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Human Nutrition and Metabolism

(n-3) Fatty Acid Supplementation in Moderately Hypertriglyceridemic Adults Changes Postprandial Lipid and Apolipoprotein B Responses to a Standardized Test Meal¹

Lesley F. Tinker^*,,3, Elizabeth J Parks, Stephen R. Behr^**, Barbara O. Schneeman^*, and Paul A. Davis²

^* Division of Clinical Nutrition and Metabolism, Department of Internal Medicine, School of Medicine and Department of Nutrition, College of Agricultural and Environmental Sciences, University of California, Davis, CA 95616 and ^** Medical Nutrition Research and Development, Ross Products Division of Abbott Laboratories, Columbus, OH 43215

²To whom correspondence should be addressed.

	ABSTRACT

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The effects of (n-3) fatty acids on the postprandial state were investigated by monitoring the alimentary responses to identical test meals fed to adults [n = 11; fasting triacylglycerol (TG) 2.55 ± 0.24 mmol/L; mean ± SEM] after a self-selected diet baseline period (BLP) and then after a 6-wk (n-3) fatty acid period (FOP) [~5.2 g (n-3) fatty acids] and a 6-wk control oil period (COP) administered in random order. Samples were drawn immediately prior to the test meal (time 0) and then hourly from 2 to 6 h postmeal. Postprandial plasma triacylglycerol (TG) and TG-rich lipoprotein (TRL) TG apo B48, and B100 absolute concentrations were significantly lower after FOP than after COP or BLP, while plasma cholesterol was unchanged. Normalizing the results as increments over time 0 eliminated the diet effect on all but plasma TG. Time remained a significant effect for plasma TG, TRL TG, and TRL TC. Finally, only absolute TRL B48 and absolute and incremental plasma TG concentrations displayed significant time-diet interactions. These results suggest that postprandial TRL apo B reductions are likely caused by (n-3) fatty acid suppression of both hepatic and intestinal apoB secretion/synthesis. Altered TRL metabolism, i.e. changes in postprandial TG, cholesterol, apo B48, and increase in LDL particle size, may represent an additional mechanism for the reduced heart disease risk associated with fish [(n-3) fatty acid] consumption.

KEY WORDS: • humans • (n-3) fatty acids • apolipoprotein B • triacylglycerol rich lipoproteins • postprandial lipemia

	INTRODUCTION

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The study of risk factors for cardiovascular disease has focused on the concentration and composition of plasma lipoproteins and lipids present during the fasting state. However, the fed state represents a major portion of the body's metabolic time, and a typical American eating pattern results in an alimentary or postprandial state in excess of 18 h/d. Further, studies have linked alterations in postprandial lipemia with coronary vascular disease (Groot et al. 1991 , Patsch et al. 1992 , Uiterwaal et al. 1994 , Zilversmit 1995 ). Dietary components alter the type and magnitude of postprandial lipemia. For example, both Cohen (1988a and 1988b) and Chen et al. (1993a and 1993b) have reported that increased dietary carbohydrate content elevated triacylglycerol (TG)⁴ concentration during postprandial lipemia. Harris et al. (1993 and 1998) as well as Weintraub et al. (1998) have reported that dietary fats containing different fatty acids alter the extent and character of postprandial lipid metabolism. Chronic ingestion of fish oils [(n-3) fatty acids] by normal human volunteers dramatically reduced postprandial lipemia produced by a fatty meal (Harris et al. 1988a ). Likewise, chronic feeding of both (n-3)and (n-6) fatty acids reduced the level of postprandial lipemia that occurs in response to a meal containing other fatty acids. Williams et al. (1992) have reported that moderate (n-3) fatty acid supplementation reduced postprandial triacylglycerol response during the 210-min period following a standard early morning meal. They also reported that fish oil supplementation eliminated the expected postprandial triacylglycerol peak in response to an evening meal when fed to nonfasted subjects.

The intake of fish oil either as oil or as fish was associated with a decreased risk of coronary heart disease, although fish consumption as a means of preventing or reducing coronary heart disease has recently been challenged (Ascherio et al. 1995 , Connor and Connor 1990 ). Our study was designed to investigate the effect of chronic (n-3) fatty acid intake, as a fish oil supplemented formula, on both fasting and postprandial plasma lipid and lipoprotein metabolism in a mixed population of moderately hypertriglyceridemic adults. We hypothesized that chronic consumption of fish oil could alter the assembly and secretion of lipoproteins and thus affect the composition and concentration of postprandial lipoproteins. The objectives of the present study were twofold: 1) to determine if fish oil supplementation, which lowers fasting TG, would alter LDL composition and particle size and 2) to characterize and quantitate the effect of the chronic or background diet (fish oil, control, or baseline) on the postprandial concentration, and temporal behavior, of plasma lipids and apo B species in response to a standardized test meal. Using a cross-over feeding design, we approached these questions by examining the effects of consuming an (n-3) fatty acid-containing liquid supplement compared to the same supplement containing monounsaturated fatty acids. We characterized changes in both fasting lipid variables and postprandial lipid response to identical, standardized test meals at the beginning of the study, the end of the first supplement period, and then again at the end of the second supplement period.

	MATERIALS AND METHODS

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Healthy male or female volunteers 21–65 y of age with type IIb or IV hypertriglyceridemia (plasma TG levels >1.7 mmol/L, plasma HDL levels <1.0 mmol/L) and not severely overweight, defined by body mass index (BMI) (kg/m) (BMI < 31.1 male; BMI < 32.3 female) were recruited (Abraham et al. 1983 , Van Itallie 1985 ). The clinical aspects of the study were reviewed and approved by the institutional review board of the University of California, Davis. All subjects gave written, informed consent for participation in the study. Potential volunteers were excluded if they were taking lipid lowering medications, had diabetes, glucose intolerance, or hyperinsulinemia or were allergic to fish or casein. Volunteers were recruited from the Cardiac Risk Reduction Clinic, University of California, Davis Medical Center; the student health facility at the University of California, Davis; local family practice physicians; and by word-of-mouth. Sixty-nine persons responded to our recruitment efforts. Eighteen persons met the study criteria and started the study; fasting data are presented for 12 persons because five subjects withdrew from the study, and one person's baseline plasma triacylglycerol level dropped below the study criteria. Subject plasma triacylglycerol concentrations at baseline period (BLP) were 2.55 ± 0.24 mmol/L (mean ± SEM) and HDL concentrations were 0.76 ± 0.06 mmol/L. Of the enrolled subjects, one smoked cigarettes (~10/day), one had had a prior myocardial infarction, one was taking an antihypertensive medication (Atenolol), one routinely took vitamin-E (800 mg/d) and four persons were taking aspirin up to 325 mg/day. All subjects had been at their previous body weight for at least 6 mo. Body mass index at baseline ranged in females from 22.7–32.0 (mean 29.1 ± 2.1) and in males from 24.0–28.6 (mean 25.8 ± 0.6). Ethnic backgrounds included two Asian, one Mexican American, one with part Native American ancestry, and eight non-Hispanic white.

Experimental protocol.

Upon entry into the study, subjects were randomly assigned to one of two treatment sequences. All volunteers were trained with respect to the protocol requirements during the 2–3 wk run-in period (BLP), which preceded the two 6-wk experimental blocks. Volunteers were free living and maintained their usual lifestyle, eating, and exercise habits. Their energy intake was adjusted downward to accommodate the energy supplied in the liquid supplements. Biweekly, in-person or telephone contact was maintained between study personnel and subjects. Compliance with the study protocol was evaluated by a variety of approaches. Consistency of nutrient intake was evaluated by 24-h food records and food frequency questionnaires. Subjects completed 24-h food records during the entire study period; 7 d of food records at the conclusion of baseline (BLP), control (COP), and fish oil periods (FOP) were analyzed (Nutritionist lll, version 7.2, N-Squared Computing, Silverton, OR) for energy, carbohydrate, protein, fat, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), cholesterol, -tocopherol, and dietary fiber. Data are 7-d averages. The two experimental formulas were identically packaged and identified solely by code number. Consumption of the experimental formulas was verified based on changes in the fatty acid composition of LDL. Maintenance of body weight was evaluated; initial weight was measured at the screening visit and every 2–3 wk subsequently throughout the study. Height was measured once at the screening visit. Measures taken during the BLP were averaged to provide one measure for BLP; the same was done to provide a single weight and body mass index measure for COP and FOP blocks.

The fish oil as well as the control oil supplement was a homogenous, vanilla flavored liquid containing, in the case of the fish oil, 13.2 g fish oil [3.7 g EPA, 1.5 g DHA], or in the case of the control oil, an isocaloric control formulation containing 13.8 g monounsaturated fat source (8.9 g high oleic safflower and soy oil)]. In addition to the oil, both liquids contained 9.9 g protein, 19.7 g carbohydrate, and 3.4 g dietary fiber. Both liquids were formulated and supplied by Ross Laboratories (Columbus, OH) with the use of a commercially available formulation (Glucerna^TM) as basis and differed only in their fatty acid composition [64% 18:1 (n-9), 19% 18:2 (n-6) fatty acids in control oil versus 28.2% 20:5 (n-3), 11.6% 22:6 (n-3) fatty acids in fish oil], while all other nutrients remained the same. Vitamin E (25 mg -tocopherol) was added to each bottle of both formulas to prevent a decline in subjects' vitamin E levels, as had been reported in other studies (Meydani 1992 ).

Postprandial experimental sessions.

At the conclusion of BLP, COP, and FOP study periods, each volunteer consumed an identical test meal after a 14-h, overnight fast. The test meal consisted of white bread, hard boiled egg, cooked oatmeal, whole milk, margarine, peanut butter, jelly, and orange juice, and the energy content of the meals was adjusted by sex (3202 kJ for males and 2587 kJ for females). The test meal calculated nutrient composition was 14% energy from protein, 43% energy from carbohydrate, and 43% energy from fat, with a ratio of 0.8:1 between polyunsaturated and saturated fatty acids (Nutritionist III version 7.2; N-Squared Computing). The orange juice was supplemented with 133 IU vitamin A per kg subject weight (40 µg retinol; Aquasol A Drops, 5,000 USP units/0.1 mL; Rorer Pharmaceuticals, Fort Washington, PA).

Blood collection and sampling scheme.

Prior to the test meal, each subject had an indwelling antecubital vein catheter (patency was maintained with a normal saline drip) inserted and a 0 h blood sample drawn. They were then presented with the test meal and allowed 20 min to consume it. At 20 and 40 min and 1, 2, 3, 4, 5, and 6 h after the presentation of the meal, blood samples were collected into EDTA-containing tubes (final concentration 1 g EDTA/L blood) via the indwelling catheter and placed on ice. During the postprandial experimental sessions, volunteers were allowed to drink water and engage in reading, talking, watching movies, and sleeping.

Biochemical analyses—Plasma, TRL, and LDL lipids.

Plasma was separated from chilled whole blood by centrifuging at 1200 x g for 20 min. Plasma aliquots were frozen at -20°C for later analysis of triacylglycerol, total cholesterol, HDL-cholesterol, apo Al, apoB, glucose, insulin, and retinyl esters. The triacylglycerol rich fraction (TRL), i.e. chylomicrons and VLDL in plasma, was separated from fresh plasma by density ultracentrifugation (d < 1.0063 kg/L, 18 h at 172,000 x g) as previously described (Lindgren 1975 ). TRL aliquots were frozen at -20°C for later analysis of triacylglycerol, cholesterol, and retinyl esters.

Plasma and TRL triacylglycerol, total cholesterol, and HDL-cholesterol analyses were performed in the University California Davis Lipid Assay Laboratory (Centers for Disease Control and Prevention/National Heart, Lung, and Blood Institute lipid standardization program number LSP-206) using a Gilford Impact 400E Clinical Chemistry Analyzer (Corning, Oberlin, OH) and Ciba Corning reagents. LDL cholesterol was determined by calculation (Friedewald et al. 1972 ).

Plasma apo A1 and B were analyzed in the University California Davis Lipid Assay Laboratory by automated rate immunonephlometry on a Beckman Array Protein System (Beckman Instruments, Brea, CA) using reagents, calibrators, and controls supplied by Beckman. Plasma glucose was analyzed enzymatically (Glucose Trinder Reagent; Ciba Corning) in the University California Davis Lipid Assay Laboratory (Trinder 1969 ). Plasma insulin was measured by single antibody RIA using polyethylene glycol to separate antibody-bound from free insulin (Desbuquois and Aurbach 1971 , Yalow and Berson 1960 ). Insulin tracer (125I-labeled, 70 Tbq/mmol), human insulin standard, and insulin antibody were obtained from Amersham (Arlington Heights, IL), Novo Nordisk (Novo Nordisk Immunochemical Department, NovoBiolabs, Wilton, CT) and Radioassay Systems Lab (Carson, CA), respectively.

Retinyl ester determination was done as described by van Kuijk et al. (1985) . Immediately prior to extraction, plasma samples were spiked with retinyl heptadecanoate as an internal standard and extracted with hexane/water. The hexane layer lipid extract was dried under nitrogen, redissolved in a minimal amount of hexane, and a 20 µL sample analyzed on a Shimadzu LC600 HPLC equipped with a SupelcoSil LC-18 (5 µm, 25 cm x 4.6 mm) column (Shimadzu Scientific Instrument, Columbia, MD). The eluent was 70% acetonitrile, 10% methanol, 20% 2-propanol, and 0.01% ammonium acetate flowing at 2 mL/min, and the eluting peaks were detected at 325 nm and quantitated using a Shimadzu SPD 6AV detector/integrator.

The concentration of apo B48 and apo B100 in the TRL fraction (d < 1.0063) was determined by denaturing SDS-PAGE as described by Schneeman et al. (1993) . Briefly, the TRL were delipidated and electrophoresed in the presence of 2% SDS on a 3–10% gradient polyacrylamide gel. As B48 and B100 are present in differing concentrations, two different sized sample aliquots were electrophoresed in parallel to allow for the quantitation of both proteins. After staining with Coomassie Blue, the gels were scanned (Hoefer gel scanner, Hoefer, San Francisco, CA), and peak heights were converted to protein concentration based on a standard curve relating peak height to apo B48 and B100 concentration obtained using a plasma-derived standard with known apo B48 and B100 concentrations (Schneeman et al. 1993 ).

For lipoprotein fatty acid analysis, total plasma LDL (d 1.0063–1.063 kg/L) was isolated by sequential ultracentifugation as detailed by Lindgren (1975) . The fatty acid content of the LDL was determined essentially as described by Frankel et al (1994) . Briefly, LDL lipids were extracted with chloroform-methanol and fatty acid species, and the content was determined by gas chromatographic analysis of the fatty acid methyl esters obtained by transesterification.

LDL particle size was analyzed nondenaturing, polyacrylamide gradient, gel electrophoresis as described by Rainwater et al. 1992 ). Samples were obtained from plasma that had been subjected to ultracentrifugation at d = 1.0063 kg/L for 18 h at 4°C. The top fraction containing triacylglycerol rich lipoproteins was removed, and the infranatant (d >1.0063 kg/L) collected and frozen for LDL particle size analysis. The infranatant (density >1.0063 kg/L) containing the LDL was applied to a 2–16% gradient gel and electrophoresed under nondenaturing conditions for 24 h at 125 V constant voltage at 4–8% C in Tris-borate running buffer. The gels were fixed and stained for lipid with Oil Red O dye and were scanned using a scanning densitometer. Samples from an individual subject from each of the three dietary periods were analyzed on a single gel along with a reference sample, which contained LDL of size 27.1 nm, to determine the relative differences in migration distances among the treatment periods.

Statistical analyses.

For fasting values, repeated measures ANOVA (SAS 6.07; PROC: GLM) with one between factor (sequence) and one within factor (diet) was used to compute the probability of the F statistic ~ 0 for the model. Single degree of freedom planned F statistics (orthogonal contrasts) were used to test fish oil versus control and fish oil versus ~ 0 baseline (Winer 1971a and 1971b ). Data are presented as means ± SEM. For postprandial studies, repeated measures ANOVA (BMDP 2V, 1990, BMDP Statistical Software, Los Angeles, CA) with 1 between factor (sequence) and 2 within factors (diet and time) was used to compute the probability of the F statistic ~ 0 for the model. When diet but not time was a significant factor, fasting values were used for means comparisons by contrasts. When diet and time were both significant factors, a single number representing postprandial values was calculated, and means comparisons by contrasts were conducted as with the fasting value analyses.

	RESULTS

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Dietary response.

No differences in energy intake, percentage energy from protein, percentage energy from alcohol, dietary cholesterol, dietary fiber, or percentage fat from saturated fat were noted among the three dietary periods (Table 1). Fat intake as percentage energy increased during COP and FOP relative to BLP with a concomitant decrease in carbohydrate intake during COP and FOP compared to BLP. Vitamin E intake increased during COP and FOP compared to BLP, as expected with the vitamin E-supplemented formula. Polyunsaturated fatty acids as a percentage of fat intake were higher during the FOP compared to COP or BLP, attributable to the high polyunsaturated fat content of the fish oil-containing formula. Monounsaturated fatty acids as a percentage of fat intake were higher during the COP than during the FOP, which was attributable to the high monounsaturated fat content of the oleic oil-containing formula.

Table 2

After each dietary period, the postprandial response to a test meal was examined. Following the FOP, postprandial plasma triacylglycerol concentrations (Fig. 1 A) were significantly lower than the concentrations following the COP and BLP. To more readily compare results across the different diet periods, the results were expressed as increments over baseline by subtracting the fasting TG concentrations obtained at the start of each test meal session (time 0) from the values obtained postprandially (2, 3, 4, 5, and 6 h). The calculated increments are shown in Table 3 . Using either the absolute plasma TG concentration or the incremental values, repeated measures ANOVA revealed significant overall effects for diet, time, and time x diet interactions. In contrast to changes in TG, plasma total, HDL and LDL cholesterol concentration (LDL and HDL data not shown), or increments showed no differences either among the different dietary periods or in the time course of postprandial lipemia (Table 4).

View larger version (20K): [in this window] [in a new window]   Figure 1. Postprandial lipid responses in humans to ingestion of a standard test meal after the baseline, fish oil, or control oil periods. The results are presented as mean (n = 11) ± SEM. * indicates a significant difference between the fish oil diet period analyte level and its level at the same time point for the other two diet periods (i.e., control oil and baseline). A solid symbol indicates that this value is significantly (P < 0.05) different from time 0 value for that particular dietary group. The significant (P < 0.05) main effects are noted on each panel. (A) Plasma total triglyceride. (B) Plasma triacylglycerol-rich lipoproteins (TRL) triglyceride. (C) Plasma TRL triglyceride cholesterol.

The postprandial TRL cholesterol response showed a pattern similar to TG in that both diet and time were significant. TRL cholesterol concentration increased significantly during the postprandial period, and at all times the values after FOP were significantly lower than after the BLP and COP (Fig. 1 C). Expressed as increments, the changes in postprandial TRL cholesterol showed a significant time effect, but no significant overall diet effect. The interaction of time x diet tended to be significant (P = 0.09) because of different patterns of response among the dietary treatments (Table 3) .

The distribution of total cholesterol between TRL and other lipoprotein fractions was altered by the dietary fatty acid supplements. The ratio of TRL Cholesterol (TRLChol) to total cholesterol (TChol) differed significantly due to both diet and time. The ratio was significantly lower in fasting subjects after the FOP than either the COP or BLP. During postprandial lipemia, the TRLChol/TChol ratio did not shift significantly after BLP. In contrast, both the COP and FOP TRLChol/TChol ratios increased significantly compared to their respective fasting ratios. And this difference was significant from time 0 after the COP at 2 and at 3 h after FOP (Table 4) .

The TRL apo B100 postprandial concentration was significantly lower after FOP than after either COP or BLP at all time points (Fig. 2 A). However, neither time nor time x diet interaction terms were significant. The postprandial TRL apo B100 expressed as increments showed no significant diet, time, or time x diet interactions (data not shown).

View larger version (17K): [in this window] [in a new window]   Figure 2. Postprandial apolipoprotein B48 and B100 responses in humans to ingestion of a standard test meal after the baseline, fish oil, or control oil periods. The results are presented as mean (n = 11) ± SEM. * indicates a significant difference between the fish oil diet period analyte level and its level at the same time point for the other two diet periods (i.e., control oil and baseline). A solid symbol indicates that this value is significantly (P < 0.05) different from time 0 value for that particular dietary group. # indicates a significant difference between the control oil/fish oil mean at that time. The significant (P < 0.05) main effects are noted on each panel. (A) The TRL apolipoprotein B100 (B) TRL apolipoprotein B48. (C) TRL apolipoprotein B48 to TRL apolipoprotein B100.

The ratio of hepatically derived apo B (i.e., TRL B100) relative to intestinally derived apo B (i.e., TRL B48) as a function of time postprandially is reported in Fig. 2C . The ratio varied significantly by time postprandial, and the time x diet interaction term tended to be significant (P = 0.098). The interaction is reflected in the fact that the ratio did not differ at fasting, but did differ significantly among the dietary treatments after the test meal. And the ratio tended to be lower after the FOP than the other diet periods (P < 0.07).

In addition to the use of apo B48 and B100 as markers of the intestinal and hepatic contribution to the postprandial lipemia, test meals contained retinol, which is packaged as retinyl ester and secreted in the chylomicrons. Retinyl palmitate levels showed the same temporal patterns as B48, which also indicates intestinal lipoprotein secretion and postprandial concentrations were significantly lower after FOP (data not shown).

	DISCUSSION

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Numerous studies have documented that long-chain (n-3) fatty acids, such as those present in fish oils, reduce fasting plasma triacylglycerol and VLDL in normal as well as hypertriglyceridemic subjects (Agren et al. 1996 , Albert et al. 1998 , Bergeron et al. 1995 , Harris 1996 , Lairon 1996 , Singh et al. 1997 ). Consistent with these findings, the present study demonstrates that consumption of (n-3) fatty acids in a liquid dietary supplement significantly reduced fasting triacylglycerol and VLDL concentrations in a mixed population of adult hypertriglyceridemics. Compliance with the study protocol was verified not only by these reductions, but also by the enrichment of (n-3) fatty acids in plasma LDL as previously reported (Frankel et al. 1994 ). These data also indicated increased propanal production upon in vitro oxidization of the LDL isolated from subjects in this study, another characteristic of (n-3) fatty acid enrichment (Frankel et al. 1994 ). Further, we observed no changes in fasting plasma glucose or insulin, consistent with the report of Williams et al. (1992) .

The changes in plasma TG, TC, and apolipoprotein B caused by differences in the fatty acid compositions of the dietary supplements provide insight into the potential mechanism(s) by which (n-3) fatty acids alter TG metabolism. Fasting TRL apo B100 absolute concentrations were reduced to roughly half of those found after either the control oil or baseline periods. This reduced concentration of TRL apo B100 persisted throughout the postprandial period; however, when the data were examined as increments above the fasting concentration, the overall diet effect was not significant. These data, combined with the absence of an overall postprandial time effect, indicate that TRL apo B100 concentration is not responsive to acute input of dietary fat (i.e., individual meal). However, the changes noted in response to differing fatty acid supplements indicate that TRL apo B100 concentration does respond to long-term (dietary) fatty acid content. In other studies, conducted in young male subjects with relatively low fasting TG concentrations, a postprandial accumulation of hepatic-derived TRL was reported (Bergeron and Havel 1995 , Schneeman et al., 1993 ). In addition to low fasting TG levels, a high saturated fatty acid intake in the background or chronically consumed diet may have contributed to this accumulation (Bennett et al. 1995 , Bergeron and Havel 1995 , Bravo et al. 1995 ). In contrast to the lack of change in apo B100, apo B48 TRL concentration showed significant overall effects for diet, time, and time x diet interactions when expressed as absolute levels. When expressed as increments, TRL apo B48 increments were lower after the FOP than after COP or BLP, and this effect was significant at each postprandial time point. Taken together, these data indicate that, as expected, TRL apo B48 levels are responsive to acute dietary input (i.e., the test meal) and that the TRL apo B48 response is modified by the fatty acid composition of the chronically consumed diets. Further, the variation in postprandial B48/B100 ratio over time was driven by changes in intestinal (B48) input, reflecting the initial increase then subsequent decrease of intestinal (B48) input following the meal. Interestingly, diet did not alter the ratio of hepatic (B100) to intestinal (B48) TRL at fasting (BLP: 0.023 ± 0.006; COP: 0.030 ± 0.003; FOP: 0.032 ± 0.009). Thus, despite marked differences in the fasting lipid and apolipoprotein concentrations resulting from altered dietary fatty acid composition, a mechanism appears to exist to maintain a relatively fixed ratio of intestinal and hepatic input at fasting.

In earlier studies, Harris et al. (1988a) and Weintraub et al. (1988) have argued that the lower fasting and lower postprandial triacylglycerol increases caused by fish oil feeding results from changes in postprandial lipoprotein secretion. However, these studies were done using indirect measures. In a follow-up study, Harris and Muzio (1993) demonstrated that, while fish oil reduced postprandial chylomicronemia, lipid emulsion clearance times were unaffected, suggesting no changes in plasma lipoprotein clearance related to fish oil consumption. Other studies using radioactive tracers (radioiodinated VLDL and labeled glycerol) have demonstrated that fish oil compared to safflower oil reduced daily VLDL apo B and TG production (Nestel et al. 1984 ) and that TRL clearance was not stimulated by switching to a highly polyunsaturated diet from a saturated fat diet because fractional catabolic rates were unchanged (Cortese et al. 1983 ). Moreover, given that chylomicron fatty acid composition is subject to intestinal regulation (Buhner et al. 1995 ), it appears unlikely that fish oil consumption could induce compositional changes of sufficient magnitude to dramatically alter clearance. However, other studies have reported that changing dietary fatty acids alters plasma lipid levels by affecting chylomicron clearance (De Bruin et al. 1993 , Demacker et al. 1991 ). This effect was not observed in the recent study by Bergeron and Havel (1995) , where no differences in chylomicron clearance were found. Moreover, Harris (1997) et al. recently reported, in contrast to their and other earlier reports, that (n-3) fatty acid altered lipase activity, and this effect may contribute to induced reduction in triglyceride level. However, as pointed out by Harris et al., lipase activities were investigated using a different technique, i.e., endogenous, nonheparin-stimulated lipase activities, and the utility of these measures to overall lipid metabolism remains to be established. Moreover, the conclusion that (n-3) fatty acids act to suppress hepatic secretion of apo B is further strengthened by in vitro data from Lin et al. (1995) indicating that fish oil suppresses TG secretion and apo B secretion in cultured, primary, human hepatocytes. The overall conclusion of this study, which agrees with that of Weintraub et al. (1988) , Nestel et al. (1984) , Harris et al. (1988) and Harris and Muzio (1993) , is that the major effect of (n-3) fatty acids is to suppress both hepatic and intestinal secretion of apo B. These apparent disagreements may arise from difficulties in interpreting plasma retinyl ester concentrations, particularly in light of the observations of Karpe et al. (1993 and 1995) , indicating that retinyl esters per lipoprotein particle varied markedly under the influence of the fatty acid composition of the meal. The use of retinyl esters as specific markers for intestinally derived lipoproteins was questioned (Cohn et al. 1993 ), although more recent data from Karpe and coworkers (1995) indicates that plasma retinyl ester specifically labels intestinally derived lipoproteins. The present study utilized the more definitive technique, i.e., quantitation of apo B48 and B100, to analyze the apolipoprotein B species present in the particles in the TRL fraction and thus identify the source of postprandial triacylglycerol containing particles, i.e., intestinal versus hepatic. Our study did, however, measure retinyl esters as a secondary assessment, and this gave results essentially similar to the apolipoprotein B derived data.

Suppressing hepatic synthesis or secretion of apoB by chronic consumption of (n-3) fatty acid clearly affects postprandial behavior of the triglyceride-rich lipoprotein apo B species. The reduced, incremental response of apo B48 after the FOP provides further evidence that intestinal packaging of absorbed dietary fat is strongly influenced by the enterocyte's long-term milieu (i.e., background diet), which is in agreement with the report of Bergeron and Havel (1995) . In the absence of apparent changes in plasma clearance, along with the test meals being identical for all periods, the lower TRL B48 incremental responses after FOP, when combined with no overall differences because of diet on postprandial TRL TG increments, argues that smaller amounts of apo B48 are secreted to package relatively unchanged amounts of secreted lipids. Consequently, intestinally derived B48 TRL secreted postprandially after the FOP were apparently larger particles relative to those found after either COP or BLP. Further, based on compositional data, VLDL, or hepatically-derived TRL, from the FOP were apparently smaller than from after the COP or BLP (Redgrave and Carlson 1979 ). These differences in TRL particles may alter their interactions with lipases and be reflected in the increase in LDL particle size noted in this study (Brunzell et al. 1973 , Cortner et al. 1992 ). Relatively smaller VLDL, as observed after FOP, would compete poorly with large TRL particles (i.e., the B48 TRL) for lipoprotein lipase during postprandial lipemia (Brunzell et al. 1973 ). Differences in TG content of apo B100 TRL were associated with conversion to either a larger, less dense LDL or a potentially atherogenic, small, dense LDL (Feingold et al. 1992 , Packard and Shepherd 1997 ).

In the current study, fish oil feeding induced changes in postprandial TRL metabolism that have potentially important consequences for heart disease via the linkage of TRL to reverse cholesterol transport. TRL are linked with reverse cholesterol transport because gram quantities of cholesterol, primarily as cholesterol ester, move from HDL to TRL per day in humans (Mann et al. 1991 ). Although Lassel et al. (1998) have suggested that postprandial-phase TRL do not increase cholesterol movement and that the bulk of CE transfer occurs from HDL to LDL, their conclusions are problematic because they used a two-meal model along with an assay system, which ignores differences in metabolism/turnover between acceptors. Moreover, the report of Chung et al. (1998) highlights the extent to which TRL, particularly chylomicrons via cholesteryl ester transfer protein (CETP) and lecithin-cholesterol acyl transferase-mediated events, move cholesterol between various tissues and plasma acceptors. In our study, the postprandial increment in TRL TG was lower after fish oil feeding than after the control or baseline period, yet the TRL cholesterol increment was not reduced. This observation suggests that on a relative basis (n-3) fatty acids enhanced cholesterol movement into the TRL fraction during FOP. Further, CETP mediates cholesterol ester transfer to larger, more triacylglycerol-rich particles (Mann et al. 1991 , Karpe et al. 1993b ), thus transfer of CE to larger B48 TRL should be favored. This type of transfer could be important for cholesterol homeostasis because B48 TRL cholesterol is restricted to hepatic uptake by receptor processes that are insensitive to hepatic cholesterol content, whereas uptake of B100 TRL cholesterol is regulated by tissue cholesterol content and not restricted to hepatic uptake but occurs in peripheral tissues as well (Dietschy 1998 ).

In summary, we have examined in the same subjects, the fasting and postprandial plasma lipid and lipoprotein response(s) to identical, standardized test meals after dietary supplementation with a fish oil based formula and compared those responses to the postprandial plasma lipid and lipoprotein response(s) to the identical test meal after dietary supplementation with a similar product formulated with predominantly monounsaturated fatty acids (control oil). In addition, a further comparison was obtained by determining the postprandial plasma lipid and lipoprotein response(s) to identical, standardized test meals during each subject's freely feeding, self-selected diet (baseline). Fish oil reduced fasting plasma TG concentration by over 35% and increased fasting LDL size without altering plasma insulin or glucose levels. Further, postprandial lipemia evoked by the identical standardized test meals after each dietary period indicated that fish oil feeding resulted in marked reductions in the absolute concentration of TG as well as both TRL apolipoprotein B species along with changes in TRL cholesterol. Fish oil feeding may reduce atherogenesis by reducing hepatic production of atherogenic cholesterol-enriched remnant particles; enhancing production of larger, less atherogenic LDL particles; and altering plasma cholesterol dynamics. All of which might contribute to lower heart disease risk associated with fish consumption.

	ACKNOWLEDGMENTS

 
The authors would like to thank Diane Richter and Rita Tezanos-Pinto for their expert technical assistance.

	FOOTNOTES

 
¹ Supported in part by the NIH Clinical Nutrition Research Unit (DK 35747) and a grant from Ross Products, Columbus, Ohio.

³ Current address: Women's Health Initiative Clinical Coordinating Center, Fred Hutchinson Cancer Center, Seattle, WA.

⁴ Abbreviations used: CETP, cholesteryl ester transfer protein; EPA, eicosapentaenoic acid; TC, total cholesterol; TChol, total cholesterol; TG, triacylglycerol; TRL, triacylglycerol-rich lipoproteins; TRLChol, TRL Cholesterol.

Manuscript received September 29, 1998. Initial review completed November 3, 1998. Revision accepted March 2, 1999.

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