Chylomicrons stimulate incretin secretion in mouse and human cells.
Chylomicrons stimulate incretin secretion in mouse and human cells.
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DOI：
10.1007/s00125-017-4420-2
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发表时间：
2017-12
期刊：
影响因子：
8.2
通讯作者：
Reimann F
中科院分区：
文献类型：
--
作者：
Psichas A;Larraufie PF;Goldspink DA;Gribble FM;Reimann F
脂质是胰高血糖素样肽 (GLP)-1 和葡萄糖依赖性促胰岛素肽 (GIP) 分泌的有效刺激物。传统上，这种效应被认为涉及肠内分泌细胞顶端表面的游离脂肪酸受体 1 (FFA1) 和 G 蛋白偶联受体 119 (GPR119) 对脂质消化产物的感知。然而，最近的证据表明，脂质实际上可能是在基底外侧被感知的，并且脂肪酸吸收和乳糜微粒合成可能是它们对肠肽释放产生刺激作用的先决条件。因此，我们在体外研究了乳糜微粒对 GLP-1 和 GIP 分泌的影响。使用 GLUTag 细胞以及小鼠和人类来源的十二指肠培养物研究了乳糜微粒对肠促胰岛素分泌的影响。通过药理学抑制和小（短）干扰 RNA (siRNA) 介导的敲低来评估脂蛋白脂肪酶 (LPL) 和 FFA1 在 GLUTag 细胞中的作用。通过对负载 Fura-2 的 GLUTag 细胞进行成像来确定乳糜微粒对细胞内钙浓度 ([Ca2+]i) 的影响。在初始设置中，使用用 FFA1 拮抗剂 GW1100 处理的 L 细胞特异性 Gpr119 敲除培养物研究了 FFA1 和 GPR119 的贡献。乳糜微粒刺激 GLUTag 细胞释放 GLP-1，以及人和鼠十二指肠培养物分泌 GLP-1 和 GIP。用奥利司他抑制脂肪酶或 siRNA 介导的 Lpl 敲低后，乳糜微粒触发的 GLUTag 细胞的 GLP-1 分泌基本上被消除。在 GLUTag 细胞中，GW1100 和 siRNA 介导的 Ffar1 敲低均减少了对乳糜微粒反应的 GLP-1 分泌，并且与 FFA1 Gq 偶联一致，乳糜微粒引发了 [Ca2+]i 的增加。然而，LPL 和 FFA1 抑制对小鼠培养物中乳糜微粒介导的肠促胰岛素分泌没有显着影响。此外，即使存在 GW1100，GPR119 的缺失也不影响响应乳糜微粒的 GLP-1 分泌。乳糜微粒刺激 GLUTag 细胞以及人类和小鼠十二指肠培养物分泌肠促胰岛素激素。在 GLUTag 细胞中，发现该分子途径涉及 LPL 介导的脂肪分解，导致脂质物质的释放，从而激活 FFA1 并升高细胞内钙。本文的在线版本 (10.1007/s00125-017-4420-2) 包含经过同行评审但未经编辑的补充材料，可供授权用户使用。
Lipids are a potent stimulus for the secretion of glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP). Traditionally, this effect was thought to involve the sensing of lipid digestion products by free fatty acid receptor 1 (FFA1) and G-protein coupled receptor 119 (GPR119) on the apical surface of enteroendocrine cells. However, recent evidence suggests that lipids may in fact be sensed basolaterally, and that fatty acid absorption and chylomicron synthesis may be a prerequisite for their stimulatory effect on gut peptide release. Therefore, we investigated the effect of chylomicrons on GLP-1 and GIP secretion in vitro. The effect of chylomicrons on incretin secretion was investigated using GLUTag cells and duodenal cultures of both murine and human origin. The role of lipoprotein lipase (LPL) and FFA1 in GLUTag cells was assessed by pharmacological inhibition and small (short) interfering RNA (siRNA)-mediated knockdown. The effect of chylomicrons on intracellular calcium concentration ([Ca2+]i) was determined by imaging GLUTag cells loaded with Fura-2. In the primary setting, the contributions of FFA1 and GPR119 were investigated using L cell-specific Gpr119 knockout cultures treated with the FFA1 antagonist GW1100. Chylomicrons stimulated GLP-1 release from GLUTag cells, and both GLP-1 and GIP secretion from human and murine duodenal cultures. Chylomicron-triggered GLP-1 secretion from GLUTag cells was largely abolished following lipase inhibition with orlistat or siRNA-mediated knockdown of Lpl. In GLUTag cells, both GW1100 and siRNA-mediated Ffar1 knockdown reduced GLP-1 secretion in response to chylomicrons, and, consistent with FFA1 Gq-coupling, chylomicrons triggered an increase in [Ca2+]i. However, LPL and FFA1 inhibition had no significant effect on chylomicron-mediated incretin secretion in murine cultures. Furthermore, the loss of GPR119 had no impact on GLP-1 secretion in response to chylomicrons, even in the presence of GW1100. Chylomicrons stimulate incretin hormone secretion from GLUTag cells as well as from human and murine duodenal cultures. In GLUTag cells, the molecular pathway was found to involve LPL-mediated lipolysis, leading to the release of lipid species that activated FFA1 and elevated intracellular calcium. The online version of this article (10.1007/s00125-017-4420-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
5.7
作者：
Kuemmerle NB;Rysman E;Lombardo PS;Flanagan AJ;Lipe BC;Wells WA;Pettus JR;Froehlich HM;Memoli VA;Morganelli PM;Swinnen JV;Timmerman LA;Chaychi L;Fricano CJ;Eisenberg BL;Coleman WB;Kinlaw WB
通讯作者：
Kinlaw WB
影响因子：
7.7
作者：
Hein GJ;Baker C;Hsieh J;Farr S;Adeli K
通讯作者：
Adeli K
影响因子：
4.8
作者：
Habib, Abdella M.;Richards, Paul;Gribble, Fiona M.
通讯作者：
Gribble, Fiona M.
影响因子：
3
作者：
Hodge, Daryl;Glass, Leslie L.;Reimann, Frank
通讯作者：
Reimann, Frank
影响因子：
2.5
作者：
Christensen, Louise W.;Kuhre, Rune E.;Holst, Jens J.
通讯作者：
Holst, Jens J.