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J. Biol. Chem., Vol. 283, Issue 41, 27369-27382, October 10, 2008

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Group IVA Phospholipase A₂ Is Necessary for the Biogenesis of Lipid Droplets^*

Albert Gubern¹, Javier Casas, Miquel Barceló-Torns², David Barneda³, Xavier de la Rosa, Roser Masgrau, Fernando Picatoste, Jesús Balsinde, María A. Balboa, and Enrique Claro⁴

From the Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, E-08193 Barcelona and Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, E-47003 Valladolid, Spain

Lipid droplets (LD) are organelles present in all cell types, consisting of a hydrophobic core of triacylglycerols and cholesteryl esters, surrounded by a monolayer of phospholipids and cholesterol. This work shows that LD biogenesis induced by serum, by long-chain fatty acids, or the combination of both in CHO-K1 cells was prevented by phospholipase A₂ inhibitors with a pharmacological profile consistent with the implication of group IVA cytosolic phospholipase A₂ (cPLA₂). Knocking down cPLA₂ expression with short interfering RNA was similar to pharmacological inhibition in terms of enzyme activity and LD biogenesis. A Chinese hamster ovary cell clone stably expressing an enhanced green fluorescent protein-cPLA₂ fusion protein (EGFP-cPLA₂) displayed higher LD occurrence under basal conditions and upon LD induction. Induction of LD took place with concurrent phosphorylation of cPLA₂ at Ser⁵⁰⁵. Transfection of a S505A mutant cPLA₂ showed that phosphorylation at Ser⁵⁰⁵ is key for enzyme activity and LD formation. cPLA₂ contribution to LD biogenesis was not because of the generation of arachidonic acid, nor was it related to neutral lipid synthesis. cPLA₂ inhibition in cells induced to form LD resulted in the appearance of tubulo-vesicular profiles of the smooth endoplasmic reticulum, compatible with a role of cPLA₂ in the formation of nascent LD from the endoplasmic reticulum.

Received for publication, January 28, 2008 , and in revised form, June 10, 2008.

^* This work was supported in part by Grants SAF 2004-01698 and SAF 2007-60055 from the Spanish Ministry of Education and Science and Grant PI03/0528 from the Spanish Ministry of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S7.

¹ Recipient of a graduate fellowship from Universitat Autònoma de Barcelona.

² Recipient of graduate fellowship from Ministerio de Educación y Ciencia.

³ Recipient of graduate fellowship from Generalitat de Catalunya.

⁴ To whom correspondence should be addressed: Institut de Neurociències i Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Edifici M2, Campus de la Universitat Autònoma de Barcelona, E-08193 Bellaterra (Barcelona), Spain. Tel.: 34-935814150; Fax: 34-935811573; E-mail: enrique.claro{at}uab.es.

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