Orexin A protects cells from apoptosis by regulating FoxO1 and mTORC1 through the OX1R/PI3K/AKT signaling pathway in hepatocytes
Orexin A protects cells from apoptosis by regulating FoxO1 and mTORC1 through the OX1R/PI3K/AKT signaling pathway in hepatocytes
复制标题
Orexin A 通过肝细胞中的 OX1R/PI3K/AKT 信号通路调节 FoxO1 和 mTORC1，从而保护细胞免于凋亡
DOI：
10.3892/ijmm.2014.1769
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发表时间：
2014-07-01
影响因子：
5.4
通讯作者：
Guo, Lei
中科院分区：
文献类型：
--
作者：
Ju, Shu-Jing;Zhao, Yuyan;Guo, Lei
食欲素A和B是多功能神经肽，参与食物摄取、能量代谢、葡萄糖调节和觉醒的调节。它们通过两种G蛋白偶联受体（GPCR）发出信号：食欲素受体1（OX 1 R）和食欲素受体2（OX 2 R）。先前的研究表明，食欲素在其他细胞类型中通过OX 1 R偶联与PI 3 K/AKT信号通路相互作用，但很少参与肝细胞。在本研究中，逆转录（RT）-PCR和蛋白质印迹分析显示，在体外大鼠肝细胞中OX 1 R mRNA的表达和激活被外源性食欲素A（10-（10）至10（-6）M）以剂量依赖性方式上调。结果表明，增食欲素A影响细胞增殖和保护细胞免于凋亡。此外，抑制研究表明，食欲素A诱导叉头框01（FoxO 1）和雷帕霉素的哺乳动物靶蛋白1（mTORC 1）磷酸化，而OX 1 R拮抗剂（SB 334867，10（-6）M），AKT拮抗剂（PF-04691502，10（-6）M）、FoxO 1抑制剂（AS 1842856，10（-6）M）或mTORC 1抑制剂（依维莫司，10（-5）M）可阻断食欲素A的这些作用。本研究结果表明，食欲素A可能通过OX 1 R/PI 3 K/AKT信号通路调节FoxO 1和mTORC 1对大鼠肝细胞凋亡的影响。
Orexin A and B are multifunctional neuropeptides that are involved in the regulation of food intake, energy metabolism, glucose regulation and wakefulness. They signal through two G-protein-coupled receptors (GPCR): orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). Previous studies have shown that orexins interact with PI3K/AKT signaling pathways through OX1R-coupling in other cell types, but are seldom involved in hepatocytes. In the present study, reverse transcription (RT)-PCR and western blot analysis revealed that OX1R mRNA expression and activation in rat hepatocytes in vitro were upregulated by exogenous orexin A (10-(10) to 10(-6) M) in a dose-dependent manner. The result showed that orexin A affects increasing cell proliferation and protects cells from apoptosis. Additionally, inhibition studies showed that orexin A induced forkhead box 01 (FoxO1) and mammalian target of rapamycin 1 (mTORC1) phosphorylation, while OX1R antagonist (SB334867, 10(-6) M), AKT antagonist (PF-04691502, 10(-6) M), FoxO1 inhibitor (AS1842856, 10(-6) M) or mTORC1 inhibitor (everolimus, 10(-5) M) blocked these effects of orexin A. The results of the present study showed a possible effect of orexin A on cell apoptosis in regulating FoxO1 and mTORC1 through the OX1R/PI3K/AKT signaling pathway in rat hepatocytes.