Phytosphingosine is a novel activator of GPR120
Phytosphingosine is a novel activator of GPR120
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DOI：
10.1093/jb/mvy017
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发表时间：
2018-07-01
影响因子：
2.7
通讯作者：
Mitsutake, Susumu
中科院分区：
文献类型：
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作者：
Nagasawa, Tomotaka;Nakamichi, Hikaru;Mitsutake, Susumu
GPR 120是长链脂肪酸的受体，在小肠内分泌细胞、L细胞和脂肪组织中表达。GPR 120的激活促进肠促胰岛素GLP-1的分泌，已知其对抗代谢综合征具有作用。因此，GPR 120是II型糖尿病药物的潜在靶点。在这项研究中，我们进行了配体筛选GPR 120的甘油和鞘氨醇型脂质及其衍生物使用转化生长因子α-脱落测定。我们发现，植物鞘氨醇（PHS）激活GPR 120的方式与天然配体α-亚麻酸（ALA）和上级的合成配体GW 9508。PHS的IC_（50）为33.4 μ M，ALA为31.0 μ M，GW 9508为41.7 μ M。此外，特异性拮抗剂AH 7614可抑制PHS诱导的GPR 120活化。迄今为止发现的许多天然或合成配体是具有羧基的化合物。然而，PHS不具有羧基，这表明其与GPR 120的相互作用方式可能与其他配体的相互作用方式显著不同。由于PHS富含酵母细胞膜，我们的研究结果表明发酵食品中发现的PHS可能通过激活GPR 120而具有抗糖尿病作用。
GPR120 is a receptor for long chain fatty acids and is expressed in small intestinal endocrine cells, L cells and adipose tissue. Activation of GPR120 promotes the secretion of incretin GLP-1, which is known to have effects on anti-metabolic syndrome. As such, GPR120 is a potential target of pharmaceuticals for type II diabetes. In this study, we performed ligand-screening for GPR120 on glycero-and sphingo-type lipids and their derivatives using a Transforming Growth Factor alpha-shedding assay. We found that phytosphingosine (PHS) activates GPR120 in a manner comparable to the natural ligand a-linolenic acid (ALA) and superior to that of the synthetic ligand GW9508. The IC50 value of PHS was 33.4 mu M, of ALA was 31.0 mu M and of GW9508 was 41.7 mu M. Additionally, PHS-induced activation of GPR120 was inhibited by the specific antagonist AH7614. Many of the natural or synthetic ligands found thus far are compounds with carboxyl groups. However, PHS does not possess a carboxyl group, suggesting that its manner of interaction with GPR120 may be significantly different from that of other ligands. Since PHS is rich in the plasma membrane of yeast, our results imply that PHS found in fermented food could have effects on anti-diabetes through activation of GPR120.