期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：11
页码：3415-3420
DOI：10.1073/pnas.1416463112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceHedgehog proteins regulate development and tissue homeostasis. They signal through activation of the transmembrane protein Smoothened. Smoothened hyperactivation underlies development of many tumors. Smoothened activity can be modulated by several synthetic small molecules, which have shown promise in the clinic. However, occurrence of resistance-inducing mutations limits their effectiveness. Little is known about endogenous small molecules that may inhibit Smoothened in vivo. Previous work suggested that lipids present in lipoproteins are required for Smoothened inhibition in vivo. Here, we use biochemical fractionation and lipidomics to identify these lipids as endocannabinoids and show that their activity as Smoothened inhibitors has been conserved from flies to mammals. Endocannabinoids may provide useful templates for the design of new therapeutic Smoothened antagonists. Hedgehog ligands control tissue development and homeostasis by alleviating repression of Smoothened, a seven-pass transmembrane protein. The Hedgehog receptor, Patched, is thought to regulate the availability of small lipophilic Smoothened repressors whose identity is unknown. Lipoproteins contain lipids required to repress Smoothened signaling in vivo. Here, using biochemical fractionation and lipid mass spectrometry, we identify these repressors as endocannabinoids. Endocannabinoids circulate in human and Drosophila lipoproteins and act directly on Smoothened at physiological concentrations to repress signaling in Drosophila and mammalian assays. Phytocannabinoids are also potent Smo inhibitors. These findings link organismal metabolism to local Hedgehog signaling and suggest previously unsuspected mechanisms for the physiological activities of cannabinoids.
