Fatty Acid Synthase Cooperates with Glyoxalase 1 to Protect against Sugar Toxicity

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.脂肪酸（Fatty acid, FA）代谢失调在多种人类疾病中均有发生，包括代谢综合征、2型糖尿病以及癌症。因此，FA代谢酶是潜在的药物治疗靶点，但这类治疗的效果必须在机体与细胞层面进行精准评估。在健康机体中，三酰甘油（triacylglycerols, TAGs，由三个FA单元酯化结合至甘油骨架构成）的合成会响应膳食糖类而增强。TAG的储存与合成能力饱和与2型糖尿病的进展密切相关。糖类毒性可能依赖于晚期糖基化终末产物（advanced-glycation-end-products, AGEs），这类产物通过胺基团与糖类或其衍生物α-氧代醛的羰基发生共价结合而形成。乙二醛（methylglyoxal, MG）是一种高反应性的α-氧代醛，可通过糖酵解的非酶促反应生成。乙二醛酶1（Glyoxalase 1, Glo1）能够中和MG，减轻其有害作用。本研究借助果蝇遗传学技术构建了脂肪酸合酶（Fatty acid synthase, FASN）突变体，以此探究该突变在膳食糖补充条件下产生的影响。研究发现，FASN突变体具有致死性，但可通过适当的脂质饮食挽救。被挽救的个体未表现出胰岛素抵抗，却对膳食糖类极度敏感，并会积累AGEs。我们证实，FASN与Glo1可在系统层面和细胞自主层面协同抵御糖类毒性。研究观察到，随着膳食蔗糖浓度升高，FASN突变体细胞的体积逐渐减小。在细胞自主层面的遗传互作实验中，我们对FASN突变体细胞中的糖酵解酶或Glo1进行调控，结果表明这种糖类依赖性的细胞体积减小是MG衍生AGEs积累的直接后果。综上，本研究结果表明，若细胞可获取胞外脂质，FASN对于细胞生长并非必需。与之相反，FA合成似乎是限制细胞自主层面MG衍生AGEs积累的必要条件，这支持了“MG是细胞内层面毒性最强的α-氧代醛”这一观点。