The G-Protein−Coupled Receptor GPR40 Directly Mediates Long-Chain Fatty Acid−Induced Secretion of Cholecystokinin

游离脂肪酸受体1 GPR120 胆囊收缩素 亚油酸 受体 α-亚麻酸 游离脂肪酸受体 生物 脂肪酸 分子生物学 分泌物 内科学 生物化学 化学 内分泌学 G蛋白偶联受体 多不饱和脂肪酸 六烯酸 医学 兴奋剂
作者
Alice P. Liou,Xiaoyong Lu,Yoshitatsu Sei,Xilin Zhao,Susanne Pechhold,Ricardo J. Carrero,Helen E. Raybould,Stephen A. Wank
出处
期刊:Gastroenterology [Elsevier]
卷期号:140 (3): 903-912.e4 被引量:242
标识
DOI:10.1053/j.gastro.2010.10.012
摘要

Long-chain fatty acid receptors G-protein-coupled receptor 40 (GPR40) (FFAR1) and GPR120 have been implicated in the chemosensation of dietary fats. I cells in the intestine secrete cholecystokinin (CCK), a peptide hormone that stimulates digestion of fat and protein, but these cells are rare and hard to identify. We sought to determine whether dietary fat-induced secretion of CCK is directly mediated by GPR40 expressed on I cells.We used fluorescence-activated cell sorting to isolate a pure population of I cells from duodenal mucosa in transgenic mice that expressed green fluorescent protein under the control of the CCK promoter (CCK-enhanced green fluorescent protein [eGFP] bacterial artificial chromosome mice). CCK-eGFP cells were evaluated for GPR40 expression by quantitative reverse transcription polymerase chain reaction and immunostaining. GPR40(-/-) mice were bred with CCK-eGFP mice to evaluate functional relevance of GPR40 on long-chain fatty acid-stimulated increases in [Ca(2+)]i and CCK secretion in isolated CCK-eGFP cells. Plasma levels of CCK after olive oil gavage were compared between GPR40(+/+) and GPR40(-/-) mice.Cells that expressed eGFP also expressed GPR40; expression of GPR40 was 100-fold greater than that of cells that did not express eGFP. In vitro, linoleic, oleic, and linolenic acids increased [Ca(2+)]i; linolenic acid increased CCK secretion by 53% in isolated GPR40(+/+) cells that expressed eGFP. In contrast, in GPR40(-/-) that expressed eGFP, [Ca(2+)]i response to linoleic acid was reduced by 50% and there was no significant CCK secretion in response to linolenic acid. In mice, olive oil gavage significantly increased plasma levels of CCK compared with pregavage levels: 5.7-fold in GPR40(+/+) mice and 3.1-fold in GPR40(-/-) mice.Long-chain fatty acid receptor GPR40 induces secretion of CCK by I cells in response to dietary fat.
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