title: Oleic and linoleic fatty acids downregulate Slc2a4/GLUT4 expression via NFKB and SREBP1 in skeletal muscle cells.
abstract: Oleic (OA) and linoleic (LA) fatty acids may be important regulators of Slc2a4 gene (GLUT4 protein) in skeletal muscle, thus participating in insulin resistance. We investigated the effect of OA and LA on the Slc2a4/GLUT4 expression in L6 muscle cells; as well as potential transcriptional regulators. OA and LA (50-400 µM) decreased the Slc2a4/GLUT4 expression in a dose-dependent way (maximum of ~50%, P < 0.001). OA and LA did not alter the Slc2a4-binding activity of oxysterols-receptor-LXR-alpha and peroxisome-proliferator-activated-receptor-gamma; but decreased the Slc2a4-binding activity of the sterol-regulatory-element-binding-protein-1 (SREBP1) enhancer (50%, P < 0.001), and increased (~30%, P < 0.001) the nuclear proteins binding into the Slc2a4-nuclear-factor-NF-kappa-B-binding site (repressor), and the phosphorylation of the inhibitors of nuclear-factor-kappa-B-kinase alpha/beta (150-300%, P < 0.001). In sum, OA and LA are potent inhibitors of the Slc2a4/GLUT4 expression in muscle cells; an effect involving reduced SREBP1 and increased NFKB transcriptional activity. These regulations may participate in the fatty acid-related pathophysiology of insulin resistance.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Ana Cláudia
authors.initials: AC
authors.lastname: Poletto
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Daniela Tomie
authors.initials: DT
authors.lastname: Furuya
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: David-Silva
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Ebersbach-Silva
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Camilo Lellis
authors.initials: CL
authors.lastname: Santos
authors.affiliation: Department of Internal Medicine, Endocrinology, and Laboratory for Cellular and Molecular Endocrinology (LIM-25), School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Maria Lúcia
authors.initials: ML
authors.lastname: Corrêa-Giannella
authors.affiliation: Lipids Laboratory (LIM10), School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Marisa
authors.initials: M
authors.lastname: Passarelli
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: ubiratan@icb.usp.br.
authors.forename: Ubiratan Fabres
authors.initials: UF
authors.lastname: Machado
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D051275:Glucose Transporter Type 4 / Q000235:genetics* / Q000378:metabolism; D019787:Linoleic Acid / Q000494:pharmacology*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics*; D019301:Oleic Acid / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*
chemical_list: D051275:Glucose Transporter Type 4; D016328:NF-kappa B; C495693:Slc2a4 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D019301:Oleic Acid; D019787:Linoleic Acid
keywords: Electrophoretic mobility shift assay; Insulin resistance; LXR-α; PPAR-γ; Transcription factors; Unsaturated fatty acid