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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.

Author information

1
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.
2
Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232-6602, USA.
3
University of Arkansas, Stable Isotope Laboratory, 850 W Dickson Street, Fayetteville, AR 72701, USA.
4
Institute of Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, Bonn, Germany.
5
Kennedy Institute of Rheumatology, Nuffield Dept. of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
6
Retrotope, Inc, 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USA.
7
Retrotope, Inc, 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USA. Electronic address: misha@retrotope.com.

Abstract

BACKGROUND AND AIMS:

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.

METHODS:

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.

RESULTS:

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%).

CONCLUSIONS:

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.

KEYWORDS:

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

[Indexed for MEDLINE]

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