Endocannabinoid 2-Arachodonoyl Glycerol (2-AG) Requires The Insulin And SREBP Pathways To Modulate Cholesterol Metabolism In Caenorhabditis elegans

BRUNO HERNÁNDEZ CRAVERO; DIEGO DE MENDOZA; GASTÓN PREZ; CECILIA VRANYCH

Rosario

Congreso; 2nd Latin American Worm Meeting; 2020

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. We have recently demonstrated (Galles et a., 2018, Sci. Reports) that endocannabinoid 2-AG plays an important role in C. elegans through its modulation of sterol mobilization. However, the mechanism by which 2-AG controls cholesterol trafficking remains poorly understood. Here we show that neither the C. elegans cannabinoid receptors NPR-19 involved in nociception and feeding or NPR-32 required for regenerative axon navigation, are involved in 2-AG mediated cholesterol trafficking. Moreover, the double mutant npr-19; npr-32 remainedsensitive to the 2-AG rescue, confirming that cholesterol trafficking is not modulated by these GPCRs coupled receptors. By contrast, we found that the insulin-IGF1 signaling pathway as well as the orthologous of the sterol regulatory element-binding protein SREBP, SBP1, are essential in the 2-AG suppression of dauer formation induced by cholesterol depletion. These results suggest a novel signaling pathway mediated by endocannabinoids that modulates sterol metabolism in C. elegans.