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

Abstract

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.

Retracted: Palmitate‐induced C/EBP homologous protein activation leads to NF‐κB‐mediated increase in BACE1 activity and amyloid beta genesis

“…A recent study demonstrated that treatment with exogenous palmitate increases Aβ levels in SK‐N‐MC neuroblastoma cells by activating the G‐protein‐coupled receptor 40/Akt/mammalian target of rapamycin/HIF1α and the G‐protein‐coupled receptor 40/Akt/NF‐κB signaling pathways (Kim et al . ). However, no in vivo study to date has characterized the effects of a palmitate‐enriched diet per se on the transcriptional regulation of BACE1 expression and Aβ genesis and characterized the mechanisms.…”

“…Therefore, the inference drawn from the aforementioned studies, in the context of enhanced Ab burden in the brain as a consequence of diet, cannot exclusively be ascribed to the saturated fat content, but also to the presence of other macromolecular variables that make-up the constitution of the respective diet. A recent study demonstrated that treatment with exogenous palmitate increases Ab levels in SK-N-MC neuroblastoma cells by activating the G-proteincoupled receptor 40/Akt/mammalian target of rapamycin/ HIF1a and the G-protein-coupled receptor 40/Akt/NF-jB signaling pathways (Kim et al 2017). However, no in vivo study to date has characterized the effects of a palmitateenriched diet per se on the transcriptional regulation of BACE1 expression and Ab genesis and characterized the mechanisms.…”

“…The transcriptional regulation of BACE1 by NF-jB transcriptional activity has been very well characterized (Bourne et al 2007;Buggia-Prevot et al 2008;Marwarha 2011a;Chen et al 2012;Ghribi 2012b, 2017b;Marwarha et al 2013Marwarha et al , 2014b. There is also extensive evidence that NF-jB signaling and transcriptional activity regulates Ab production either through the regulation of BACE1 activity or independent of BACE1 activity (Tomita et al 2000;Paris et al 2007;Pandey et al 2009;Chami et al 2012;Kim et al 2017). A few studies have shown that NF-jB transcriptional activity represses BACE1 promoter activity and BACE1 expression (Bourne et al 2007).…”

Upregulation of free fatty acid receptors in periodontal tissues of patients with metabolic syndrome and periodontitis

“…Our previous studies have shown that SFA augments LPS‐induced proinflammatory gene expression in macrophages and vascular endothelial cells by amplifying TLR4‐mediated inflammatory signaling such as mitogen‐activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) cascades . These findings strongly suggest that free fatty acid receptors such as GPR40 and CD36 are involved in SFA‐enhanced proinflammatory gene expression since SFA engages GPR40 and CD36, which mediate MAPK and NFκB signaling activation . The role of GPR40 and CD36 in the upregulation of proinflammatory cytokine expression was further supported by our findings that inhibition of GPR40 or CD36 attenuated proinflammatory cytokine expression in gingival fibroblasts stimulated by palmitate and LPS (Figure ).…”

“…Previous studies have shown that SFA has a higher affinity than unsaturated fatty acid to bind GPR40 . It has been shown that GPR40 mediate palmitate‐enhanced amyloid‐β production by activating inflammatory signaling pathways in neuronal cells . It has been also shown that GPR40 mediated thiazolidinediones‐activated proinflammatory signaling pathways .…”