Abstract
Long-chain fatty acid possesses myriad roles in the biological function of the cells, not only as an energy substrate but also as substrates for cell membrane synthesis and as precursors for intracellular signaling molecules. However, little is known about the biological pathways that are stimulated by long-chain fatty acid. In order to identify the pathway of long-chain fatty acid, we performed 2-dimensional gel electrophoresis in the cells treated with or without oleate, and then analyzed 648 protein spots using PDQuest software and narrowed down 22 significant changing spots by statistical criterion. We also tried to determine these spots by MALDI-QIT-TOF-MS and SWISSPROT database query. We identified 11 proteins and predicted the biological network using available data sets from protein-protein interaction database. This prediction indicated that several protein kinase Cs (PKCs) underlie longchain fatty acid signaling. Indeed, oleate stimulated predicted PKC pathways. In expression array, oleate significantly up-regulated only PKC epsilon, but not other PKCs, in transcriptional levels. Collectively, our proteomics and network analysis implicates that PKC epsilon pathway plays an important role in long-chain fatty acid signaling.
Highlights
Long-chain fatty acids (LCFAs) are an important source of energy and possess myriad effects on various tissues [1], while, LCFAs play a pivotal role in the pathogenesis of insulin resistance and type 2 diabetes [2,3,4]
We for the first time demonstrated that several protein kinase Cs (PKCs) underlie LCFA signaling using combination with 2-DE, differential expression analysis, MALDI-QIT-TOF-MS and pathway analysis based on protein-protein interaction (PPI)
We demonstrated that the translocation of predicted PKCs are enhanced by LCFA
Summary
Long-chain fatty acids (LCFAs) are an important source of energy and possess myriad effects on various tissues [1], while, LCFAs play a pivotal role in the pathogenesis of insulin resistance and type 2 diabetes [2,3,4]. Patients with insulin resistance and type 2 diabetes possess symptom of lipid metabolism disorder, especially high blood LCFAs level [5]. Two transcriptional factors are thought to control LCFA signaling. Three PPARs have been identified in mammals, PPAR alpha, beta/delta and gamma [6,7] These are thought to have a critical role in energy and lipid metabolism. GPR40, one of the G protein-coupled receptors (GPCRs), was reported to bind to LCFAs [9,10,11]. We and other groups demonstrated that functioning G protein-coupled receptor for LCFAs, GPR40 induces cell-proliferation via mitogenic extracellular kinase (MEK) 1/2/extracellular signalregulated kinase (ERK) 1/2 and phosphatidylinositol 3-kinase (PI3K)/ Akt pathways in normal and malignant mammary epithelial cells [12,13]. Signaling pathways of LCFAs have still not been completely elucidated
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