title: Arachidonic acid actions on functional integrity and attenuation of the negative effects of palmitic acid in a clonal pancreatic β-cell line.
abstract: Chronic exposure of pancreatic β-cells to saturated non-esterified fatty acids can lead to inhibition of insulin secretion and apoptosis. Several previous studies have demonstrated that saturated fatty acids such as PA (palmitic acid) are detrimental to β-cell function compared with unsaturated fatty acids. In the present study, we describe the effect of the polyunsaturated AA (arachidonic acid) on the function of the clonal pancreatic β-cell line BRIN-BD11 and demonstrate AA-dependent attenuation of PA effects. When added to β-cell incubations at 100 μM, AA can stimulate cell proliferation and chronic (24 h) basal insulin secretion. Microarray analysis and/or real-time PCR indicated significant AA-dependent up-regulation of genes involved in proliferation and fatty acid metabolism [e.g. Angptl (angiopoietin-like protein 4), Ech1 (peroxisomal Δ3,5,Δ2,4-dienoyl-CoA isomerase), Cox-1 (cyclo-oxygenase-1) and Cox-2, P<0.05]. Experiments using specific COX and LOX (lipoxygenase) inhibitors demonstrated the importance of COX-1 activity for acute (20 min) stimulation of insulin secretion, suggesting that AA metabolites may be responsible for the insulinotropic effects. Moreover, concomitant incubation of AA with PA dose-dependently attenuated the detrimental effects of the saturated fatty acid, so reducing apoptosis and decreasing parameters of oxidative stress [ROS (reactive oxygen species) and NO levels] while improving the GSH/GSSG ratio. AA decreased the protein expression of iNOS (inducible NO synthase), the p65 subunit of NF-κB (nuclear factor κB) and the p47 subunit of NADPH oxidase in PA-treated cells. These findings indicate that AA has an important regulatory and protective β-cell action, which may be beneficial to function and survival in the 'lipotoxic' environment commonly associated with Type 2 diabetes mellitus.
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute and UCD Institute of Sport and Health, UCD Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Deirdre C
authors.initials: DC
authors.lastname: Keane
authors.forename: Hilton K
authors.initials: HK
authors.lastname: Takahashi
authors.forename: Shalinee
authors.initials: S
authors.lastname: Dhayal
authors.forename: Noel G
authors.initials: NG
authors.lastname: Morgan
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.forename: Philip
authors.initials: P
authors.lastname: Newsholme
mesh_terms: D016718:Arachidonic Acid / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000096:biosynthesis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010168:Palmitates / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D016861:Cyclooxygenase Inhibitors; D007328:Insulin; D016859:Lipoxygenase Inhibitors; D009573:Nitrites; D010168:Palmitates; D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D005978:Glutathione