Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans

Autores
Hernández Cravero, Bruno; Gallino, Sofia Ludmila; Florman, Jeremy; Vranych, Cecilia Verónica; Diaz, Philippe; Elgoyhen, Ana Belen; Alkema, Mark J.; de Mendoza, Diego
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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-medi-ated 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.
Fil: Hernández Cravero, Bruno. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Gallino, Sofia Ludmila. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Florman, Jeremy. University Of Massachussets. Medical School. School Of Medicine. Departament Of Neurology; Estados Unidos
Fil: Vranych, Cecilia Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Diaz, Philippe. University of Montana; Estados Unidos
Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Alkema, Mark J.. University Of Massachussets. Medical School. School Of Medicine. Departament Of Neurology; Estados Unidos
Fil: de Mendoza, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Materia
NEMATODE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/201418
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/201418
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegansHernández Cravero, BrunoGallino, Sofia LudmilaFlorman, JeremyVranych, Cecilia VerónicaDiaz, PhilippeElgoyhen, Ana BelenAlkema, Mark J.de Mendoza, DiegoNEMATODEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The 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-medi-ated 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.Fil: Hernández Cravero, Bruno. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Gallino, Sofia Ludmila. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Florman, Jeremy. University Of Massachussets. Medical School. School Of Medicine. Departament Of Neurology; Estados UnidosFil: Vranych, Cecilia Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Diaz, Philippe. University of Montana; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Alkema, Mark J.. University Of Massachussets. Medical School. School Of Medicine. Departament Of Neurology; Estados UnidosFil: de Mendoza, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaPublic Library of Science2022-11-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/201418Hernández Cravero, Bruno; Gallino, Sofia Ludmila; Florman, Jeremy; Vranych, Cecilia Verónica; Diaz, Philippe; et al.; Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans; Public Library of Science; Plos Genetics; 18; 11; 8-11-2022; 1-221553-73901553-7404CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pgen.1010346info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010346info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:02:25Zoai:ri.conicet.gov.ar:11336/201418instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:02:25.892CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans
title Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans
spellingShingle Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans
Hernández Cravero, Bruno
NEMATODE
title_short Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans
title_full Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans
title_fullStr Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans
title_full_unstemmed Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans
title_sort Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans
dc.creator.none.fl_str_mv Hernández Cravero, Bruno
Gallino, Sofia Ludmila
Florman, Jeremy
Vranych, Cecilia Verónica
Diaz, Philippe
Elgoyhen, Ana Belen
Alkema, Mark J.
de Mendoza, Diego
author Hernández Cravero, Bruno
author_facet Hernández Cravero, Bruno
Gallino, Sofia Ludmila
Florman, Jeremy
Vranych, Cecilia Verónica
Diaz, Philippe
Elgoyhen, Ana Belen
Alkema, Mark J.
de Mendoza, Diego
author_role author
author2 Gallino, Sofia Ludmila
Florman, Jeremy
Vranych, Cecilia Verónica
Diaz, Philippe
Elgoyhen, Ana Belen
Alkema, Mark J.
de Mendoza, Diego
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv NEMATODE
topic NEMATODE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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-medi-ated 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.
Fil: Hernández Cravero, Bruno. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Gallino, Sofia Ludmila. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Florman, Jeremy. University Of Massachussets. Medical School. School Of Medicine. Departament Of Neurology; Estados Unidos
Fil: Vranych, Cecilia Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Diaz, Philippe. University of Montana; Estados Unidos
Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Alkema, Mark J.. University Of Massachussets. Medical School. School Of Medicine. Departament Of Neurology; Estados Unidos
Fil: de Mendoza, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
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-medi-ated 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.
publishDate 2022
dc.date.none.fl_str_mv 2022-11-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/201418
Hernández Cravero, Bruno; Gallino, Sofia Ludmila; Florman, Jeremy; Vranych, Cecilia Verónica; Diaz, Philippe; et al.; Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans; Public Library of Science; Plos Genetics; 18; 11; 8-11-2022; 1-22
1553-7390
1553-7404
CONICET Digital
CONICET
url http://hdl.handle.net/11336/201418
identifier_str_mv Hernández Cravero, Bruno; Gallino, Sofia Ludmila; Florman, Jeremy; Vranych, Cecilia Verónica; Diaz, Philippe; et al.; Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans; Public Library of Science; Plos Genetics; 18; 11; 8-11-2022; 1-22
1553-7390
1553-7404
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pgen.1010346
info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010346
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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