Cannabinoids Activate the Insulin Pathway to Modulate Mobilization of Cholesterol in C. elegans

Abstract

The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early development 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 modulating sterol mobilization, but the mechanism is unknown. Here we show that mutations in the ocr-2 and osm-9 genes coding for transient receptors potential V (TRPV) ion channels, dramatically reduces the effect of 2-AG in cholesterol mobilization. Through genetic analysis combined with the rescuing 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 traffic through modulation of the IGF-1 signaling pathway. Author summaryAlthough cannabis extracts have been used in folklore medicine for centuries, the past few years have seen an increased interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, for treatment of many diseases of the nervous system. However, the human body naturally produces endocannabinoids that are similar to the cannabinoids present in Cannabis sativa. Our goal is to understand how endocannabinoids maintain cholesterol homeostasis in animals, underscoring the importance of cholesterol balance for healthy life. Both cholesterol excess and cholesterol deficiency can have detrimental effects on health, and a myriad of regulatory processes have thus evolved to control the metabolic pathways of sterol metabolism. The nematode C. elegans is auxotroph for sterols, that is; contrary to mammals they cannot synthesize sterols, therefore, dietary supply is essential for survival. The aim of our study was to elucidate the mechanism by which endocannabinoids abolish larval arrest of C. elegans induced by cholesterol depletion. We discovered that endocannabinoids stimulate the insulin pathway, which affects development, reproduction and life span, to modulate mobilization of cholesterol in C. elegans. Our studies have important implications for a better understanding of human pathological conditions associated with impaired cholesterol homeostasis.