Arachidonic acid derived endocannabinoids as mediators of Cholesterol trafficking in Caenorhabditis Elegans

GASTÓN PREZ; CELINA GALLES; SIDER PENKOV; SILVIA ALTABE; EXEQUIEL PORTA; GUILLERMO LABADIE; TEKIMURA KURZCHALIA; DE MENDOZA D

CAPITAL FEDERAL

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

SOCIEDADES DE BIOCIENCIAS

(1359) ARACHIDONIC ACID DERIVED ENDOCANNABINOIDS AS MEDIATORS OF CHOLESTEROL TRAFFICKING IN CAENORHABDITIS ELEGANS Gastón Prez (1), Celina Galles (1), Sider Penkov (2), Silvia Altabe (1), Exequiel Porta (3), Guillermo Labadie (3), Teymuras Kurzchalia (2), Diego De Mendoza (1) (1) Institute of Molecular and Cell Biology of Rosario, Rosario, Argentina. (2) Max Planck Institute of Molecular Cell Biology, Dresden, Germany. (3) Institute of Chemistry of Rosario, Rosario, Argentina. Proper control of cholesterol transport is crucial for physiological homeostasis in most eukaryotic cells, although the underlying mechanisms of this process remain unclear. We describe a novel role for endocannabinoid signaling molecules in cholesterol trafficking mechanisms. Loss of polyunsaturated fatty acids (PUFAs) greatly enhances the dauer constitutive phenotype of DAF-7/TGF-β Caenorhabditis elegans mutants, which are already intrinsically deficient in intracellular sterol trafficking. Further biochemical and functional analysis established that this exacerbated phenotype is provoked by suppression of the synthesis of the PUFA-derived endocannabinoids 2-arachidonoyl glycerol and anandamide. These endocannabinoids not only rescue the arrest brought on by PUFAs deficiency, but also abolish the larval arrest caused either by impaired cholesterol trafficking (derived from either defective synthesis of glucosylceramides or from deficiencies in Niemann-Pick C1 (NPC1)-like proteins) or by cholesterol starvation of wild type worms for two generation. Thus, endocannabinoids play a pivotal role in C. elegans development acting as regulators of nematode cholesterol transport processes. These findings reveal a previously unsuspected mechanism for the physiological activities of endocannabinoids, uncovering new opportunities for therapeutic intervention in cholesterol disorders.