Atherogenicity of Monosaccharides, Disaccharides and Artificial Sweeteners in the Lipid-Laden Macrophage Model System: Cell Culture and Mice Studies

Background: Glucose is known to enhance macrophage foam cell formation and atherosclerosis development. However, the role of other monosaccharides, disaccharides or artificial sweeteners in macrophage atherogenicity remains unclear.Objective: We thus compared their effects on oxidative status, cholesterol, and triglycerides accumulation which regulate foam cell formation.Results: Supplementation of C57/BL6 mice for four weeks with sweeteners revealed that glucose, fructose, mannose, lactose or sucrose significantly increased hepatic lipid peroxidation and cholesterol accumulation, as well as mouse peritoneal macrophages (MPM) generation of ROS and lipid content. Supplementation with artificial sweeteners showed no significant pro-oxidative/atherogenic effects in the mice liver or aorta. Yet, cyclamate and sucralose significantly increased MPM ROS generation, and all artificial sweeteners increased MPM cholesterol content. In cultured J774A.1 macrophage cell line, glucose demonstrated the most pro-oxidative/atherogenic effects and significantly increased reactive oxygen species (ROS) generation (by 80%), cellular protein oxidation (by 119%), the accumulation of cholesterol and triglycerides (by 65% and 51%, respectively), and the macrophage phagocytosis capacity (by 177%). Mechanistically, glucose attenuated HDL-mediated cholesterol efflux from macrophages (by 17%) and enhanced their triglyceride biosynthesis rate (by 51%). Although to a lesser extent, mannose or cyclamate demonstrated pro-oxidative/ atherogenic effects and significantly increased cellular ROS generation, cholesterol content, triglyceride content and macrophage phagocytosis capacity.Conclusions: Taking together, the above results indicate the key pro-oxidative/atherogenic role for glucose as compared to other monosaccharides, as well as disaccharides or artificial sweeteners. Finally, the detrimental pro-atherogenic effects on macrophage foam cell formation of mannose or cyclamate, and to a lesser extent fructose, aspartame and saccharin are now clearly shown.