title: Bisphenol A Induces Fatty Liver by an Endocannabinoid-Mediated Positive Feedback Loop.
abstract: The xenoestrogen bisphenol A (BPA) is a widespread plasticizer detectable within several ecosystems. BPA is considered a metabolic disruptor, affecting different organs; however, little is known about its mechanism of action in the liver, in which it triggers triglyceride accumulation. Adult zebrafish (Danio rerio) exposed to BPA developed hepatosteatosis, which was associated with an increase in the liver levels of the obesogenic endocannabinoids 2-arachidonoylglycerol and anandamide and a concomitant decrease in palmitoylethanolamide. These changes were associated with variations in the expression of key endocannabinoid catabolic and metabolic enzymes and an increase in the expression of the endocannabinoid receptor cnr1. Acute and chronic in vitro treatments with nano- and micromolar BPA doses showed increased anandamide levels in line with decreased activity of fatty acid amide hydrolase, the main anandamide hydrolytic enzyme, and induced triglyceride accumulation in HHL-5 cells in a CB1-dependent manner. We conclude that BPA is able to produce hepatosteatosis in zebrafish and human hepatocytes by up-regulating the endocannabinoid system.
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente (A.M., F.M., G.G., O.C.), Università Politecnica delle Marche, 60131 Ancona, Italy; Endocannabinoid Research Group (A.M., C.S., M.A., V.D.), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (NA), Italy; Dipartimento di Biomedicina Comparata e Alimentazione (G.R.), Universitá degli Studi di Padova, 35020 Legnaro (PD), Italy; Department of Bioengineering (C.S., D.R.O.), Imperial College London, London SW7 2AZ, United Kingdom; and Istituto Nazionale Biostrutture e Biosistemi (F.M., O.C.), 00136, Roma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Martella
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente (A.M., F.M., G.G., O.C.), Università Politecnica delle Marche, 60131 Ancona, Italy; Endocannabinoid Research Group (A.M., C.S., M.A., V.D.), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (NA), Italy; Dipartimento di Biomedicina Comparata e Alimentazione (G.R.), Universitá degli Studi di Padova, 35020 Legnaro (PD), Italy; Department of Bioengineering (C.S., D.R.O.), Imperial College London, London SW7 2AZ, United Kingdom; and Istituto Nazionale Biostrutture e Biosistemi (F.M., O.C.), 00136, Roma, Italy.
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Silvestri
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente (A.M., F.M., G.G., O.C.), Università Politecnica delle Marche, 60131 Ancona, Italy; Endocannabinoid Research Group (A.M., C.S., M.A., V.D.), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (NA), Italy; Dipartimento di Biomedicina Comparata e Alimentazione (G.R.), Universitá degli Studi di Padova, 35020 Legnaro (PD), Italy; Department of Bioengineering (C.S., D.R.O.), Imperial College London, London SW7 2AZ, United Kingdom; and Istituto Nazionale Biostrutture e Biosistemi (F.M., O.C.), 00136, Roma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Maradonna
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente (A.M., F.M., G.G., O.C.), Università Politecnica delle Marche, 60131 Ancona, Italy; Endocannabinoid Research Group (A.M., C.S., M.A., V.D.), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (NA), Italy; Dipartimento di Biomedicina Comparata e Alimentazione (G.R.), Universitá degli Studi di Padova, 35020 Legnaro (PD), Italy; Department of Bioengineering (C.S., D.R.O.), Imperial College London, London SW7 2AZ, United Kingdom; and Istituto Nazionale Biostrutture e Biosistemi (F.M., O.C.), 00136, Roma, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Gioacchini
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente (A.M., F.M., G.G., O.C.), Università Politecnica delle Marche, 60131 Ancona, Italy; Endocannabinoid Research Group (A.M., C.S., M.A., V.D.), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (NA), Italy; Dipartimento di Biomedicina Comparata e Alimentazione (G.R.), Universitá degli Studi di Padova, 35020 Legnaro (PD), Italy; Department of Bioengineering (C.S., D.R.O.), Imperial College London, London SW7 2AZ, United Kingdom; and Istituto Nazionale Biostrutture e Biosistemi (F.M., O.C.), 00136, Roma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Allarà
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente (A.M., F.M., G.G., O.C.), Università Politecnica delle Marche, 60131 Ancona, Italy; Endocannabinoid Research Group (A.M., C.S., M.A., V.D.), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (NA), Italy; Dipartimento di Biomedicina Comparata e Alimentazione (G.R.), Universitá degli Studi di Padova, 35020 Legnaro (PD), Italy; Department of Bioengineering (C.S., D.R.O.), Imperial College London, London SW7 2AZ, United Kingdom; and Istituto Nazionale Biostrutture e Biosistemi (F.M., O.C.), 00136, Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Radaelli
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente (A.M., F.M., G.G., O.C.), Università Politecnica delle Marche, 60131 Ancona, Italy; Endocannabinoid Research Group (A.M., C.S., M.A., V.D.), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (NA), Italy; Dipartimento di Biomedicina Comparata e Alimentazione (G.R.), Universitá degli Studi di Padova, 35020 Legnaro (PD), Italy; Department of Bioengineering (C.S., D.R.O.), Imperial College London, London SW7 2AZ, United Kingdom; and Istituto Nazionale Biostrutture e Biosistemi (F.M., O.C.), 00136, Roma, Italy.
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Overby
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente (A.M., F.M., G.G., O.C.), Università Politecnica delle Marche, 60131 Ancona, Italy; Endocannabinoid Research Group (A.M., C.S., M.A., V.D.), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (NA), Italy; Dipartimento di Biomedicina Comparata e Alimentazione (G.R.), Universitá degli Studi di Padova, 35020 Legnaro (PD), Italy; Department of Bioengineering (C.S., D.R.O.), Imperial College London, London SW7 2AZ, United Kingdom; and Istituto Nazionale Biostrutture e Biosistemi (F.M., O.C.), 00136, Roma, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente (A.M., F.M., G.G., O.C.), Università Politecnica delle Marche, 60131 Ancona, Italy; Endocannabinoid Research Group (A.M., C.S., M.A., V.D.), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (NA), Italy; Dipartimento di Biomedicina Comparata e Alimentazione (G.R.), Universitá degli Studi di Padova, 35020 Legnaro (PD), Italy; Department of Bioengineering (C.S., D.R.O.), Imperial College London, London SW7 2AZ, United Kingdom; and Istituto Nazionale Biostrutture e Biosistemi (F.M., O.C.), 00136, Roma, Italy.
authors.forename: Oliana
authors.initials: O
authors.lastname: Carnevali
mesh_terms: D000577:Amides; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001559:Benzhydryl Compounds; D002460:Cell Line; D063388:Endocannabinoids / Q000378:metabolism*; D052244:Endocrine Disruptors; D004983:Ethanolamines / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects*; D005989:Glycerides / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010169:Palmitic Acids / Q000378:metabolism; D010636:Phenols; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D000577:Amides; D001095:Arachidonic Acids; D001559:Benzhydryl Compounds; D063388:Endocannabinoids; D052244:Endocrine Disruptors; D004983:Ethanolamines; D005989:Glycerides; D010169:Palmitic Acids; D010636:Phenols; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D014280:Triglycerides; D029961:Zebrafish Proteins; C000608945:Cnr1 protein, zebrafish; C005958:palmidrol; C094503:glyceryl 2-arachidonate; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C078814:anandamide