Oxidized Cholesterol in the Diet Accelerates the Development of Atherosclerosis in LDL Receptor– and Apolipoprotein E–Deficient Mice

Staprãns, Ilona; Pan, Xian-Mang; Rapp, Joseph H.; Grünfeld, Carl; Feingold, Kenneth R.

doi:10.1161/01.atv.20.3.708

Cited by 86 publications

(93 citation statements)

References 59 publications

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“…34 In addition, it has been shown that oxidized cholesterol and oxidized lipids in the diet accelerate the development of atherosclerosis in mice and rabbits. [35][36][37] In those studies, the dietary levels of oxidation byproducts were significantly increased by heating vitamin E-depleted corn oil or cholesterol to 100°C for several hours. In contrast, in the present study, all diets were refrigerated until time of use and were not vitamin E-depleted.…”

Section: Discussionmentioning

confidence: 99%

Circulating Autoantibodies to Oxidized LDL Correlate With Arterial Accumulation and Depletion of Oxidized LDL in LDL Receptor–Deficient Mice

Tsimikas

Palinski

Witztum

2001

ATVB

139

105

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Abstract-Autoantibodies to oxidized low density lipoprotein (OxLDL) are elevated in some human populations with increased risk of atherosclerosis. To determine whether autoantibody levels to epitopes of OxLDL reflect the extent of aortic atherosclerosis and the content of OxLDL, we measured IgG and IgM autoantibody titers to malondialdehyde (MDA)-LDL and copper-oxidized LDL (Cu-OxLDL) in 43 LDL receptor-deficient mice consuming atherogenic and regression diets. Antibody titers were correlated to percent atherosclerotic surface area, aortic weight, and aortic OxLDL content, measured as the in vivo uptake of 125 I-MDA2, a monoclonal antibody to MDA-LDL. All mice were fed an atherogenic diet for 6 months, and 1 group was euthanized. The other 3 groups were fed an atherogenic diet (fat/CHOL group), normal mouse chow (chow group), or mouse chow supplemented with vitamins E and C (chowϩVIT group) for an additional 6 months. After dietary intervention, compared with their own baseline, autoantibody titers to MDA-LDL and Cu-OxLDL increased significantly in the fat/CHOL group, whereas they did not change or decreased significantly in the chow and chowϩVIT groups. Aortic weight and surface area showed significant progression in the fat/CHOL group, mild progression in the chow group, and no progression in the chowϩVIT group (PϽ0.001), whereas OxLDL content actually decreased in the latter 2 groups (PϽ0.001). Significant correlations were seen with MDA-LDL autoantibody titers and OxLDL content (IgM, Rϭ0.64 and Pϭ0.0009; IgG, Rϭ0.52 and Pϭ0.009), as well as with percent surface area and aortic weight. These data support the hypothesis that autoantibody titers to OxLDL reflect changes in OxLDL content in atherosclerotic lesions of LDL receptor-deficient mice. Whether autoantibody titers to OxLDL will provide similar valuable insights into the extent of human atherosclerosis, particularly anatomic measurements of plaque burden and OxLDL content, remains to be determined.

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Section: Discussionmentioning

confidence: 99%

Circulating Autoantibodies to Oxidized LDL Correlate With Arterial Accumulation and Depletion of Oxidized LDL in LDL Receptor–Deficient Mice

Tsimikas

Palinski

Witztum

2001

ATVB

139

105

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“…Cholesterol is also converted to a variety of oxysterols as a precursor to bile acid synthesis. Due to processing, heating or prolonged storage of animal-derived foods, the typical Western diet contains substantial quantities of oxidized cholesterol [131,132]. Studies in feeding animal models and epidemiological studies in humans have indicated that the addition of oxidized cholesterol to the diet increases the development of atherosclerosis [132].…”

Section: Ezetimibe: Oxysterol Effectsmentioning

confidence: 99%

Ezetimibe: cholesterol lowering and beyond

Bays¹,

Neff

Tomassini

et al. 2008

Expert Review of Cardiovascular Therapy

135

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“…Recently, we have demonstrated that oxidized cholesterol in the diet also accelerates fatty streak lesion formation in aortas of cholesterol-fed rabbits (22). In LDL receptor-deficient and apolipoprotein E (apoE)-deficient mice (murine models in which atherosclerosis more closely resemble human lesions), again the feeding of oxidized cholesterol resulted in a significant increase in aortic fatty streak lesions (23). Thus, our observations in animals clearly demonstrate that diets containing oxidized lipids, either oxidized fatty acids or cholesterol, increase the development of atherosclerosis.…”

Section: Journal Of Lipid Researchmentioning

confidence: 99%

Oxidized cholesterol in the diet is a source of oxidized lipoproteins in human serum

Staprãns

Pan

Rapp

et al. 2003

Journal of Lipid Research

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The aim of this study was to determine in humans whether oxidized cholesterol in the diet is absorbed and contributes to the pool of oxidized lipids in circulating lipoproteins. When a meal containing 400 mg cholestan-5 ␣ ,6 ␣ -epoxy-3 ␤ -ol ( ␣ -epoxy cholesterol) was fed to six controls and three subjects with Type III hyperlipoproteinemia, ␣ -epoxy cholesterol in serum was found in chylomicron/ chylomicron remnants (CM/RM) and endogenous (VLDL, LDL, and HDL) lipoproteins. In controls, ␣ -epoxy cholesterol in CM/RM was decreased by 10 h, whereas in endogenous lipoproteins it remained in the circulation for 72 h. In subjects with Type III hyperlipoproteinemia, ␣ -epoxy cholesterol was mainly in CM/RM. In vitro incubation of the CM/RM fraction containing ␣ -epoxy cholesterol with human LDL and HDL that did not contain ␣ -epoxy cholesterol resulted in a rapid transfer of oxidized cholesterol from CM/RM to both LDL and HDL. In contrast, no transfer was observed when human serum was substituted with rat serum, suggesting that cholesteryl ester transfer protein is mediating the transfer. Thus, ␣ -epoxy cholesterol in the diet is incorporated into the CM/RM fraction and then transferred to LDL and HDL, contributing to lipoprotein oxidation. Moreover, LDL containing ␣ -epoxy cholesterol displayed increased susceptibility to further copper oxidation in vitro. It is possible that oxidized cholesterol in the diet accelerates atherosclerosis by increasing oxidized cholesterol levels in circulating LDL and chylomicron remnants. A large body of evidence supports the hypothesis that oxidized lipoproteins, particularly oxidized LDL, play a pathogenic role in atherosclerosis (1, 2). Oxidized LDL has numerous atherogenic properties with a variety of cell types in culture, including induction of inflammatory genes, stimulation of monocyte chemotactic factor production, the potentiation of monocyte-endothelial cell adhesion, accelerated deposition of lipids in macrophages, cytotoxicity with endothelial cells, and modulation of growth factors. Additionally, oxidized LDL-like particles and lipid peroxidation products are present in atherosclerotic lesions (3, 4). Moreover, it has been shown that antioxidants in the diet can slow the progression of atheroscerosis in animal models (5-7).Thus, there is strong evidence that oxidized lipoproteins play a key role in atherogenesis, but the site and mechanisms by which lipoproteins are oxidized is far from resolved. It is not clear whether oxidized lipoproteins form locally in the artery wall, as suggested by several investigators (1, 2), or are sequestered in atherosclerotic lesions following the uptake of circulating oxidized lipoproteins. We have been focusing our studies on the role of diet and have demonstrated that potentially atherogenic oxidized lipoproteins in the circulation are at least partially derived from oxidized lipids in food and contribute to atherosclerosis in animal models.The American diet contains large quantities of oxidized fatty acids (8, 9) and oxidized ...

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Oxidized Cholesterol in the Diet Accelerates the Development of Atherosclerosis in LDL Receptor– and Apolipoprotein E–Deficient Mice

Cited by 86 publications

References 59 publications

Circulating Autoantibodies to Oxidized LDL Correlate With Arterial Accumulation and Depletion of Oxidized LDL in LDL Receptor–Deficient Mice

Circulating Autoantibodies to Oxidized LDL Correlate With Arterial Accumulation and Depletion of Oxidized LDL in LDL Receptor–Deficient Mice

Ezetimibe: cholesterol lowering and beyond

Oxidized cholesterol in the diet is a source of oxidized lipoproteins in human serum

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