Palmitic Acid-BSA enhances Amyloid-β production through GPR40-mediated dual pathways in neuronal cells: Involvement of the Akt/mTOR/HIF-1α and Akt/NF-κB pathways.
Palmitic Acid-BSA enhances Amyloid-β production through GPR40-mediated dual pathways in neuronal cells: Involvement of the Akt/mTOR/HIF-1α and Akt/NF-κB pathways.
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DOI：
10.1038/s41598-017-04175-w
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发表时间：
2017-06-28
影响因子：
4.6
通讯作者：
Han HJ
中科院分区：
文献类型：
--
作者：
Kim JY;Lee HJ;Lee SJ;Jung YH;Yoo DY;Hwang IK;Seong JK;Ryu JM;Han HJ
脂肪酸(FA)对阿尔茨海默病(AD)的病理生理作用已广为人知，这可能是由基因组效应介导的；然而，它们的非基因组作用仍然难以捉摸。本研究的目的是探讨细胞外棕榈酸(PA)调节β-淀粉样蛋白(A-β)产生的非基因组机制，该机制可能在肥胖与AD的发生之间提供联系。在肥胖小鼠模型中，高脂饮食(HFD)显著增加了小鼠大脑中APP和BACE1的表达水平以及AD的病理变化。我们进一步发现，PA与牛血清白蛋白(PA-BSA)偶联可通过G蛋白偶联受体40(GPR40)增加SK-N-MC细胞APP和BACE1的表达及Aβ的产生。PA-BSA与GPR40的偶联可显著诱导Akt的激活，这是mTOR/p70S6K1介导的HIF-1α表达所必需的，也是促进APP和BACE1基因转录活性的核因子-κB磷酸化所必需的。此外，抑制APP和BACE1的表达显著减少PA-BSA处理的SK-N-MC细胞Aβ的产生。综上所述，这些结果表明，胞外PA与GPR40偶联可诱导SK-N-MC细胞APP和BACE1的表达，从而通过Akt-mTor-HIF-1β和Akt-NF-αB途径促进Aκ的产生。
The pathophysiological actions of fatty acids (FAs) on Alzheimer’s disease (AD), which are possibly mediated by genomic effects, are widely known; however, their non-genomic actions remain elusive. The aim of this study was to investigate the non-genomic mechanism of extra-cellular palmitic acid (PA) regulating beta-amyloid peptide (Aβ) production, which may provide a link between obesity and the occurrence of AD. In an obese mouse model, a high-fat diet (HFD) significantly increased the expression levels of APP and BACE1 as well as the AD pathology in the mouse brain. We further found that PA conjugated with bovine serum albumin (PA-BSA) increased the expression of APP and BACE1 and the production of Aβ through the G protein-coupled receptor 40 (GPR40) in SK-N-MC cells. PA-BSA coupling with GPR40 significantly induced Akt activation which is required for mTOR/p70S6K1-mediated HIF-1α expression and NF-κB phosphorylation facilitating the transcriptional activity of the APP and BACE1 genes. In addition, silencing of APP and BACE1 expression significantly decreased the production of Aβ in SK-N-MC cells treated with PA-BSA. In conclusion, these results show that extra-cellular PA coupled with GPR40 induces the expression of APP and BACE1 to facilitate Aβ production via the Akt-mTOR-HIF-1α and Akt-NF-κB pathways in SK-N-MC cells.