title: New insights into the organ-specific adverse effects of fumonisin B1: comparison between lung and liver.
abstract: Fumonisin B1 (FB1) is a well-known inhibitor of de novo sphingolipid biosynthesis, due to its ability to inhibit ceramide synthases (CerS) activity. In mammals, this toxin triggers broad clinical symptoms with multi-organ dysfunction such as hepatotoxicity or pulmonary edema. The molecular mechanism of CerS inhibition by FB1 remains unknown. Due to the existence of six mammalian CerS isoforms with a tissue-specific expression pattern, we postulated that the organ-specific adverse effects of FB1 might be due to different CerS isoforms. The sphingolipid contents of lung and liver were compared in normal and FB1-exposed piglets (gavage with 1.5 mg FB1/kg body weight daily for 9 days). The effect of the toxin on each CerS was deduced from the analysis of its effects on individual ceramide (Cer) and sphingomyelin (SM) species. As expected, the total Cer content decreased by half in the lungs of FB1-exposed piglets, while in contrast, total Cer increased 3.5-fold in the livers of FB1-exposed animals. Our data also indicated that FB1 is more prone to bind to CerS4 and CerS2 to deplete lung and to enrich liver in d18:1/C20:0 and d18:1/C22:0 ceramides. It also interact with CerS1 to enrich liver in d18:1/C18:0 ceramides. Cer levels were counterbalanced by those of SM. In conclusion, these results demonstrate that the specificity of the effects of FB1 on tissues and organs is due to the effects of the toxin on CerS4, CerS2, and CerS1.
authors.affiliation: INRA, UMR1331 Toxalim, Research Centre in Food Toxicology, 31027, Toulouse, France, Nicolas.Loiseau@toulouse.inra.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Loiseau
authors.forename: Arnaud
authors.initials: A
authors.lastname: Polizzi
authors.forename: Aude
authors.initials: A
authors.lastname: Dupuy
authors.forename: Nicole
authors.initials: N
authors.lastname: Therville
authors.forename: Mirindra
authors.initials: M
authors.lastname: Rakotonirainy
authors.forename: Jennifer
authors.initials: J
authors.lastname: Loy
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Viadere
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cossalter
authors.forename: Jean-Denis
authors.initials: JD
authors.lastname: Bailly
authors.forename: Olivier
authors.initials: O
authors.lastname: Puel
authors.forename: Martine
authors.initials: M
authors.lastname: Kolf-Clauw
authors.forename: Justine
authors.initials: J
authors.lastname: Bertrand-Michel
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
authors.forename: Isabelle P
authors.initials: IP
authors.lastname: Oswald
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000633:toxicity; D037341:Fumonisins / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013107:Sphingolipids / Q000096:biosynthesis; D051049:Sphingosine N-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013552:Swine; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D037341:Fumonisins; D008565:Membrane Proteins; D013107:Sphingolipids; D025521:Tumor Suppressor Proteins; C056933:fumonisin B1; C493790:CERS1 protein, human; C438311:CERS2 protein, human; C000599706:CERS4 protein, human; D051049:Sphingosine N-Acyltransferase