Sensing of fatty acids for octanoylation of ghrelin involves a gustatory G-protein.
Sensing of fatty acids for octanoylation of ghrelin involves a gustatory G-protein.
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DOI：
10.1371/journal.pone.0040168
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Depoortere I
中科院分区：
文献类型：
--
作者：
Janssen S;Laermans J;Iwakura H;Tack J;Depoortere I
Ghrelin是能量和葡萄糖动态平衡的重要调节器。Ser3的辛酰化对于Ghrelin的生物学效应是必不可少的，但参与辛酰化的机制尚不清楚。我们研究了味觉G蛋白、α-Gustducin以及游离脂肪酸受体GPR40和GPR120是否参与了Ghrelin细胞的脂肪酸感知机制。野生型(WT)和α-Gustducin基因敲除(GRESS−/−)小鼠在2周内接受三辛酸甘油酯强化饮食(OD)。测定胃促生长素水平和胃排空功能。免疫荧光染色研究GPR40、GPR120与Ghrelin或α-Gustducin/α-转导蛋白的共定位。研究了GPR120在中长链脂肪酸对Ghrelinoma细胞株MGN3-1释放Ghrelin的影响中的作用。在体内外研究了GPR40激动剂MEDICA16和GPR120激动剂格列酸对Ghrelin释放的影响。饲喂OD可显著增加WT小鼠胃部的辛酰生长激素水平，但不能增加GRESS−/−小鼠的胃辛酰生长素水平。WT组小鼠胃排空速度加快，而GRESS−/−组小鼠胃排空速度无明显变化。GPR40与去辛酰基Ghrelin、α-Gustducin或α-转导蛋白阳性细胞共定位于胃内，但不与辛酰基Ghrelin、Ghgdin或GPR40-转导蛋白阳性细胞共定位。GPR120仅与Ghrelin共定位于十二指肠。在MGN3-1细胞中加入辛酸或α-亚麻酸可分别增加和降低辛酰Ghrelin水平。GPR120 siRNA不能阻断这两种作用。MEDICA16和格列叶酸在体外对Ghrelin的分泌没有影响，但口服格列叶酸增加了血浆Ghrelin的水平。这项研究首次提供了α-Gustducin参与Ghrelin辛酰化的证据，并表明Ghrelin细胞可以直接感知长链和中链脂肪酸。GPR120而不是GPR40可能在Ghrelin细胞的脂质感受级联中起作用。
Ghrelin is an important regulator of energy – and glucose homeostasis. The octanoylation at Ser3 is essential for ghrelin’s biological effects but the mechanisms involved in the octanoylation are unknown. We investigated whether the gustatory G-protein, α-gustducin, and the free fatty acid receptors GPR40 and GPR120 are involved in the fatty acid sensing mechanisms of the ghrelin cell. Wild-type (WT) and α-gustducin knockout (gust−/−) mice were fed a glyceryl trioctanoate-enriched diet (OD) during 2 weeks. Ghrelin levels and gastric emptying were determined. Co-localization between GPR40, GPR120 and ghrelin or α-gustducin/α-transducin was investigated by immunofluorescence staining. The role of GPR120 in the effect of medium and long chain fatty acids on the release of ghrelin was studied in the ghrelinoma cell line, MGN3-1. The effect of the GPR40 agonist, MEDICA16, and the GPR120 agonist, grifolic acid, on ghrelin release was studied both in vitro and in vivo. Feeding an OD specifically increased octanoyl ghrelin levels in the stomach of WT mice but not of gust−/− mice. Gastric emptying was accelerated in WT but not in gust−/− mice. GPR40 was colocalized with desoctanoyl but not with octanoyl ghrelin, α-gustducin or α-transducin positive cells in the stomach. GPR120 only colocalized with ghrelin in the duodenum. Addition of octanoic acid or α-linolenic acid to MGN3-1 cells increased and decreased octanoyl ghrelin levels, respectively. Both effects could not be blocked by GPR120 siRNA. MEDICA16 and grifolic acid did not affect ghrelin secretion in vitro but oral administration of grifolic acid increased plasma ghrelin levels. This study provides the first evidence that α-gustducin is involved in the octanoylation of ghrelin and shows that the ghrelin cell can sense long- and medium-chain fatty acids directly. GPR120 but not GPR40 may play a role in the lipid sensing cascade of the ghrelin cell.
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