Accepted Manuscript

Title: 1 H-NMR metabonomics can differentiate the early atherogenic effect of dairy products in hyperlipidemic hamsters 1 H-NMR metabonomics can differentiate the early atherogenic effect of dairy products in hyperlipidemic hamsters, This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 1 1 1 H-NMR metabonomics can differentiate the early atherogenic effect of dairy products in 2 hyperlipidemic hamsters 3 4 2 2 Abstract 1 Diet is an important environmental factor modulating the onset of atherosclerosis. The 2 aim of this study was to evaluate the effects of different dairy-based food products on early 3 atherogenesis using both conventional and metabonomic approaches in hyperlipidemic 4 hamsters. The hamsters received up to 200 g/kg of fat as anhydrous butter or cheese made 5 from various milk fats or canola-based oil (CV), in addition to a non-atherogenic low-fat diet. 6 Aortic cholesteryl ester loading was considered to be an early atherogenic point, and 7 metabolic changes linked to atherogenesis were measured using plasma 1 H-NMR-based 8 metabonomics. The lowest atherogenicity was obtained with the plant-oil cheese diet, 9 followed by the dairy fat cheese diet, while the greatest atherogenicity was observed with the 10 butter diet (P < 0.05). Disease outcome was correlated with conventional plasma biomarkers 11 (total cholesterol, triglycerides, LDL cholesterol, R 2 =0.42-0.60). NMR plasma metabonomics 12 selectively captured part of the diet-induced metabotypes correlated with aortic cholesteryl 13 esters (R 2 =0.63). In these metabotypes, VLDL lipids, cholesterol, and N-acetylglycoproteins 14 (R 2 range: 0.45-0.51) were the most positively correlated metabolites, whereas a 15 multimetabolite response at 3.75ppm, albumin lysyl residues, and trimethylamine-N-oxide 16 were the most negatively correlated metabolites (R 2 range: 0.43-0.63) of the aortic cholesteryl 17 esters. Collectively, these metabolites predicted 89% of atherogenic variability compared to 18 the 60% predicted by total plasma cholesterol alone. In conclusion, we show that the food 19 environment can modulate the atherogenic effect of dairy fat. This proof-of-principle study 20 demonstrates the first use of plasma metabonomics for improving the prognosis …