Genetic Blockade of NAAA Cell-specifically Regulates Fatty Acid Ethanolamides (FAEs) Metabolism and Inflammatory Responses

N-Acylethanolamine acid amidase (NAAA) is a lysosomal enzyme responsible for the hydrolysis of fatty acid ethanolamides (FAEs). However, the role of NAAA in FAEs metabolism and regulation of pain and inflammation remains mostly unknown. Here, we generated NAAA-deficient (NAAA-/-) mice using CRISPR-Cas9 technique, and found that deletion of NAAA increased PEA and AEA levels in bone marrow (BM) and macrophages, and elevated AEA levels in lungs. Unexpectedly, genetic blockade of NAAA caused moderately effective anti-inflammatory effects in lipopolysaccharides (LPS)-induced acute lung injury (ALI), and poor analgesic effects in carrageenan-induced hyperalgesia and sciatic nerve injury (SNI)-induced mechanical allodynia. These data contrasted with acute (single dose) or chronic NAAA inhibition by F96, which produced marked anti-inflammation and analgesia in these models. BM chimera experiments indicated that these phenotypes were associated with the absence of NAAA in non-BM cells, whereas deletion of NAAA in BM or BM-derived cells in rodent models resulted in potent analgesic and anti-inflammatory phenotypes. When combined, current study suggested that genetic blockade of NAAA regulated FAEs metabolism and inflammatory responses in a cell-specifical manner.

GPR119 and GPR55 as Receptors for Fatty Acid Ethanolamides, Oleoylethanolamide and Palmitoylethanolamide

Oleoylethanolamide and palmitoylethanolamide are members of the fatty acid ethanolamide family, also known as acylethanolamides. Their physiological effects, including glucose homeostasis, anti-inflammation, anti-anaphylactic, analgesia, and hypophagia, have been reported. They have affinity for different receptor proteins, including nuclear receptors such as PPARα, channels such as TRPV1, and membrane receptors such as GPR119 and GPR55. In the present review, the pathophysiological functions of fatty acid ethanolamides have been discussed from the perspective of receptor pharmacology and drug discovery.

Separation of Fatty Acid Ethanolamides using High Performance Liquid Chromatography

This study aimed to separate fatty acid ethanolamides (FAE) through an enzymatic reaction of ethanolamine and the Terminalia catappa (Local name: Ketapang) seed oil by using reverse-phase high-performance liquid chromatography (RP-HPLC). A 4.6 mm × 150 mm, 5 μm SunFire C18 column was used. Separation optimization was performed by analyzing different variables, which includes mobile phase composition (acetonitrile/water), flow rate and sample concentration. The separation results showed that the retention time for all components was 4.5; 2.4; 12.9; and 6.3 min for fatty acid ethanolamides: oleoylethanolamide, linoleoylethanolamide, stearyl diethanolamide and palmitoylethanolamide, respectively. Inter-peak resolution of >1.5 indicated that each component was accurately separated.

Molecular Targets of Fatty Acid Ethanolamides in Asthma

Asthma is a common allergic pathology of the respiratory tract that requires the study of mechanisms underlying it, due to severe forms of the disease, which are refractory to therapy. The review is devoted to the search for molecular targets of fatty acid ethanolamides in asthma, in particular palmitoylethanolamide (PEA), which has been successfully used in the treatment of chronic inflammatory and neurodegenerative diseases, in the pathogenesis of which the nervous and immune systems are involved. Recently, the potentially important role of neuro-immune interactions in the development of allergic reactions has been established. Many of the clinical symptoms accompanying allergic airway inflammation are the result of the activation of neurons in the airways, so the attention of researchers is currently focused on neuro-immune interactions, which can play an important role in asthma pathophysiology. A growing number of scientific works confirm that the key molecule in the implementation of these inter-systemic interactions is nerve growth factor (NGF). In addition to its classic role in nervous system physiology, NGF is considered as an important factor associated with the pathogenesis of allergic diseases, particularly asthma, by regulating of mast cell differentiation. In this regard, NGF can be one of the targets of PEA in asthma therapy. PEA has a biological effect on the nervous system, and affects the activation and the degranulation of mast cells.

Synthesis, biological evaluation, and structure activity relationship (SAR) study of pyrrolidine amide derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors

N-Acylethanolamine acid amidase (NAAA) is one of the key enzymes involved in the degradation of fatty acid ethanolamides (FAEs), especially for palmitoylethanolamide (PEA).

Dietary fatty acid composition impacts plasma fatty acid ethanolamide levels and body composition in golden Syrian hamsters

Fatty acid ethanolamides (FAEs) are a class of lipid amides that regulate numerous pathophysiological functions.

Synthesis and characterization of the first inhibitor ofN-acylphosphatidylethanolamine phospholipase D (NAPE-PLD)

ARN19874 is a quinazolinedione sulfonamide derivative that inhibits NAPE-PLD, a membrane-associated enzyme that cleavesN-acylphosphatidylethanolamines (NAPEs) into fatty acid ethanolamides (FAEs).

Interactions between dietary oil treatments and genetic variants modulate fatty acid ethanolamides in plasma and body weight composition

Fatty acid ethanolamides (FAE), a group of lipid mediators derived from long-chain fatty acids (FA), mediate biological activities including activation of cannabinoid receptors, stimulation of fat oxidation and regulation of satiety. However, how circulating FAE levels are influenced by FA intake in humans remains unclear. The objective of the present study was to investigate the response of six major circulating FAE to various dietary oil treatments in a five-period, cross-over, randomised, double-blind, clinical study in volunteers with abdominal obesity. The treatment oils (60 g/12 552 kJ per d (60 g/3000 kcal per d)) provided for 30 d were as follows: conventional canola oil, high oleic canola oil, high oleic canola oil enriched with DHA, flax/safflower oil blend and corn/safflower oil blend. Two SNP associated with FAE degradation and synthesis were studied. Post-treatment results showed overall that plasma FAE levels were modulated by dietary FA and were positively correlated with corresponding plasma FA levels; minor allele (A) carriers of SNP rs324420 in gene fatty acid amide hydrolase produced higher circulating oleoylethanolamide (OEA) (P=0·0209) and docosahexaenoylethanolamide (DHEA) levels (P=0·0002). In addition, elevated plasma DHEA levels in response to DHA intake tended to be associated with lower plasma OEA levels and an increased gynoid fat mass. In summary, data suggest that the metabolic and physiological responses to dietary FA may be influenced via circulating FAE. Genetic analysis of rs324420 might help identify a sub-population that appears to benefit from increased consumption of DHA and oleic acid.