2-Arachydonoyl Glycerol (2-AG) Drives TRPV-Dependent Sensory Signals That Increase The Intracellular Cholesterol Trafficking In Caenorhabditis elegans

C. VRANYCH; B. HERNANDEZ CRAVERO; D. DE MENDOZA; S. GALLINO

Madison

Conferencia; 2022 C. elegans ?Topics? Meeting ?Metabolism, Aging, Pathogenesis, and Stress? (MAPS 2022); 2022

University of Wisconsin

Cholesterol is an essential constituent of eukaryotes membranes and its derivate metabolites also serve as signaling molecule that are crucial for growth, development, and differentiation. Dysregulation of cholesterol metabolism is strongly associated with the development of cardiovascular disorders and neurodegeneration. Caenorhabditis elegans is especially suited to genetically studying organismal orchestration of cholesterol metabolism. This worm requires exogenous cholesterol to survive and perturbations in cholesterol trafficking result in an early development larval arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is critical. We have recently demonstrated that the endocannabinoid 2-arachidonoylglycerol (2-AG) plays a key role in C. elegans modulating sterol mobilization (Galles et al, Sci Rep. 2018; 6398). However, the mechanism by which 2-AG controls cholesterol trafficking in C. elegans is not known. Here we show that 2-AG controls cholesterol homeostasis trough pathways that are independent of C. elegans neuropeptide receptors mediating endocannabinoid-dependent regulation of regenerative axon navigation and aversive behavior. We found that the calcium-activated regulator of neural dense-core vesicle exocytosis (DCVs) UNC-31 is essential for 2-AG-mediated stimulation of cholesterol mobilization. This result, combined with mutant analysis, suggested that 2-AG-dependent cholesterol traffic requires signaling of insulin peptides through the DAF-2 insulin receptor. In addition, mutations in the ocr-2 and osm-9 genes coding for transient receptors potential type V (TRPV) ion channels, dramatically reduces the effect of 2-AG in cholesterol mobilization. These findings indicate that 2-AG act as endogenous modulators of TRPV signal transduction to control intracellular sterol traffic through modulation of DCVs secretion.