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2-OMe-lysophosphatidylcholine analogues are GPR119 ligands and activate insulin secretion from βTC-3 pancreatic cells: Evaluation of structure-dependent biological activity

Drzazga, Anna ; Sowińska, Agata ; Krzemińska, Agnieszka ; Okruszek, Andrzej ; Paneth, Piotr ; Koziołkiewicz, Maria ; Gendaszewska-Darmach, Edyta

BBA - Molecular and Cell Biology of Lipids, January 2018, Vol.1863(1), pp.91-103 [Peer Reviewed Journal]

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  • Title:
    2-OMe-lysophosphatidylcholine analogues are GPR119 ligands and activate insulin secretion from βTC-3 pancreatic cells: Evaluation of structure-dependent biological activity
  • Author: Drzazga, Anna ; Sowińska, Agata ; Krzemińska, Agnieszka ; Okruszek, Andrzej ; Paneth, Piotr ; Koziołkiewicz, Maria ; Gendaszewska-Darmach, Edyta
  • Description: GPR119 receptor has been proposed as a metabolic regulator playing a pivotal role in the modulation of glucose homeostasis in type 2 diabetes. GPR119 was identified on pancreatic β cells and its ligands have the ability to enhance glucose-stimulated insulin secretion (GSIS). Lysophosphatidylcholine (LPC) was shown to potentiate GSIS and our present studies indicate that 2-methoxy-lysophosphatidylcholine (2- -LPC) analogues, unable to undergo 1 → 2 acyl migration, stimulate GSIS from murine βTC-3 pancreatic cells even more efficiently. Moreover, biological assays in engineered Tango™ GPR119-bla U2OS cells were carried out to ascertain the agonist activity of 2- -LPC at GPR119. 2- -LPC possessing in sn-1 position the residues of myristic, palmitic, stearic and oleic acid were also evaluated as factors regulating [Ca ] mobilization and cAMP levels. Extension of these studies to R- and S-enantiomers of 14:0 2- -LPC revealed that the overall impact on GSIS does not depend on chirality, however, the intracellular calcium mobilization data show that the R enantiomer is significantly more active than S one. Taking into account differences in chemical structure between various native LPCs and their 2-methoxy counterparts the possible binding mode of 2- -LPC to the GPR119 receptor was determined using molecular modeling approach.
  • Is Part Of: BBA - Molecular and Cell Biology of Lipids, January 2018, Vol.1863(1), pp.91-103
  • Identifier: ISSN: 1388-1981 ; E-ISSN: 1879-2618 ; DOI: 10.1016/j.bbalip.2017.10.004
  • Subjects: Lysophosphatidylcholine (Lpc) ; Gpr119 ; Diabetes ; Gsis ; Cytotoxicity ; Intracellular Calcium Mobilization ; Camp Accumulation ; Molecular Modeling ; Biology ; Chemistry ; Anatomy & Physiology
  • Language: English
  • Source: ScienceDirect Journals (Elsevier)

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