Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans

The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early developmental arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is critical. Previously, we demonstrated that the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) plays a key role in C. elegans since it modulates sterol mobilization. However, the mechanism remains unknown. Here we show that mutations in the ocr-2 and osm-9 genes, coding for transient receptors potential V (TRPV) ion channels, dramatically reduce the effect of 2-AG in cholesterol mobilization. Through genetic analysis in combination with the rescue of larval arrest induced by sterol starvation, we found that the insulin/IGF-1signaling (IIS) pathway and UNC-31/CAPS, a calcium-activated regulator of neural dense-core vesicles release, are essential for 2-AG-mediated stimulation of cholesterol mobilization. These findings indicate that 2-AG-dependent cholesterol trafficking requires the release of insulin peptides and signaling through the DAF-2 insulin receptor. These results suggest that 2-AG acts as an endogenous modulator of TRPV signal transduction to control intracellular sterol trafficking through modulation of the IGF-1 signaling pathway Fil: Hernández Cravero, Bruno. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratorio de Fisiología Microbiana (IBR-CONICET); Argentina. Fil: Vranych, Cecilia V. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratorio de Fisiología Microbiana (IBR-CONICET); Argentina. Fil: De Mendoza, Diego. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratorio de Fisiología Microbiana (IBR-CONICET); Argentina. Fil: GallinoI, Sofía. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres". Laboratorio de Fisiología y Genética de la Audición (INGEBI-CONICET); Argentina. Fil: Elgoyhen, Ana Belén. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres". Laboratorio de Fisiología y Genética de la Audición (INGEBI-CONICET); Argentina. Fil: Florman, Jeremy. University of Massachusetts Medical School. Department of Neurobiology; United States. Fil: AlkemaI, Mark J. University of Massachusetts Medical School. Department of Neurobiology; United States. Fil: Diaz, Philippe. University of Montana. Department of Biomedical and Pharmaceutical Sciences; United States.