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  • 标题:Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ω3- and ω6-long-chain-PUFA deficiency
  • 本地全文:下载
  • 作者:Ina Hammels ; Erika Binczek ; Ina Hammels
  • 期刊名称:JLR Papers In Press
  • 印刷版ISSN:0022-2275
  • 电子版ISSN:1539-7262
  • 出版年度:2019
  • 卷号:60
  • 期号:8
  • 页码:1396-1409
  • DOI:10.1194/jlr.M094664
  • 出版社:American Society for Biochemistry and Molecular Biology
  • 摘要:Mammalian ω3- and ω6-PUFAs are synthesized from essential fatty acids (EFAs) or supplied by the diet. PUFAs are constitutive elements of membrane architecture and precursors of lipid signaling molecules. EFAs and long-chain (LC)-PUFAs are precursors in the synthesis of endocannabinoid ligands of Gi/o protein-coupled cannabinoid receptor (CB)1 and CB2 in the endocannabinoid system, which critically regulate energy homeostasis as the metabolic signaling system in hypothalamic neuronal circuits and behavioral parameters. We utilized the auxotrophic fatty acid desaturase 2-deficient ( fads2 −/−) mouse, deficient in LC-PUFA synthesis, to follow the age-dependent dynamics of the PUFA pattern in the CNS-phospholipidome in unbiased dietary studies of three cohorts on sustained LC-PUFA-free ω6-arachidonic acid- and DHA-supplemented diets and their impact on the precursor pool of CB1 ligands. We discovered the transformation of eicosa-all cis -5,11,14-trienoic acid, uncommon in mammalian lipidomes, into two novel endocannabinoids, 20:35,11,14-ethanolamide and 2-20:35,11,14-glycerol. Their function as ligands of CB1 has been characterized in HEK293 cells. Labeling experiments excluded Δ8-desaturase activity and proved the position specificity of FADS2. The fads2 −/− mutant might serve as an unbiased model in vivo in the development of novel CB1 agonists and antagonists.
  • 关键词:fatty acid desaturase 2-deficient mouse model ; arachidonic acid ; diet effects ; lipid metabolism ; ω3 fatty acids ; cannabinoid receptor 1 ; polyunsaturated fatty acid ; 20:35;11;14-endocannabinoids ; endocannabinoid system-orexin-circuitry ; surrogate cannabinoid receptor 1 ligands
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