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Companion Animals Models of Human Disease
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Canine leukoencephalomyelopathy (LEMP) is a juvenile-onset neurodegenerative disorder of the CNS white matter currently described in Rottweiler and Leonberger dogs(107). Genome-wide association study (GWAS) allowed LEMP mapping in a Leonberger cohort to dog chromosome 18. Subsequent whole genome re-sequencing of a Leonberger case enabled the identification of a single private homozygous non-synonymous missense variant located in the highly conserved metallo-beta-lactamase domain of the N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD) gene, encoding an enzyme of the endocannabinoid system. Sequencing this gene in LEMP-affected Rottweilers identified a different frameshift variant, which is predicted to replace the C-terminal metallo-beta-lactamase domain of the wild type protein. Haplotype analysis of SNP array genotypes revealed that the frameshift variant was present in diverse haplotypes in Rottweilers, and also in Great Danes, indicating an old origin of this second NAPEPLD variant. The identification of different NAPEPLD variants in dog breeds affected by leukoencephalopathies with heterogeneous pathological features, implicates the NAPEPLD enzyme as important in myelin homeostasis, and suggests a novel candidate gene for myelination disorders in people.
Pharmacological approaches to treat intestinal pain
Published in Expert Review of Clinical Pharmacology, 2023
Mikolaj Swierczynski, Adam Makaro, Agata Grochowska, Maciej Salaga
The enzymes taking part in ECS may be another target in the development of novel analgesics. It was showed that the expression of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), which synthesize endocannabinoids, is decreased in duodenal samples obtained from postinfectious IBS patients [123]. Some studies suggested that decreased levels of NAPE-PLD and increased levels of degrading FAAH are responsible for the downregulated activity of ECS in gut disorders [124,125]. These observations have not resulted in clinical implications yet, however, animal studies provided interesting conclusions. Fichna et al. showed that PF-3845, a selective FAAH inhibitor, displayed antinociceptive effect in mice [126]. Moreover, another study showed that the inhibition of MGL attenuates murine colitis [127].
Effect of different bile acids on the intestine through enterohepatic circulation based on FXR
Published in Gut Microbes, 2021
Junwei Xiang, Zhengyan Zhang, Hongyi Xie, Chengcheng Zhang, Yan Bai, Hua Cao, Qishi Che, Jiao Guo, Zhengquan Su
The dynamic balance among intestinal epithelial cells, the intestinal flora and the intestinal mucosa is very important for maintaining intestinal permeability and normal tissue function. BAs have amphiphilic properties, and when combined with polar phospholipids, dietary lipids can be incorporated into the mixed solution in the intestinal lumen. This incorporation results in a micellization process, which is essential for fat absorption and systemic energy balance. In cells, BAs can be inserted into cell membranes, including plasma membranes; supraphysiolgical doses can also damage cell membranes and cause cell lysis. The hydrophobicity of BAs determines their cytotoxicity, which decreases in the following order: UDCA <CA <CDCA <DCA <LCA.76 Hydrophobic BAs have high affinity for lipids and can damage mitochondria. DCA can colocalize with the outer mitochondrial membrane and disrupt its structure. Hydrophobic BAs have been shown to cause HepG2 cell apoptosis through endoplasmic reticulum stress. N-acyl phosphatidylethanolamine D (NAPE-PLD), an enzyme expressed in the brain and intestines, can convert membrane lipids into unique active lipids, and hydrophobic substrates can bind and stabilize NAPE-PLD. LCA has been shown to inhibit NAPE-PLD, while CDCA and DCA have been shown to activate NAPE-PLD; these difference may be attributed to the different hydroxyl sites in different BAs.7
Different roles for the acyl chain and the amine leaving group in the substrate selectivity of N-Acylethanolamine acid amidase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Andrea Ghidini, Laura Scalvini, Francesca Palese, Alessio Lodola, Marco Mor, Daniele Piomelli
NAAA’s best known substrate, PEA4, is a member of the fatty acid ethanolamide (FAE) family of lipid messengers, which also includes anandamide (arachidonoylethanolamide) and oleoylethanolamide (OEA). Anandamide is an endogenous agonist for cannabinoid receptors, the target of Δ9-tetrahydrocannabinol in cannabis11, while PEA and OEA activate the ligand-operated transcription factor, peroxisome proliferator activated receptor-α (PPAR-α), to regulate energy balance12–14, pain15, and inflammation16,17. NAAA plays a key role in the control of the cellular levels of PEA. In healthy tissues, this lipid mediator is generated by the action of a structurally unique phospholipase D (N-acylphosphatidylethanolamine phospholipase D, NAPE-PLD) that cleaves the glycerophospholipid precursor, N-palmitoylphosphatidylethanolamine, to produce FAE and phosphatidic acid18–20. PEA formation contributes to tissue homeostasis by recruiting PPAR-α-dependent transcriptional programs that enhance host defence and curb inflammatory responses21,22. Suprathreshold inflammatory stimuli cause a rapid reduction in tissue PEA content, which may enable in turn the development of inflammation22. This decline in tissue PEA levels is due to a two-pronged process that involves the suppression of NAPE-PLD transcription23 and the enhancement of NAAA expression and activity24.