Laboratory of Food Safety and Science, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, Saga 840-8502, Japan.
Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon 791-0295, Japan.
J Biochem. 2018 Jul 1;164(1):27-32. doi: 10.1093/jb/mvy017.
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 α-shedding assay. We found that phytosphingosine (PHS) activates GPR120 in a manner comparable to the natural ligand α-linolenic acid (ALA) and superior to that of the synthetic ligand GW9508. The IC50 value of PHS was 33.4 μM, of ALA was 31.0 μM and of GW9508 was 41.7 μM. 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.
GPR120 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。GPR120 的激活促进肠促胰岛素 GLP-1 的分泌，已知其对代谢综合征有影响。因此，GPR120 是治疗 2 型糖尿病药物的潜在靶点。在这项研究中，我们使用转化生长因子 α 脱落测定法对甘油和神经鞘氨醇型脂质及其衍生物对 GPR120 进行了配体筛选。我们发现植鞘氨醇（PHS）以与天然配体 α-亚麻酸（ALA）相当的方式激活 GPR120，优于合成配体 GW9508。PHS 的 IC50 值为 33.4 μM，ALA 的 IC50 值为 31.0 μM，GW9508 的 IC50 值为 41.7 μM。此外，PHS 诱导的 GPR120 激活被特异性拮抗剂 AH7614 抑制。迄今为止发现的许多天然或合成配体都是具有羧基的化合物。然而，PHS 不具有羧基，这表明其与 GPR120 的相互作用方式可能与其他配体显著不同。由于 PHS 在酵母质膜中含量丰富，我们的结果表明，发酵食品中发现的 PHS 通过激活 GPR120 可能对糖尿病有治疗作用。
