title: Simultaneous activation of p38 and JNK by arachidonic acid stimulates the cytosolic phospholipase A2-dependent synthesis of lipid droplets in human monocytes.
abstract: Exposure of human peripheral blood monocytes to free arachidonic acid (AA) results in the rapid induction of lipid droplet (LD) formation by these cells. This effect appears specific for AA in that it is not mimicked by other fatty acids, whether saturated or unsaturated. LDs are formed by two different routes: (i) the direct entry of AA into triacylglycerol and (ii) activation of intracellular signaling, leading to increased triacylglycerol and cholesteryl ester formation utilizing fatty acids coming from the de novo biosynthetic route. Both routes can be dissociated by the arachidonyl-CoA synthetase inhibitor triacsin C, which prevents the former but not the latter. LD formation by AA-induced signaling predominates, accounting for 60-70% of total LD formation, and can be completely inhibited by selective inhibition of the group IVA cytosolic phospholipase A(2)α (cPLA(2)α), pointing out this enzyme as a key regulator of AA-induced signaling. LD formation in AA-treated monocytes can also be blocked by the combined inhibition of the mitogen-activated protein kinase family members p38 and JNK, which correlates with inhibition of cPLA(2)α activation by phosphorylation. Collectively, these results suggest that concomitant activation of p38 and JNK by AA cooperate to activate cPLA(2)α, which is in turn required for LD formation possibly by facilitating biogenesis of this organelle, not by regulating neutral lipid synthesis.
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, 47003 Valladolid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Guijas
authors.forename: Gema
authors.initials: G
authors.lastname: Pérez-Chacón
authors.forename: Alma M
authors.initials: AM
authors.lastname: Astudillo
authors.forename: Julio M
authors.initials: JM
authors.lastname: Rubio
authors.forename: Luis
authors.initials: L
authors.lastname: Gil-de-Gómez
authors.forename: María A
authors.initials: MA
authors.lastname: Balboa
authors.forename: Jesús
authors.initials: J
authors.lastname: Balsinde
mesh_terms: D016718:Arachidonic Acid / Q000494:pharmacology*; D002478:Cells, Cultured; D002849:Chromatography, Gas; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D014280:Triglycerides; D016718:Arachidonic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054513:Group IV Phospholipases A2