Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1
Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1
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DOI：
10.1074/jbc.m412385200
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发表时间：
2005-05-20
影响因子：
4.8
通讯作者：
Tsujimoto, G
中科院分区：
文献类型：
--
作者：
Katsuma, S;Hatae, N;Tsujimoto, G
游离脂肪酸（FFAs）提供重要的能量来源，也作为信号分子。已知FFAs通过其G蛋白偶联受体（gpcr）发挥多种生理反应，如GPR40家族。最近，我们发现了一种新的FFA受体GPR120，它能促进胰高血糖素样肽-1的分泌（Hirasawa, a ., Tsumaya， K., Awaji， T., Katsuma， S., Adachi， T., Yamada， M., Sugimoto， Y., Miyazaki， S.，和Tsujimoto， G.（2005）医学杂志，11,90-94）。本研究表明，FFAs可抑制血清剥夺诱导的小鼠肠内分泌STC-1细胞凋亡，该细胞对不饱和长链FFA表达GPR120和GPR40两种类型的gpcr。我们首先发现亚麻酸能有效激活STC-1细胞中的ERK和Akt/蛋白激酶B （Akt）。ERK激酶抑制剂显著降低了亚麻酸的抗凋亡作用。磷脂酰肌醇3-激酶（PI3K）（其主要靶点是Akt）的抑制剂显著降低了抗凋亡作用。转染Akt显性阴性形式的STC-1细胞也抑制了抗凋亡作用。这些结果表明，ffa对STC-1细胞的抗凋亡作用需要激活ERK和PI3K-Akt通路。瞬时转染STC-1细胞GPR120 cDNA，而非GPR40 cDNA，增强了对caspase-3激活的抑制作用。RNA干扰实验表明，GPR120的表达降低，而GPR40的表达不降低，导致ERK活化降低，FFAs对caspase-3的抑制作用减弱。综上所述，这些结果表明FFAs主要通过GPR120促进ERK和PI3K-Akt通路的激活，从而导致STC-1细胞的抗凋亡作用。
Free fatty acids (FFAs) provide an important energy source and also act as signaling molecules. FFAs are known to exert a variety of physiological responses via their G protein-coupled receptors (GPCRs), such as the GPR40 family. Recently, we identified a novel FFA receptor, GPR120, that promotes secretion of glucagon-like peptide-1 (Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., Sugimoto, Y., Miyazaki, S., and Tsujimoto, G. (2005) Nat. Med. 11, 90-94). Here we showed that FFAs inhibit serum deprivation-induced apoptosis of murine enteroendocrine STC-1 cells, which express two types of GPCRs, GPR120 and GPR40, for unsaturated long chain FFA. We first found that linolenic acid potently activated ERK and Akt/protein kinase B (Akt) in STC-1 cells. ERK kinase inhibitors significantly reduced the antiapoptotic effects of linolenic acid. Inhibitors for phosphatidylinositol 3-kinase (PI3K), a major target of which is Akt, significantly reduced the anti-apoptotic effects. Transfection of STC-1 cells with the dominant-negative form of Akt also inhibited the anti-apoptotic effect. These results suggested that the activation of ERK and PI3K-Akt pathways is required for FFA-induced anti-apoptotic effects on STC-1 cells. Transient transfection of STC-1 cells with GPR120 cDNA, but not GPR40 cDNA, enhanced inhibition of caspase-3 activation. RNA interference experiments showed that reduced expression of GPR120, but not GPR40, resulted in reduced ERK activation and reduced effects of FFAs on caspase-3 inhibition. Collectively, these results demonstrated that FFAs promote the activation of ERK and PI3K-Akt pathways mainly via GPR120, leading to the anti-apoptotic effect of STC-1 cells.