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Atherosclerosis. 2017 Sep;264:100-107. doi: 10.1016/j.atherosclerosis.2017.06.916. Epub 2017 Jun 21.

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

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Dept. of Medicine, Div. of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; Leiden Metabolic Research Services, Leiden University Medical Center, Leiden, The Netherlands.
Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232-6602, USA.
University of Arkansas, Stable Isotope Laboratory, 850 W Dickson Street, Fayetteville, AR 72701, USA.
Institute of Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, Bonn, Germany.
Kennedy Institute of Rheumatology, Nuffield Dept. of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
Retrotope, Inc, 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USA.
Retrotope, Inc, 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USA. Electronic address:



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.


Atherosclerosis; Cholesterol metabolism; Hypercholesterolemia; Lipid peroxidation; Polyunsaturated fatty acids

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