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

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


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.

MeSH terms

  • 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 / blood
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Biomarkers / blood
  • Cholesterol / blood*
  • Cholesterol Ester Transfer Proteins / genetics
  • Dinoprost / blood
  • Disease Models, Animal
  • F2-Isoprostanes / blood
  • Fatty Acids, Unsaturated / pharmacology*
  • Female
  • Genetic Predisposition to Disease
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / genetics
  • Hypercholesterolemia / pathology
  • Lipid Peroxidation / drug effects*
  • Mice, Knockout, ApoE
  • Phenotype
  • Plaque, Atherosclerotic
  • Time Factors
  • Weight Gain / drug effects


  • Anticholesteremic Agents
  • Antioxidants
  • Apolipoprotein E3
  • Biomarkers
  • Cholesterol Ester Transfer Proteins
  • F2-Isoprostanes
  • Fatty Acids, Unsaturated
  • apolipoprotein E3 (Leidein)
  • Cholesterol
  • Dinoprost