Deuterium-reinforced polyunsaturated fatty acids protect against atherosclerosis by lowering lipid peroxidation and hypercholesterolemia

• Published in: Atherosclerosis Vol. 264; pp. 100 - 107
• Main Authors: Berbée, Jimmy F.P., Mol, Isabel M., Milne, Ginger L., Pollock, Erik, Hoeke, Geerte, Lütjohann, Dieter, Monaco, Claudia, Rensen, Patrick C.N., van der Ploeg, Lex H.T., Shchepinov, Mikhail S.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.09.2017
• Subjects: Adiposity - drug effects; Animals; Anticholesteremic Agents - pharmacology; Antioxidants - pharmacology; Aorta - drug effects; Aorta - metabolism; Aorta - pathology; Aortic Diseases - blood; Aortic Diseases - genetics; Aortic Diseases - pathology; Aortic Diseases - prevention & control; Apolipoprotein E3 - genetics; Atherosclerosis; Atherosclerosis - blood; Atherosclerosis - genetics; Atherosclerosis - pathology; Atherosclerosis - prevention & control; Biomarkers - blood; Cardiovascular; Cholesterol - blood; Cholesterol Ester Transfer Proteins - genetics; Cholesterol metabolism; Dinoprost - blood; Disease Models, Animal; F2-Isoprostanes - blood; Fatty Acids, Unsaturated - pharmacology; Female; Genetic Predisposition to Disease; Hypercholesterolemia; Hypercholesterolemia - blood; Hypercholesterolemia - drug therapy; Hypercholesterolemia - genetics; Hypercholesterolemia - pathology; Lipid peroxidation; Lipid Peroxidation - drug effects; Mice, Knockout, ApoE; Phenotype; Plaque, Atherosclerotic; Polyunsaturated fatty acids; Time Factors; Weight Gain - drug effects; Lipid peroxidation; Hypercholesterolemia; Polyunsaturated fatty acids; Cholesterol metabolism; Atherosclerosis
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2017.06.916

Oxidative modification of lipoproteins is a crucial step in atherosclerosis development. Isotopic-reinforced polyunsaturated fatty acids (D-PUFAs) are more resistant to reactive oxygen species-initiated chain reaction of lipid peroxidation than regular hydrogenated (H-)PUFAs. We aimed at investigating the effect of D-PUFA treatment on lipid peroxidation, hypercholesterolemia and atherosclerosis development. Transgenic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, were pre-treated with D-PUFAs or control H-PUFAs-containing diet (1.2%, w/w) for 4 weeks. Thereafter, mice were fed a Western-type diet (containing 0.15% cholesterol, w/w) for another 12 weeks, while continuing the D-/H-PUFA treatment. D-PUFA treatment markedly decreased hepatic and plasma F2-isoprostanes (approx. −80%) and prostaglandin F2α (approx. −40%) as compared to H-PUFA treatment. Moreover, D-PUFAs reduced body weight gain during the study (−54%) by decreasing body fat mass gain (−87%) without altering lean mass. D-PUFAs consistently reduced plasma total cholesterol levels (approx. −25%), as reflected in reduced plasma non-HDL-cholesterol (−28%). Additional analyses of hepatic cholesterol metabolism indicated that D-PUFAs reduced the hepatic cholesterol content (−21%). Sterol markers of intestinal cholesterol absorption and cholesterol breakdown were decreased. Markers of cholesterol synthesis were increased. Finally, D-PUFAs reduced atherosclerotic lesion area formation throughout the aortic root of the heart (−26%). D-PUFAs reduce body weight gain, improve cholesterol handling and reduce atherosclerosis development by reducing lipid peroxidation and plasma cholesterol levels. D-PUFAs, therefore, represent a promising new strategy to broadly reduce rates of lipid peroxidation, and combat hypercholesterolemia and cardiovascular diseases. •D-PUFAs decrease lipid peroxidation products in hyperlipidemic mice.•D-PUFAs reduce body weight and body fat mass gain.•D-PUFAs lower plasma cholesterol levels and improve cholesterol handling.•D-PUFAs reduce atherosclerotic lesion formation.