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Articles

Low Fat and High Monounsaturated Fat Diets Decrease Human Low Density Lipoprotein Oxidative Susceptibility In Vitro^{1 ,2}

Rebecca L. Hargrove^*, Terry D. Etherton^*,, Thomas A. Pearson^**, Earl H. Harrison and Penny M. Kris-Etherton^*3

^* Graduate Program in Nutrition, Department of Dairy and Animal Science, The Pennsylvania State University, University Park, PA 16802; ^** University of Rochester School of Medicine, Rochester, NY 14642; and Human Nutrition Research Center, U.S. Department of Agriculture-ARS, Beltsville, MD 20705

³To whom correspondence should be addressed. E-mail: pmk3{at}psu.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Oxidative modification of low density lipoprotein (LDL) is thought to play an important role in the development of atherosclerosis. Some studies have found that LDL enriched in monounsaturated fatty acids (MUFA) are less susceptible to oxidation than LDL enriched in polyunsaturated fatty acids (PUFA). A high MUFA diet is an alternative to a lower-fat blood cholesterol-lowering diet. Less is known about the effects of high MUFA versus lower-fat blood cholesterol-lowering diets on LDL oxidative susceptibility. The present study was designed to evaluate the effects of men and women consuming diets high in MUFA (peanuts plus peanut butter, peanut oil and olive oil) on LDL oxidative susceptibility, and to compare these effects with those of a Step II blood cholesterol-lowering diet. A randomized, double-blind, five-period crossover design (n = 20) was used to study the effects of the following diets on LDL-oxidation: average American [35% fat, 15% saturated fatty acids (SFA)], Step II (25% fat, 7% SFA), olive oil (35% fat, 7% SFA), peanut oil (35% fat, 7% SFA) and peanuts plus peanut butter (35% fat, 8% SFA). The average American diet resulted in the shortest lag time (57 ± 6 min) for LDL oxidized ex vivo, whereas the Step II, olive oil and peanuts plus peanut butter diets resulted in a lag time of 66 ± 6 min (P 0.1). The slower rate of oxidation [nmol dienes/(min · mg LDL protein)] observed when subjects comsumed the olive oil diet (24 ± 2) versus the average American (28 ± 2), peanut oil (28 ± 2) and peanuts plus peanut butter diets (29 ± 2; P 0.05) was associated with a lower LDL PUFA content. The results of this study suggest that lower-fat and higher-fat blood cholesterol-lowering diets high in MUFA have similar effects on LDL oxidative resistance. In addition, our results suggest that different high MUFA sources varying in the ratio of MUFA to PUFA can be incorporated into a high MUFA diet without increasing the susceptibility of LDL to oxidation.

KEY WORDS: • dietary fat • nuts • peanuts • low density lipoprotein oxidation • conjugated dienes • humans

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Oxidative modification of low density lipoprotein (LDL)⁴ is thought to play an important role in the development of atherosclerosis (1 2 3 4) . Dietary manipulations that increase LDL oxidative resistance could potentially delay the progression of this disease. Although both monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) lower total and LDL-cholesterol levels when substituted for saturated fatty acids (SFA), LDL from subjects fed diets enriched in MUFA are less susceptible to oxidation compared with those from subjects consuming diets high in PUFA (5 6 7 8) . Sources of MUFA have generally included an oleic acid-enriched sunflower oil and olive oil, whereas conventional sunflower oil or safflower oil has been used as a PUFA source. The effects of other dietary sources of MUFA and PUFA on LDL-oxidation have not been thoroughly investigated.

The major sources of energy in nuts are unsaturated fatty acids. Nuts are also a source of vitamin E, an antioxidant that protects against LDL-oxidation in vitro (9 10 11 12 13) . In addition, nuts are sources of dietary fiber, plant protein, vitamins (e.g., folic acid, vitamin B-6 and niacin), minerals (e.g., magnesium, zinc, copper and potassium) and a variety of phytochemicals (14) . Epidemiologic studies have demonstrated an inverse association between frequent nut consumption and incidence of coronary heart disease (CHD) (15 16 17) , and it is possible that the fatty acid composition and antioxidant content of nuts could increase resistance of LDL to oxidation. Several studies have demonstrated that diets high in nuts favorably affect plasma lipid concentrations (18 19 20 21 22) , but few studies have examined the effects of such diets on LDL oxidative susceptibility. To date, only one study has examined the effects of diets high in peanuts on the susceptibility of LDL to oxidative modification (23) . In this study, a low fat, high MUFA diet decreased LDL oxidative susceptibility ex vivo. However, the majority of dietary MUFA in this study was supplied by peanuts enriched in oleic acid, rather than more commonly consumed peanuts and peanut products. The high oleic acid peanut cultivar contained 76–80% of the lipid content as MUFA, whereas typical peanuts contain 50% of the lipid content as MUFA and 32% as PUFA.

An objective of this study was to evaluate the effects of diets high in MUFA from different food sources, including one with conventional peanuts plus peanut butter and others high in peanut oil or olive oil on LDL oxidative susceptibility. In addition, we compared these effects with those of a Step II blood cholesterol-lowering diet as well as a higher fat average American diet. A Step II diet (<30% energy from total fat, < 7% energy from saturated fat, < 200 mg/d of cholesterol) has been recommended for maximal cholesterol-lowering effects (24) , but its effects on LDL-oxidation are unclear. One study showed that LDL isolated from subjects consuming a high carbohydrate diet was more prone to oxidation than LDL isolated from subjects consuming a high MUFA diet (25) . In contrast, it also has been demonstrated that a very low fat diet in combination with daily exercise can increase LDL oxidative resistance (26) . In addition, a recent study reported that both a Step I diet (29% total fat, 9% SFA) and a low saturated fat diet (25% total fat, 6% SFA) decreased the oxidative susceptibility of LDL, compared with an average American diet (34% total fat, 15% SFA) (27) . In this study, %MUFA and %PUFA were held constant in the experimental diets. We also identified a positive correlation between total and LDL-cholesterol levels and LDL oxidative susceptibility in vitro, suggesting that the quantity of LDL may be an important determinant of oxidative modification. Higher-fat diets high in MUFA and low in SFA and cholesterol have been shown to favorably affect plasma lipids, lipoproteins and LDL oxidative susceptibility (25 ,28 ,29) . Typical MUFA sources include olive oil and canola oil, but little is known about the effects of other MUFA sources, such as peanuts, peanut butter and peanut oil. If these food sources are shown to beneficially affect several CHD risk factors (e.g., plasma lipids and LDL oxidative susceptibility), they could be used as substitutes for olive oil and canola oil in blood cholesterol-lowering diets. We have reported the effects of four blood cholesterol-lowering diets that varied in type and amount of fat on plasma lipids and lipoproteins (19) . In the present study, we examined the effects of these diets on LDL-oxidation, LDL fatty acid composition and LDL vitamin E and carotene content.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects.

Twenty-six subjects (11 male and 15 female) began this study. Subjects were recruited by a formal screening process that included a telephone interview, a brief physical examination consisting of height and weight measurements, blood pressure measures, a blood draw for baseline information and chemistries and a diet run-in period. Recruited subjects were healthy men and women 20 to 60 y of age who had serum total, LDL and high density lipoprotein (HDL)-cholesterol concentrations between the 25th and 90th percentiles for age, race and gender (mean total cholesterol: 4.88 mmol/L; mean LDL-cholesterol: 3.05 mmol/L; mean HDL-cholesterol: 1.32 mmol/L) and serum triglycerides below the 90th percentile (mean triglycerides: 1.16 mmol/L). Subjects signed a consent form agreeing to participate in the study after reading a description of experimental procedures. The study was approved by The Pennsylvania State University Institutional Review Board.

Experimental design.

A randomized, double-blind five-period cross-over study design was used. Each diet period lasted 3.5 wk, with a compliance break of 4–11 d separating diet periods. To facilitate recruitment, six diet periods were available, but subjects were only required to participate in five. Thus, the randomization scheme included the free diet period.

Subjects were randomly assigned to receive one of five experimental diets. Over the course of the study, each subject consumed each diet. Subjects ate breakfast and dinner at the Metabolic Diet Study Center Monday through Friday, and lunches and weekend meals were packed. Subjects consumed an amount of food consistent with their energy needs and they were weighed every day during the week before dinner to ensure that weight was maintained.

Experimental diets.

The five experimental diets included an average American diet and four blood cholesterol-lowering diets, i.e., a Step II diet, a diet high in olive oil, a diet high in peanut oil and a diet high in a combination of peanuts and peanut butter. One blood cholesterol-lowering diet was low in total fat (i.e., Step II diet was designed to provide 25% of energy from fat), and three were higher in total fat from MUFA (i.e., the olive oil, peanut oil and peanuts and peanut butter diets provided 35% of energy from fat). The high MUFA diets were designed so that one half of the daily fat allowance was provided by olive oil, peanut oil or a combination of peanuts and peanut butter, respectively. All blood cholesterol-lowering diets were designed to provide 200 mg of cholesterol/d and 20 g of dietary fiber/d.

A 7-d cycle menu was planned using the Nutritionist IV database (N-Squared Computing, First DataBank Division, San Bruno, CA), and all menus were designed to be nutritionally adequate. Proximate analyses were also performed to determine the amounts of protein, carbohydrate and total fat in the five diets. The Kjeldahl method was used to determine protein content, and total fat content was determined by ether extraction. The percentages of saturated, monounsaturated and polyunsaturated fat were determined by gas chromatography. Table 1 shows the assayed macronutrient composition of the five test diets.

Blood samples were collected on two separate days at the end of each diet period for the lipid endpoints. Experienced phlebotomists collected blood in the morning after a 12-h fast. On each of the 2 d, 20 mL of blood was collected into two 10-mL silicone gel-coated tubes for lipid analyses. Serum was separated by low speed centrifugation. For the LDL-oxidation measurements, an additional 30 mL of blood was collected from each subject on 1 of the 2 d. Blood was collected into 10-mL Vacutainer tubes (VWR Scientific Products, West Chester, PA) containing an anticoagulant, sodium ethylene diamine etracetic acid. Plasma was separated by low speed centrifugation, and the water-soluble anitoxidant TROLOX (Aldrich Chemical Co., Milwaukee, WI) was added to the plasma to a final concentration of 1 µmol/L.

Serum was divided into 1.5-mL cryovials and stored at -80°C until the end of the study. LDL was quantified using the Friedewald equation [LDL-cholesterol = total cholesterol - (HDL-cholesterol + triglyceride/5)] (30) after serum concentrations of total cholesterol and HDL-cholesterol (Roche Reagents, Branchburg, NJ) and triglycerides (Sigma Chemical Reagents, Chicago, IL) were determined using enzymatic methods. Samples were analyzed at the Mary Imogene Bassett Research Institute (Cooperstown, NY) for plasma lipids and lipoproteins. These data were reported previously (19) .

Oxidation of LDL.

LDL was isolated by density gradient ultracentrifugation (31) . A density gradient was formed by adjusting 4 mL of plasma to d = 1.21 with potassium bromide and then sequentially layering 2.0–2.5 mL of three salt solutions above the plasma (d = 1.063 kg/L; d = 1.019 kg/L; d = 1.006 kg/L). Samples were then centrifuged in a Beckman Coulter SW40 or SW41 swinging bucket rotor (Beckman Coulter, Fullerton, CA) at 270,000 x g for 22 h at 10°C. Immediately after centrifugation, the LDL fraction was collected. LDL samples (0.45 mL) were preserved in a 100-g/L sucrose solution to prevent structural and biological changes because of freezing. It has been demonstrated that LDL preserved in sucrose maintains its normal physical and biological properties for as long as 18 mo (32) . LDL samples were purged with nitrogen and stored at -80°C.

At the end of the study, LDL samples were grouped and analyzed by subject for the oxidation analyses. LDL was dialyzed for 24 h at 4°C in the dark against a 0.01 mol/L phosphate-buffered saline buffer that contained 0.1 g chloramphenicol/L and was also purged with nitrogen. The buffer was changed three times during the 24-h period. Protein analyses were determined before dialysis (33) . Within 24 h of dialysis, conjugated diene formation was monitored as previously described (34) . LDL protein (100 µg) was diluted to 1 mL with phosphate-buffered saline buffer and oxidation was initiated by adding 1 mmol/L CuCl₂ solution to a final concentration of 0.01 mmol/L. Oxidation was measured in a Beckman Coulter Model 50 ultraviolet spectrophotometer at an absorbance of 234 nm at 3-min intervals for 3 h at 37°C. From these measurements, lag time, rate of oxidation and total amount of conjugated dienes formed were determined for each sample (34) . Rate of oxidation and conjugated dienes were determined from the maximum rate of oxidation (Abs₂₃₄/min) and maximum absorbance (Abs₂₃₄) and using the molar extinction coefficient for conjugated lipid hydroperoxides (₂₃₄ = 29,500 mol^-1 L cm^-1).

Before measuring LDL-oxidation in the frozen samples, we also measured the variation attributable to the oxidation method across days using eight replicates of a single LDL sample. On four different days, conjugated dienes were measured in duplicate. The coefficient of variation across all days was 6% for lag time, 14% for rate of oxidation and 7% for total amount of dienes produced.

LDL fatty acids.

Lipids were extracted from the frozen LDL samples using the Folch method (35) . LDL samples (0.45 mL) were thawed, and 50 µL of butylated hydroxyl toluene (0.02 mol/L) was added to each sample to prevent autooxidation. Lipids were extracted with 20 mL of a 2:1 chloroform-methanol solution (v/v). The final lipid phase was evaporated to dryness under nitrogen at 50–55°C, and the lipid residue was resuspended in 100 µL of the chloroform-methanol solution.

Fatty acids were methylated by adding boron triflouride-methanol to the lipid extracts (36) and then heating the samples to 100°C for 30 min. The lipid extract was evaporated completely under nitrogen, and the residue was resuspended in 160 µL of hexane before LDL fatty acid composition was determined by gas chromatography. Fatty acids were measured in a Hewlett Packard 5890 gas chromatograph (Analytical Instrument Recycle, Golden, CO) equipped with a Supelco SP-2330 capillary column (Supelco, Bellefonte, PA). The helium carrier flow rate was set at 30 mL/min. Oven temperature was 150°C initially (8 min), and then was increased 3°C/min to a final temperature of 190°C (20 min). The injector and detector temperatures were set at 250°C. Comparison of peak retention times of samples to those of lipid standards (GLC-6B, 14A, 61A, 63A, 68A, 87; Nu-Check-Prep, Elysian, MN) allowed for the identification of fatty acid methyl esters. Fatty acids were quantitatively determined by comparing the area of each peak to the peak area of a C17:0 internal standard (Nu-Check-Prep).

LDL vitamin E and carotenes.

LDL -tocopherol and carotenoid content (lutein, ß-cryptoxanthin, lycopene and ß-carotene) were determined using a method that has been described previously (37) . Briefly, carotenoids were extracted from the frozen LDL samples (0.45 mL) (38) , and evaporated extracts were redissolved in 200 µL of acetonitrile-isopropanol solution (1:1). Both carotenoid and -tocopherol contents of LDL were then measured by high performance liquid chromatography (39) using a 25-cm, 4.6 ID Supercosil (Supelco, Bellefonte, PA) C18 reverse-phase column and a Waters 996 photodiode array detector (290 nm for -tocopherol and 450 nm for carotenoids). The samples were eluted using a 90:15:10:0.1 acetonitrile-dichloromethane-methanol-octanol (v/v/v/v) containing 0.01% t-butylamine mobile phase at a flow rate of 1 mL/min. Both carotenoids and -tocopherol were identified and quantified by comparison with standards.

Statistical analysis.

All statistical analyses were performed using SAS (SAS Institute, Cary, NC). Data are expressed as least squares means ± standard error, and any effects of diet or feeding period were tested using analysis of variance. Tukey-Kramer adjusted P values were used to determine differences between diets for each of the following variables: LDL-oxidation potential, LDL fatty acid composition, LDL vitamin E content and carotenes. Pearson correlation analyses tested the correlations between LDL-oxidation potential and LDL fatty acid composition and LDL antioxidants. Differences with probability values < 0.05 were considered significant. Probability values < 0.1 are also reported.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Four subjects did not complete the study due to personal conflicts. Thus, 22 subjects (9 male and 13 female) completed the study, and serum lipid analyses were performed using data from these subjects. The oxidation analyses were performed using data from 20 subjects (9 male and 11 female), because data could not be obtained from two subjects due to scheduling problems and sample loss in the laboratory.

The macronutrient profile of the five experimental diets was analyzed chemically to verify the computer estimations (Table 1) . All of the diets were similar in carbohydrate, protein and total fat content, with the exception of the Step II diet, which was higher in carbohydrate (59% of energy) and lower in total fat (25% of energy) than the other diets. The average American diet was highest in saturated fat (16% of energy) compared with 7% (Step II, olive oil, peanut oil) and 8% (peanuts plus peanut butter) in the other diets. The olive oil, peanut oil and peanuts plus peanut butter diets were enriched in MUFA, providing 17–21% of energy/d. The percentage of PUFA varied from 6 to 10% of energy/d among all test diets.

The average American diet tended to cause the shortest to LDL-oxidation lag time compared with the Step II, olive oil and peanuts plus peanut butter diets (P 0.1; Table 2 ). The olive oil diet resulted in a lower rate of LDL-oxidation than the average American, peanut oil and peanuts plus peanut butter diets (P < 0.05). No significant differences due to diet were observed in the amount of total conjugated dienes produced.

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

The faster rate of LDL-oxidation observed after consumption of the average American, peanut oil and peanuts plus peanut butter diets was associated with a greater LDL PUFA content. Rate of oxidation was significantly correlated with LDL 18:2 (r = 0.22; P 0.03) and the ratio of LDL 18:2 to 18:1 (r = 0.31; P 0.002). Other studies have shown that LDL 18:1 and 18:2 are major determinants of the rate of LDL-oxidation (40) and have also demonstrated a positive correlation between rate of oxidation and LDL 18:2 (5) , as well as an inverse association between oxidation rate and the ratio of LDL 18:1 to 18:2 (6) . Thus, the increased rate of LDL-oxidation observed after consumption of the average American and peanut diets compared with the olive oil diet was reflective of an increased amount of substrate available for oxidation in vitro. However, because the LDL particle must first be depleted of its antioxidants before oxidation can proceed, lag time may be a more relevant indicator of oxidation status in vivo than the rate of oxidation. One study reported a strong relationship (r = 0.68) between oxidative lag time and the proportion of an oxidatively modified plasma LDL in total LDL (41) . In contrast, rate of conjugated diene formation was not related to initial content of the oxidatively modified LDL. Thus, in vitro oxidation of LDL may reflect LDL oxidative status in vivo. However, additional studies are needed to determine the relationship between LDL oxidative susceptibility in vitro and atherogenesis.

There was no effect of dietary treatment on the amount of conjugated dienes produced, although a negative correlation between LDL 18:1 and conjugated diene formation was observed (r = -0.25; P 0.01). Some studies also have demonstrated a greater production of conjugated dienes after consumption of a high PUFA diet compared with a high MUFA diet (5 ,40 ,7) . That the proportion of PUFA in LDL isolated from subjects consuming the average American and peanut diets was the same could explain the similar conjugated diene formation response.

We recognize that differences in LDL oxidative susceptibility because of dietary treatment were small and not always significant and that additional studies are need to corroborate these results. However, the results seem to indicate important trends that may be of physiological importance. Better in vivo markers of LDL oxidation are needed to clearly elucidate the effects of dietary treatment on LDL oxidation and risk of CHD. It is important to note that the proportions of MUFA and PUFA in the four blood cholesterol-lowering diets had little impact on LDL oxidative susceptibility, indicating that various sources of MUFA (in addition to olive oil and canola oil) may be incorporated into a blood cholesterol-lowering diet.

Although this study was not designed to identify the mechanisms by which the peanuts and peanut butter, Step II and olive oil diets may protect LDL against the initiation of oxidation, it has been suggested that an increased consumption of dietary antioxidants might act synergistically with alterations in LDL fatty acid composition to affect LDL oxidative resistance (23) . Possibly, antioxidants present in low fat diets rich in fruits and vegetables, or antioxidants associated with peanuts, peanut butter, peanut oil and olive oil, could exert their individual and combined effects on LDL-oxidative status. For example, in the peanut diets, vitamin E could have exerted a protective effect by working in combination with other antioxidants, such as resveratrol, a compound found in both red wine and peanuts that has been shown to inhibit LDL-oxidation in vitro (42 ,43) . It would be interesting to measure changes in other plasma and LDL antioxidants, such as resveratrol, in controlled dietary studies.

Combined supplementation of various antioxidants (-tocopherol, ß-carotene and ascorbate) has been shown to increase lag time (10 ,44) and decrease the rate of LDL-oxidation (10) , but the individual effects of such antioxidants are not entirely clear. Of the antioxidants investigated, vitamin E is thought to have the strongest effect on lag time (10 ,13) . In our study, the vitamin E content of peanuts, peanut butter and peanut oil was not great enough to significantly increase LDL vitamin E levels. In addition, we found no correlation between LDL vitamin E content and lag time. This is not surprising because studies demonstrating a correlation between plasma and LDL -tocopherol concentrations and lag time involved supplementation of vitamin E in relatively high doses (12 ,13 ,44) .

Some studies have shown that ß-carotene inhibits LDL-oxidation (45 ,46) , whereas other studies have not demonstrated this effect in vitro (47 ,48) . We quantified various carotenoids (lutein, ß-cryptoxanthin, lycopene and ß-carotene) because of the large portions of fruits and vegetables that were included in the experimental diets, particularly the Step II diet. Although we did observe differences in amounts of LDL carotenoids because of dietary treatment, it remains to be seen whether these effects are of biological importance. Also, because only one carotenoid (lutein) was inversely correlated with one parameter of oxidation (rate), the physiological importance of this finding remains to be established. In contrast to our results, one study demonstrated that LDL enriched in lutein actually enhanced oxidation (37) . Also, in one study in which LDL was enriched with lutein, lycopene and ß-carotene in vitro, only ß-carotene inhibited LDL-oxidation (46) . Clearly, the effects of various carotenes on LDL-oxidation deserve further study.

In summary, the purpose of this study was to evaluate the effects of four blood cholesterol-lowering diets on LDL oxidative resistance. Elevated blood cholesterol levels (total and LDL-cholesterol) are risk factors for CHD, and oxidation of LDL is thought to contribute to the development of atherosclerosis. One potential method to assess the effects of dietary treatment on LDL-oxidative status is to measure the susceptibility of LDL to oxidation in vitro. Although better methods are needed to assess the effects of dietary treatment on in vivo LDL-oxidation, the results of our study suggest that various blood cholesterol-lowering diets, including both lower-fat and higher-fat (high MUFA) diets, may also decrease LDL oxidative susceptibility, and thereby contribute to a decreased risk of CHD.

	FOOTNOTES

 
¹ Presented at the Experimental Biology Meeting April 18–22, 1998, San Francisco, by [Morgan, R. L., Etherton, T. D., Pearson, T. A. & Kris-Etherton, P. M.(1998)Effects of diets high in peanuts-peanut butter and peanut oil on the susceptibility of LDL to oxidative modification. FASEB J. 12: A649].

² Supported by the Peanut Institute (Albany, GA) and National Institutes of Health Grant HL 49879.

⁴ Abbreviations used: LDL, low density lipoprotein; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; CHD, coronary heart disease; HDL, high density lipoprotein.

Manuscript received October 13, 2000. Initial review completed November 22, 2000. Revision accepted March 8, 2001.

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