title: Defining the role of DAG, mitochondrial function, and lipid deposition in palmitate-induced proinflammatory signaling and its counter-modulation by palmitoleate.
abstract: Chronic exposure of skeletal muscle to saturated fatty acids, such as palmitate (C16:0), enhances proinflammatory IKK-NFκB signaling by a mechanism involving the MAP kinase (Raf-MEK-ERK) pathway. Raf activation can be induced by its dissociation from the Raf-kinase inhibitor protein (RKIP) by diacylglycerol (DAG)-sensitive protein kinase C (PKC). However, whether these molecules mediate the proinflammatory action of palmitate, an important precursor for DAG synthesis, is currently unknown. Here, involvement of DAG-sensitive PKCs, RKIP, and the structurally related monounsaturated fatty acid palmitoleate (C16:1) on proinflammatory signaling are investigated. Palmitate, but not palmitoleate, induced phosphorylation/activation of the MEK-ERK-IKK axis and proinflammatory cytokine (IL-6, CINC-1) expression. Palmitate increased intramyocellular DAG and invoked PKC-dependent RKIP(Ser153) phosphorylation, resulting in RKIP-Raf1 dissociation and MEK-ERK signaling. These responses were mimicked by PMA, a DAG mimetic and PKC activator. However, while pharmacological inhibition of PKC suppressed PMA-induced activation of MEK-ERK-IKK signaling, activation by palmitate was upheld, suggesting that DAG-sensitive PKC and RKIP were dispensable for palmitate's proinflammatory action. Strikingly, the proinflammatory effect of palmitate was potently repressed by palmitoleate. This repression was not due to reduced palmitate uptake but linked to increased neutral lipid storage and enhanced cellular oxidative capacity brought about by palmitoleate's ability to restrain palmitate-induced mitochondrial dysfunction.
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors.forename: Katherine
authors.initials: K
authors.lastname: Macrae
authors.forename: Clare
authors.initials: C
authors.lastname: Stretton
authors.forename: Christopher
authors.initials: C
authors.lastname: Lipina
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Blachnio-Zabielska
authors.forename: Marcin
authors.initials: M
authors.lastname: Baranowski
authors.forename: Jan
authors.initials: J
authors.lastname: Gorski
authors.forename: Anna
authors.initials: A
authors.lastname: Marley
authors.forename: Harinder S
authors.initials: HS
authors.lastname: Hundal
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004075:Diglycerides / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology*; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004075:Diglycerides; D005229:Fatty Acids, Monounsaturated; D010168:Palmitates; D049488:Phosphatidylethanolamine Binding Protein; C008757:palmitoleic acid; D019908:Proto-Oncogene Proteins c-raf; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D010100:Oxygen
keywords: cytokine; diacylglycerol; interleukin-6; monounsaturated fatty acid; nuclear factor kappa-B; saturated fatty acid