Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans
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Date
2022-11
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
Abstract
Description
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
Keywords
Animals, Caenorhabditis elegans, Cannabinoids, Cholesterol, Insulin, Sterols