title: Cannabinoid receptor signaling regulates liver development and metabolism.
abstract: Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite. By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but not endodermal specification: loss of cannabinoid receptor 1 (cnr1) and cnr2 activity leads to smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation. Functional assays reveal abnormal biliary anatomy and lipid handling. Adult cnr2 mutants are susceptible to hepatic steatosis. Metabolomic analysis reveals reduced methionine content in Cnr mutants. Methionine supplementation rescues developmental and metabolic defects in Cnr mutant livers, suggesting a causal relationship between EC signaling, methionine deficiency and impaired liver development. The effect of Cnr on methionine metabolism is regulated by sterol regulatory element-binding transcription factors (Srebfs), as their overexpression rescues Cnr mutant liver phenotypes in a methionine-dependent manner. Our work describes a novel developmental role for EC signaling, whereby Cnr-mediated regulation of Srebfs and methionine metabolism impacts liver development and function.
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Leah Y
authors.initials: LY
authors.lastname: Liu
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Alexa
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cortes
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schatzman-Bone
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kim
authors.affiliation: Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20982, USA.
authors.forename: Bani
authors.initials: B
authors.lastname: Mukhopadhyay
authors.affiliation: Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20982, USA.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20982, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Trista E
authors.initials: TE
authors.lastname: North
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Harvard Stem Cell Institute, Cambridge, MA 02138, USA Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Dana-Farber Cancer Institute, Boston, MA 02215, USA Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA wgoessling@partners.org.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D055432:Metabolomics; D008715:Methionine / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D002186:Cannabinoids; C000608945:Cnr1 protein, zebrafish; C518179:Cnr2 protein, zebrafish; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D029961:Zebrafish Proteins; D008715:Methionine; D003545:Cysteine
keywords: Cannabinoid receptor; Liver development; Methionine; Mouse; Zebrafish