Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea.
BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul, 08826, Republic of Korea.
Sci Rep. 2017 Jun 28;7(1):4335. doi: 10.1038/s41598-017-04175-w.
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.
脂肪酸（FAs）在阿尔茨海默病（AD）中的病理生理作用，可能通过基因组效应介导，这是广为人知的；然而，其非基因组作用仍难以捉摸。本研究旨在探讨细胞外棕榈酸（PA）调节β-淀粉样肽（Aβ）产生的非基因组机制，这可能为肥胖症与 AD 发生之间提供联系。在肥胖小鼠模型中，高脂肪饮食（HFD）显著增加了 APP 和 BACE1 的表达水平以及小鼠大脑中的 AD 病理学。我们进一步发现，与牛血清白蛋白（PA-BSA）结合的 PA 通过 G 蛋白偶联受体 40（GPR40）增加了 SK-N-MC 细胞中 APP 和 BACE1 的表达以及 Aβ的产生。PA-BSA 与 GPR40 结合可显著诱导 Akt 激活，这是 mTOR/p70S6K1 介导的 HIF-1α表达和 NF-κB 磷酸化所必需的，从而促进 APP 和 BACE1 基因的转录活性。此外，沉默 APP 和 BACE1 的表达可显著降低 SK-N-MC 细胞中 PA-BSA 处理后 Aβ的产生。总之，这些结果表明，细胞外 PA 与 GPR40 结合可诱导 APP 和 BACE1 的表达，通过 Akt-mTOR-HIF-1α 和 Akt-NF-κB 通路促进 SK-N-MC 细胞中 Aβ的产生。
