3. Maccarrone, M., Di Rienzo, M., Finazzi-Agrò, A., Rossi, A. J. Biol. Chem. (2003) [Pubmed]
  20. Characterization of the endocannabinoid system in early human pregnancy. Helliwell, R.J., Chamley, L.W., Blake-Palmer, K., Mitchell, M.D., Wu, J., Kearn, C.S., Glass, M. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  21. Tuning the oviduct to the anandamide tone. Schuel, H. J. Clin. Invest. (2006) [Pubmed]
  22. Selective inhibitors of fatty acid amide hydrolase relative to neuropathy target esterase and acetylcholinesterase: toxicological implications. Quistad, G.B., Sparks, S.E., Segall, Y., Nomura, D.K., Casida, J.E. Toxicol. Appl. Pharmacol. (2002) [Pubmed]
  23. Down-regulation of anandamide hydrolase in mouse uterus by sex hormones. MacCarrone, M., De Felici, M., Bari, M., Klinger, F., Siracusa, G., Finazzi-Agrò, A. Eur. J. Biochem. (2000) [Pubmed]
  24. FAAH and anandamide: is 2-AG really the odd one out? Di Marzo, V., Maccarrone, M. Trends Pharmacol. Sci. (2008) [Pubmed]
  25. Oleamide: an endogenous sleep-inducing lipid and prototypical member of a new class of biological signaling molecules. Boger, D.L., Henriksen, S.J., Cravatt, B.F. Curr. Pharm. Des. (1998) [Pubmed]
  26. Genetic predictors for acute experimental cold and heat pain sensitivity in humans. Kim, H., Mittal, D.P., Iadarola, M.J., Dionne, R.A. J. Med. Genet. (2006) [Pubmed]
  27. The endocannabinoid system in human keratinocytes. Evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activation protein-1, and transglutaminase. Maccarrone, M., Di Rienzo, M., Battista, N., Gasperi, V., Guerrieri, P., Rossi, A., Finazzi-Agrò, A. J. Biol. Chem. (2003) [Pubmed]
  28. Conserved chromosomal location and genomic structure of human and mouse fatty-acid amide hydrolase genes and evaluation of clasper as a candidate neurological mutation. Wan, M., Cravatt, B.F., Ring, H.Z., Zhang, X., Francke, U. Genomics (1998) [Pubmed]
  29. Differential regulation of fatty acid amide hydrolase promoter in human immune cells and neuronal cells by leptin and progesterone. Maccarrone, M., Gasperi, V., Fezza, F., Finazzi-Agrò, A., Rossi, A. Eur. J. Biochem. (2004) [Pubmed]
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