Iwasaki Kanako, Harada Norio, Sasaki Kazuki, Yamane Shunsuke, Iida Keiko, Suzuki Kazuyo, Hamasaki Akihiro, Nasteska Daniela, Shibue Kimitaka, Joo Erina, Harada Takanari, Hashimoto Toshihiro, Asakawa Yoshinori, Hirasawa Akira, Inagaki Nobuya
Department of Diabetes, Endocrinology and Nutrition (K.Iw., N.H., K.Sa., S.Y., K.Su., A.Ha., D.N., K.Sh., E.J., T.Har., N.I.), Graduate School of Medicine, and Department of Genomic Drug Discovery Science (K.Ii., A.Hi.), Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and Faculty of Pharmaceutical Sciences (T.Has., Y.A.), Tokushima Bunri University, Tokushima 770-8514, Japan.
Endocrinology. 2015 Mar;156(3):837-46. doi: 10.1210/en.2014-1653. Epub 2014 Dec 23.
Gastric inhibitory polypeptide (GIP) is an incretin secreted from enteroendocrine K cells in response to meal ingestion. Recently free fatty acid receptor G protein-coupled receptor (GPR) 120 was identified as a lipid sensor involved in glucagon-like peptide-1 secretion. However, Gpr 120 gene expression and its role in K cells remain unclear, partly due to difficulties in separation of K cells from other intestinal epithelial cells. In this study, we purified K cells using GIP-green fluorescent protein (GFP) knock-in mice, in which K cells can be visualized by GFP fluorescence. GFP-positive cells (K cells) were observed in the small intestine but not in the stomach and colon. K cell number and GIP content in K cells were significantly higher in the upper small intestine than those in the lower small intestine. We also examined the expression levels of several free fatty acid receptors in K cells. Among free fatty acid receptors, GPR120 was highly expressed in the K cells of the upper small intestine compared with the lower small intestine. To clarify the role of GPR120 on K cells in vivo, we used GPR120-deficient mice (GPR120(-/-)). GPR120(-/-) exhibited significantly lower GIP secretion (75% reduction, P < .01) after lard oil ingestion compared with that in wild-type mice. Consistently, pharmacological inhibition of GPR120 with grifolic acid methyl ether in wild-type mice significantly attenuated lard oil-induced GIP secretion. In conclusion, GPR120 is expressed abundantly in K cells of the upper small intestine and plays a critical role in lipid-induced GIP secretion.
胃抑制多肽（GIP）是一种肠促胰岛素，由肠内分泌K细胞在摄入食物后分泌。最近，游离脂肪酸受体G蛋白偶联受体（GPR）120被鉴定为参与胰高血糖素样肽-1分泌的脂质传感器。然而，Gpr 120基因表达及其在K细胞中的作用仍不清楚，部分原因是难以将K细胞与其他肠道上皮细胞分离。在本研究中，我们使用GIP-绿色荧光蛋白（GFP）基因敲入小鼠纯化K细胞，其中K细胞可通过GFP荧光可视化。在小肠中观察到GFP阳性细胞（K细胞），但在胃和结肠中未观察到。上小肠中K细胞数量和K细胞中的GIP含量显著高于下小肠。我们还检测了K细胞中几种游离脂肪酸受体的表达水平。在游离脂肪酸受体中，与下小肠相比，GPR120在上小肠的K细胞中高表达。为了阐明GPR120在体内K细胞中的作用，我们使用了GPR120缺陷小鼠（GPR120(-/-)）。与野生型小鼠相比，GPR120(-/-)在摄入猪油后表现出显著更低的GIP分泌（降低75%，P <.01）。同样，在野生型小鼠中用灰树花酸甲酯对GPR120进行药理学抑制显著减弱了猪油诱导的GIP分泌。总之，GPR120在上小肠的K细胞中大量表达，并在脂质诱导的GIP分泌中起关键作用。
