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Biochemical and Molecular Actions of Nutrients

Oxidized Fatty Acids Promote Atherosclerosis Only in the Presence of Dietary Cholesterol in Low-Density Lipoprotein Receptor Knockout Mice^{1 ,2}

Nadya Khan-Merchant^*,, Meera Penumetcha^*,, Olivier Meilhac and Sampath Parthasarathy³

^* Nutrition and Health Sciences Program, Division of Biological and Biomedical Sciences, and Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA 30322

³To whom correspondence should be addressed. E-mail: spartha{at}emory.edu.

Studies suggest that heated oils contribute to the presence of oxidized components in the circulating lipoproteins and to the development of atherosclerosis in animals. We evaluated the effects of 11–13 wk of consumption of a well defined dietary oxidized fatty acid, 13-hydroxylinoleic acid (13-HODE) (8 mg), on atherosclerotic lesion development and plasma cholesterol concentrations in mice fed diets varying in fat and cholesterol contents. LDL receptor knockout mice were used in two feeding studies. In study 1, oxidized fatty acid consumption in association with a high fat diet increased aortic lesion areas by >100% (P < 0.05). Surprisingly, oxidized fatty acid intake also tended to increase plasma total cholesterol (P = 0.12) and LDL cholesterol (P < 0.05) as well as oxidative stress as measured by higher levels of autoantibodies to oxidatively modified proteins (P = 0.008). However, in mice fed a nonpurified diet, oxidized fatty acids were not atherogenic and may even have been beneficial, as indicated by a lower plasma triglyceride (TG) concentration (P < 0.05). In study 2, mice were fed either a high fat, medium fat or low fat diet to evaluate whether the increase in aortic lesions due to oxidized fatty acid consumption in study 1 was a result of the associated higher plasma total and LDL cholesterol concentrations. In study 2, 13-HODE-treated mice in the medium and low fat diet groups but not those fed the high fat diet had larger atherosclerotic lesions (P < 0.05). Additionally, plasma total and LDL cholesterol as well as TG were not affected by HODE treatment. However, the total cholesterol:HDL cholesterol ratio was higher in treated mice (P < 0.05) and HDL cholesterol was lower in HODE-treated mice that were fed the low fat diet (P < 0.05). Our results suggest that, in mice fed cholesterol, oxidized fatty acids may be atherogenic, both in terms of increased oxidative stress (as seen in study 1) and by increasing the atherogenicity of the plasma cholesterol profile.

KEY WORDS: • lipid hydroxide • atherosclerotic lesions • plasma cholesterol • oxidized lipoproteins • autoantibodies

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