Abstract 9785: A Very-Low Carbohydrate Content in a High-Fat Diet Modifies the Plasma Metabolome and Alleviates Experimental Atherosclerosis

Background: A healthy diet is a cornerstone of CVD prevention and management. The vascular impact of very-low-carbohydrate (CHO), high-fat diets, or ketogenic diets (KD), remains unclear. Hypothesis: A KD will be protective against atherogenesis compared to a moderate-CHO, high-fat diet (HFD). Methods: Seven-week-old male apoE -/- mice, a model for human atherosclerosis, were fed two casein-based diets ad libitum for 12 weeks (Kcal%, CHO/fat/protein): KD (1/81/18) or HFD (42/40/18). Animals (6-8/group) were weighed weekly, and plasma was collected for quantification of beta-hydroxybutyrate (BHB) by a colorimetric assay, the inflammatory cytokines MCP1 and TNFα by immunoassays, and targeted metabolites by LC-MS/MS. Aortic atherosclerotic lesions were quantified ex-vivo by MRI on a 14-tesla-system. Results: KD mice weighed significantly less than HFD mice, reflecting the anti-obesogenic effect of the KD diet. Relative to HFD mice, the BHB level was markedly higher, and cytokines were significantly lower in the KD group, confirming the presence of ketosis in KD mice that alleviated the well-established fat-induced systemic inflammation. Several changes in the plasma metabolome driven by KD included a significant decrease in lipophilic metabolites, with increases in hydrophilic ones. Despite the higher fat content of KD versus HFD, KD mice presented significantly lower levels of several lipid metabolites including phosphatidylcholines, cholesterol esters, sphingomyelins, and ceramides. Consistent with the shift in energy metabolism toward fatty acid oxidation caused by the KD, the ratio of acyl-carnitines to free carnitine was significantly higher in KD than in HFD mice. Mice under nutritional ketosis displayed a distinct plasma amino acid profile evidencing a KD-induced alteration in protein metabolism. These included increased levels of the constituents of the major antioxidant glutathione, suggesting a more favorable redox status in the animals under nutritional ketosis. Lastly, the aortic plaque burden was significantly lower in the KD (4.8t±2.4 vol%) versus the HFD (12.8±6.72 vol%) group. Conclusion: Nutritional ketosis induced by the KD was associated with specific metabolic changes and an atheroprotective phenotype versus HFD.