We report the results of feeding oleate-or linoleate-enriched diets for 8 wk to mildly hypercholesterolemic subjects and the resulting alterations in composition and functional properties of their plasma LDL and HDL. LDL isolated from subjects on oleate-enriched diets was less susceptible to copper-mediated oxidation, as measured by conjugated diene and lipid peroxide formation, and less susceptible to LDL-protein modification, as evidenced by reduced LDL macrophage degradation after copper-or endothelial cell-induced oxidation. For all subjects, the percentage of 18:2 in LDL correlated strongly with the extent of conjugated diene formation (r = 0.89, P < 0.01) and macrophage degradation (r = 0.71, P < 0.01). Oxidation of LDL led to initial rapid depletion of unsaturated fatty acids in phospholipids followed by extensive loss of unsaturated fatty acids in cholesteryl esters and triglycerides. Changes in HDL fatty acid composition also occurred. However, HDL from both dietary groups retained its ability to inhibit oxidative modification of LDL. This study demonstrates that alterations in dietary fatty acid composition can effectively alter the fatty acid distribution of LDL and HDL in hypercholesterolemic subjects and that susceptibility to LDL oxidation is altered by these changes. Substitution of monounsaturated (rather than polyunsaturated) fatty acids for saturated fatty acids in the diet might be preferable for the prevention of atherosclerosis. (J. Clin. Invest. 1993. 91:668-676.)

Oxidized low-density lipoprotein (LDL) is more atherogenic than native LDL. The initial step in the oxidation is the peroxidation of polyunsaturated fatty acids. Thus, decreasing the concentration of polyunsaturated fatty acids should reduce the susceptibility of LDL to oxidation. Therefore, we tested the possibility that diets enriched in oleate might result in LDL that is less susceptible to oxidative modification. LDL isolated from subjects consuming an oleate-enriched diet, compared with LDL from subjects on a linoleate-enriched diet, contained significantly more oleate (28.7% vs 11.5%) and less linoleate (31.9% vs 50.9%). Generation of conjugated dienes was significantly lower in the LDL from the oleate group. Most important, after incubation with endothelial cells, LDL from the oleate group underwent less degradation by macrophages. These studies demonstrate the feasibility of altering the diet in a way that will not raise LDL cholesterol concentrations and yet will decrease the susceptibility of LDL to oxidative modification.

This report describes the effects of feeding linoleate-or oleate-enriched diets to subjects who were concurrently taking 1200 mg/d of a-tocopherol on the susceptibility of low-density lipoprotein (LDL) and buoyant and dense LDL subfractions to oxidation. LDL isolated from subjects who consumed linoleate-enriched diets was more susceptible to copper-mediated oxidation, as measured by formation of conjugated dienes and lipid peroxides and loss of unsaturated fatty acids, compared with LDL isolated from subjects who consumed their usual or oleate-enriched diets. In all subjects, buoyant LDL had a higher content of a-tocopherol per particle and a lower 18:2 to 18:1 ratio and was considerably more resistant to oxidation than dense LDL. Although dense LDL from all groups had comparable a-tocopherol levels, dense LDL from the linoleate group was most susceptible to oxidation, followed by that from the standard diet, whereas T here is evidence that oxidative modification of low-density lipoproteins (LDLs) occurs in vivo 14 and may increase LDL atherogenicity, as recently reviewed. Correspondence to Peter Reaven, MD, Department of Medicine 0682, University of California-San Diego, 9500 Gilman Dr, BSB 1080, La Jolla, CA 92093-0682. dense LDL isolated from the oleate diet group was most resistant. In summary, high dosages of a-tocopherol did not prevent enhanced susceptibility to oxidation of LDL isolated from subjects fed linoleate-enriched diets. Furthermore, dense LDL was more susceptible to oxidation than was buoyant LDL, and this effect was greatly exaggerated in the dense LDL isolated from subjects fed linoleate-enriched diets. Conversely, dense LDL isolated from subjects fed oleate-enriched diets was the most protected. If oxidation of LDL is important in the pathogenesis of atherosclerosis, then these data suggest that in people with increased amounts of small, dense LDL, dietary enrichment in oleic acid may decrease the susceptibility of their LDL to oxidation. (Arteriosder Thromb. 1994; 14:557-566.)

Previous studies have demonstrated that compared with more buoyant LDL, dense LDL (D-LDL) is more susceptible to oxidation and less readily protected from oxidation by antioxidant enrichment. However, diets enriched in monounsaturated fatty acids (MUFAs) appear particularly effective in protecting D-LDL from oxidation. We therefore evaluated in 12 non-insulin-dependent diabetes mellitus subjects the effects of supplementation with alpha-tocopherol (1600 IU/d) and probucol (1 g/d) alone and in combination with an MUFA-enriched diet on LDL and LDL subfraction susceptibility to oxidation and monocyte release of superoxide anion. Subjects received either alpha-tocopherol or probucol for 4 months, and during the fourth month both groups also received an MUFA-enriched diet. alpha-Tocopherol levels were significantly increased in LDL and LDL subfractions (P < .05) after 3 months of supplementation. MUFA-enriched diets led to further increases in alpha-tocopherol in LDL fractions in the alpha-tocopherol group as well as in those receiving probucol. In the alpha-tocopherol-supplemented group, lag times were increased significantly (1.6- to 2.0-fold) for all LDL fractions, although the absolute increase was least for D-LDL. Although probucol supplementation increased lag times of LDL and LDL subfractions three- to fourfold, D-LDL was still more readily oxidized. In both the alpha-tocopherol- and probucol-supplemented groups the benefit of adding MUFA-enriched diets was greatest for D-LDL, with further increases in lag time of 26% and 18%, respectively. Neither antioxidant supplementation nor the addition of an MUFA-enriched diet reduced unstimulated or phorbol ester-stimulated monocyte superoxide anion production. These data demonstrate the markedly different effects that antioxidants and diet may have on different LDL subfractions, which may be particularly important in individuals with non-insulin-dependent diabetes mellitus, who frequently have increased amounts of D-LDL.

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