Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype
Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype
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DOI：
10.1007/s00125-013-3123-6
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发表时间：
2014-02-01
期刊：
影响因子：
8.2
通讯作者：
Kleuser, Burkhard
中科院分区：
文献类型：
--
作者：
Fayyaz, Susann;Henkel, Janin;Kleuser, Burkhard
NEFA的血浆水平升高已被证明可诱导肝脏胰岛素抵抗，这有助于2型糖尿病的发展。实际上，鞘脂可以通过从头途径由饱和脂肪酸棕榈酸酯和氨基酸丝氨酸形成。除了神经酰胺，鞘氨醇1-磷酸（S1 P）已被确定为主要的生物活性脂质介质。因此，我们的目的是研究S1 P在肝胰岛素抵抗中的产生和功能。棕榈酸酯掺入鞘脂在原代人和大鼠肝细胞中进行快速分辨率液相色谱-MS/MS。在人和大鼠肝细胞以及新西兰肥胖（NZO）小鼠中研究了S1 P的影响以及S1 P受体在肝胰岛素抵抗中的参与。棕榈酸在大鼠和人肝细胞中诱导了令人印象深刻的细胞内外S1 P的形成。在喂食高脂饮食的NZO小鼠中观察到肝脏S1 P水平升高。一旦产生，S1 P就能够与棕榈酸酯类似地抵消胰岛素信号。S1 P（2）受体拮抗剂JTE-013在体内外均能消除S1 P的抑制作用。与此一致的是，免疫调节剂FTY 720-phosphate（它能与除S1 P（2）以外的所有S1 P受体结合）不能抑制胰岛素信号传导。这些数据表明棕榈酸酯被肝细胞代谢为S1 P，后者通过刺激S1 P（2）受体来损害胰岛素信号传导。特别是，S1 P（2）抑制可以被认为是治疗胰岛素抵抗的新的治疗靶点。
Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance.The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice.Palmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P(2) receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P(2), was not able to inhibit insulin signalling.These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P(2) receptor to impair insulin signalling. In particular, S1P(2) inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.