title: Fatty acid synthase cooperates with glyoxalase 1 to protect against sugar toxicity.
abstract: Fatty acid (FA) metabolism is deregulated in several human diseases including metabolic syndrome, type 2 diabetes and cancers. Therefore, FA-metabolic enzymes are potential targets for drug therapy, although the consequence of these treatments must be precisely evaluated at the organismal and cellular levels. In healthy organism, synthesis of triacylglycerols (TAGs)-composed of three FA units esterified to a glycerol backbone-is increased in response to dietary sugar. Saturation in the storage and synthesis capacity of TAGs is associated with type 2 diabetes progression. Sugar toxicity likely depends on advanced-glycation-end-products (AGEs) that form through covalent bounding between amine groups and carbonyl groups of sugar or their derivatives α-oxoaldehydes. Methylglyoxal (MG) is a highly reactive α-oxoaldehyde that is derived from glycolysis through a non-enzymatic reaction. Glyoxalase 1 (Glo1) works to neutralize MG, reducing its deleterious effects. Here, we have used the power of Drosophila genetics to generate Fatty acid synthase (FASN) mutants, allowing us to investigate the consequence of this deficiency upon sugar-supplemented diets. We found that FASN mutants are lethal but can be rescued by an appropriate lipid diet. Rescued animals do not exhibit insulin resistance, are dramatically sensitive to dietary sugar and accumulate AGEs. We show that FASN and Glo1 cooperate at systemic and cell-autonomous levels to protect against sugar toxicity. We observed that the size of FASN mutant cells decreases as dietary sucrose increases. Genetic interactions at the cell-autonomous level, where glycolytic enzymes or Glo1 were manipulated in FASN mutant cells, revealed that this sugar-dependent size reduction is a direct consequence of MG-derived-AGE accumulation. In summary, our findings indicate that FASN is dispensable for cell growth if extracellular lipids are available. In contrast, FA-synthesis appears to be required to limit a cell-autonomous accumulation of MG-derived-AGEs, supporting the notion that MG is the most deleterious α-oxoaldehyde at the intracellular level.
authors.affiliation: Université Paris-Sud 11, Orsay, France; CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Garrido
authors.affiliation: Université Paris-Sud 11, Orsay, France; CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rubin
authors.affiliation: Université Paris-Sud 11, Orsay, France; CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Poidevin
authors.affiliation: Université Paris-Sud 11, Orsay, France; CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Maroni
authors.affiliation: Université Paris-Sud 11, Orsay, France; CNRS, Laboratorie Evolution Genome et Speciation, UPR 9034, Gif-sur-Yvette, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Le Rouzic
authors.affiliation: Université Paris-Sud 11, Orsay, France; CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Parvy
authors.affiliation: Université Paris-Sud 11, Orsay, France; CNRS, Centre de Génétique Moléculaire, UPR 3404, Gif-sur-Yvette, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Montagne
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019422:Dietary Sucrose / Q000008:administration & dosage / Q000633:toxicity; D004330:Drosophila; D054890:Fatty Acid Synthase, Type I / Q000235:genetics* / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D007791:Lactoylglutathione Lyase / Q000235:genetics* / Q000378:metabolism; D008055:Lipids / Q000008:administration & dosage; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011765:Pyruvaldehyde / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: D019422:Dietary Sucrose; D017127:Glycation End Products, Advanced; D008055:Lipids; D014280:Triglycerides; D011765:Pyruvaldehyde; D054890:Fatty Acid Synthase, Type I; D007791:Lactoylglutathione Lyase