Lysophosphatidylcholine and its phosphorothioate analogues potentiate insulin secretion via GPR40 (FFAR1), GPR55 and GPR119 receptors in a different manner
Lysophosphatidylcholine and its phosphorothioate analogues potentiate insulin secretion via GPR40 (FFAR1), GPR55 and GPR119 receptors in a different manner
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DOI：
10.1016/j.mce.2017.12.002
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发表时间：
2018-09-05
影响因子：
4.1
通讯作者：
Bergsten, Peter
中科院分区：
文献类型：
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作者：
Drzazga, Anna;Kristinsson, Hjalti;Bergsten, Peter
溶血磷脂酰胆碱（LPC）是GPR119受体的内源性配体，介导葡萄糖刺激胰岛素分泌（GSIS）。我们发现LPC不仅能识别GPR119，还能识别溶血磷脂酰肌醇激活的GPR40（游离脂肪酸受体1）和GPR55，从而促进MINE胰腺β细胞系和小鼠朗格汉胰岛的GSIS。天然LPC在体内使用时不稳定，限制了其治疗价值，因此，我们提出了具有更高稳定性的硫代LPC类似物。所有改良LPCs（12:0、14:0、16:0、18:0、18:1）均显著增强GSIS。16:0硫模拟物是最有效的，与本地对应物相比，唤起2倍的强化GSIS。有趣的是，LPC类似物引发了GPR40-， gpr55 -和GPR119依赖[Ca2+](i)的信号传导，但不像未修饰的分子那样刺激cAMP的积累。因此，引入磷酸化功能不仅增加了LPC的稳定性，而且还调节了对受体靶点的亲和力，并引发了不同的信号通路。(C) 2017 Elsevier B.V.版权所有
Lysophosphatidylcholine (LPC) is an endogenous ligand for GPR119 receptor, mediating glucose-stimulated insulin secretion (GSIS). We demonstrate that LPC facilitates GSIS in MINE pancreatic beta-cell line and murine islets of Langerhans by recognizing not only GPR119 but also GPR40 (free fatty acid receptor 1) and GPR55 activated by lysophosphatidylinositol. Natural LPCs are unstable when administered in vivo limiting their therapeutic value and therefore, we present phosphorothioate LPC analogues with increased stability. All the modified LPCs under study (12:0,14:0,16:0,18:0, and 18:1) significantly enhanced GSIS. The 16:0 sulfur analogue was the most potent, evoking 2-fold accentuated GSIS compared to the native counterpart. Interestingly, LPC analogues evoked GPR40-, GPR55-and GPR119 dependent [Ca2+](i), signaling, but did not stimulate cAMP accumulation as in the case of unmodified molecules. Thus, introduction of a phosphorothioate function not only increases LPC stability but also modulates affinity towards receptor targets and evokes different signaling pathways. (C) 2017 Elsevier B.V. All rights reserved.