THE EFFECTS OF DIET ON MODULATING THE SUSCEPTIBILITY OF LOW DENSITY LIPOPROTEIN TO OXIDATIVE MODIFICATION

Open Access
- Author:
- Binkoski, Amy E.
- Graduate Program:
- Integrative Biosciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- July 22, 2004
- Committee Members:
- Penny Margaret Kris Etherton, Committee Chair/Co-Chair
John Elliot Beard, Committee Member
Terryl Johnson Hartman, Committee Member
Carla K Miller, Committee Member
Sheila Grace West, Committee Member
Richard John Frisque, Committee Member - Keywords:
- cardiovascular disease
LDL oxidation
dietary fat - Abstract:
- Oxidative modification of low density lipoprotein is thought to play an important role in the development of atherosclerosis. Three experiments were conducted that addressed different questions about the effects of diet on oxidative stress. Different population groups were studied using study-specific methodologies appropriate for each study to address research questions about the effects of diet on oxidative stress. In the first study, the combined effects of dietary fat and iron status on low-density lipoprotein (LDL) oxidation were assessed using a pharmacologic dose of an iron supplement in women with low iron status (n=26). The experimental diets were an average American diet (AAD) [36% of energy as fat; 15% saturated fatty acids (SFA)], and a Step 2 diet (26% fat; 7% SFA). Subjects consumed each diet for three weeks before crossing over to the other diet. In addition, subjects received either a supplement containing 160 mg of ferrous sulfate (50 mg elemental iron) or a placebo twice daily [supplement group received a total of 320 mg ferrous sulfate (100 mg elemental iron) daily]. Subjects consumed the iron supplement or placebo throughout both diet periods. After supplementation, serum ferritin increased in the supplement group compared to the placebo group (p = 0.008). Although iron status was improved by the high-dose iron supplement, LDL oxidative susceptibility was not affected. However, measures of LDL oxidation were affected by diet. As expected, lag time was increased after the women consumed the low fat, low SFA diet (p < 0.0001). Rate of oxidation and total dienes were not affected by diet. Therefore, the results indicate that although the low fat, low SFA diet significantly increased lag time, the addition of a therapeutic dose of iron did not affect all measures of oxidative stress measured despite improved iron status in subjects receiving the supplement. Although supplemental iron did not act as an oxidant in this study, we conclude that a blood cholesterol lowering diet can be recommended for individuals treated with supplemental iron for poor iron status to decrease cardiovascular disease risk. The second study was designed to examine the effects of different dietary fatty acid profiles in subjects with moderately elevated total cholesterol levels (n=12 M, n=19 F) on plasma lipids and lipoproteins and oxidative stress. Two experimental diets were studied that provided 30% calories from fat (either olive oil or NuSun„§ sunflower oil contributed one half of the total fat), 8.3% vs. 7.9% SFA, 17.2% vs.14.2% MUFA and 4.3% vs. 7.7% PUFA (olive oil and NuSun„§ sunflower oil, respectively), and 294 mg/day of cholesterol. The olive oil and NuSun„§ sunflower oil diets were designed to provide similar amounts of SFA whereas MUFA and PUFA levels varied, in a manner that reflected the fatty acid composition of the oils used in the respective diets. The control diet was an average American diet (34% fat, 11.2% SFA, 14.9% MUFA, 7.8% PUFA). Subjects consumed each diet for 4 weeks with a two-week compliance break before crossing over to the other diets. The NuSun„§ sunflower oil diet significantly reduced total and LDL cholesterol compared to the AAD (p<0.0001 and p=0.0006, respectively) and the olive oil diet (p=0.005 and p=0.008, respectively). In contrast, there was no effect of the olive oil diet compared to the AAD on plasma lipids and lipoproteins. Although the experimental diets were lower in total fat, plasma triglycerides did not differ among the three diets. No significant differences were observed due to diet for rate of oxidation, total dienes, lipid hydroperoxides or alpha-tocopherol. However, lag time increased following the olive oil diet as compared to the NuSun„§ sunflower oil diet (p=0.01). The greater total and LDL cholesterol lowering of NuSun„§ sunflower oil diet could be explained by its higher PUFA content compared to the olive oil diet. However, the increase in PUFA may also explain the reduction in lag time observed in response to the NuSun„§ sunflower oil diet suggestive of increased oxidative susceptibility. Despite increased oxidative susceptibility with the NuSun„§ sunflower oil diet as measured by lag time, no differences in the resulting oxidation products (total dienes and lipid hydroperoxides) were observed suggesting no adverse effects of the NuSun„§ sunflower oil diet on LDL oxidation. Thus, since PUFA are important for cholesterol-lowering, foods that replace SFA should include a balance of unsaturated fatty acids, and not be disproportionally enriched in MUFA. The last study is an analysis of data collected from a clinical nutrition study conducted at Pennington Biomedical Research Center. The objective was to evaluate the effects of two cholesterol-lowering, test diets on markers of LDL oxidation in individuals with different LDL phenotypes. Previous studies have shown that a low fat diet may be preferable for individuals expressing LDL phenotype B and contraindicated for some persons with LDL phenotype A because they may convert to LDL phenotype B, the atherogenic LDL phenotype. In this study, 87 normocholesterolemic men consumed an AAD that provided 37% of calories from total fat and 14% SFA; a Step 1 diet that provided 28% total fat and 9% SFA and a Step 2 diet that provided 24% total fat and 6% SFA. Subjects consumed each diet for six weeks in a randomized crossover design. Ten subjects converted from LDL phenotype A to LDL phenotype B during the study. The analysis included subjects who remained LDL phenotype A on all three diets (Stable A; n=55), those that remained LDL phenotype B on all three diets (Stable B; n=22), and a ¡§change¡¨ group (n=10) which converted from LDL phenotype A to LDL phenotype B in response to reductions in total and saturated fat. Greater reductions in LDL size following the Step 2 diet were observed in the ¡§change¡¨ group compared to both the Stable A group (p=0.0002) and the Stable B group (p=0.0003). At screening, both the Stable B group and the ¡§change¡¨ group had higher triglycerides (p<0.01) and lower HDL cholesterol (p<0.05) compared to the Stable A group. Reductions in apolipoprotein A1 were observed in the Stable A and Stable B subjects following both the Step 1 and Step 2 diets compared to the AAD (p<0.0001). The Stable A subjects had a further reduction in apo A1 following the Step 2 diet compared to the Step 1 diet (p=0.0006). In addition, the ¡§change¡¨ group did not have a reduction in apo A1 but did have an increase in HDL3b on the Step 2 diet compared to the AAD (p=0.02) indicative of a shift to a more dense HDL particle. Lag time, total dienes and paraoxonase activity were not different between test diets. While no differences between groups was observed for lag time or paraoxonase activity, rate of oxidation and total dienes were increased in the ¡§change¡¨ group across all diets compared to the Stable A group (p=0.03 and p=0.02, respectively) and the Stable B group (p=0.06 and p=0.06, respectively). Together, the results of the third study suggest that with reductions in dietary fat typical of those that can be achieved in a clinical setting, a diet lower in total and saturated fat is not necessarily beneficial, nor is it detrimental for persons with LDL phenotype B. Although a dietary reduction in total and saturated fat may induce some individuals with LDL phenotype A to switch to the more atherogenic LDL phenotype B, these individuals are not at increased risk in terms of lipid response. However, reductions in LDL size and a shift to a more dense HDL particle are observed in these individuals as well as increases in rate of oxidation and total dienes. Compared to those who remain LDL phenotype A or B with dietary intervention, there appear to be metabolic differences in individuals who change LDL phenotype in response to changing diet. Therefore, individuals who change LDL phenotype in response to diet appear to be at increased risk in terms of their overall lipid profile, LDL and HDL size and susceptibility of LDL to oxidation. Collectively, the results of these three studies show that different dietary interventions did not have substantive effects on measures of LDL oxidation in any of the population groups studied. There were subtle effects noted on some measures of oxidative susceptibility that appeared to be due to varying the type and amount of dietary fat. Decreasing total fat may favorably affect lag time and decreased rate of oxidation in individuals who convert from phenotype A to B in response to a Step 1 diet. Altering type of fat also may have subtle effects on measures of oxidative susceptibility. For example, a diet enriched in olive oil favorably affects lag time compared with mid-oleic sunflower oil. It will be important in future studies to evaluate whether subtle changes in measures of oxidative susceptibility are of any clinical importance.