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The Journal of Nutrition Vol. 128 No. 7 July 1998,
pp. 1104-1113
Center for Cardiovascular Disease Control, Department of Health and Clinical Sciences, University of Massachusetts-Lowell, Lowell, MA 01854 and * Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111
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ABSTRACT |
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Abstract
Introduction
Methods
Results
Discussion
References
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To examine the mechanism(s) underlying the cholesterolemic response to dietary cholesterol and saturated fatty acids, low density lipoprotein (LDL) metabolism was studied in two groups of cynomolgus monkeys fed diets containing 30 or 36% of total energy as fat. At each dietary fat level, the same group of monkeys was sequentially fed three dietary cholesterol concentrations as egg yolk in the following sequence: low (0.01 mg/kJ), medium (0.03 mg/kJ) and high (0.05 mg/kJ) for 30, 32 and 24 wk, respectively. Dietary polyunsaturated and monounsaturated fatty acids were the same in the two groups; the 6% difference in fat was due to the saturated fatty acids, 12:0 and 14:0. Serum total cholesterol, LDL cholesterol and LDL apolipoprotein B concentrations increased (P < 0.05) with dietary cholesterol in a dose-dependent manner in both fat groups. These elevations were the result of generally increasing LDL apolipoprotein B production rates, concomitant with reduced LDL apolipoprotein B fractional clearance at the high cholesterol intake. Serum HDL cholesterol and HDL apolipoprotein A-I concentrations were not affected in a consistent manner. These results demonstrate that cynomolgus monkeys are hyperresponsive to dietary cholesterol compared with humans, suggesting that this model may be useful in identifying metabolic and genetic predictors for hyperresponsiveness to dietary cholesterol in humans as well as assessing the metabolic heterogeneity of responses to dietary cholesterol.
KEY WORDS: dietary cholesterol · serum lipoproteins · LDL metabolism · cynomolgus monkeys
Although a reduction in the intake of saturated fatty acids and total energy from fat and dietary cholesterol is recommended by the American Heart Association in their diet-heart statement, none of these changes elicits as much public interest as does dietary cholesterol (American Heart Association 1996). Although numerous studies in humans have shown that the consumption of dietary cholesterol elicits a modest elevation in serum cholesterol concentrations (Ginsberg et al. 1994 Although the role of dietary cholesterol in regulating low density lipoprotein (LDL)5 metabolism has been well documented (McNamara 1990 Humans studies have contributed a great deal of information regarding the magnitude of the serum cholesterol response to dietary cholesterol; however, animal studies have provided most of the data relevant to the mechanisms underlying responsiveness. Studies in hamsters (Woollett et al. 1992 Even though the cynomolgus monkey is among the non-human primate species most sensitive to dietary cholesterol (Laber-Laird and Rudel 1989 Animals.
Adult male cynomolgus monkeys (Macaca fascicularis) between the ages of 5 and 8 y and weighing 5-7 kg were used in these studies, which were approved by the Institutional Animal Care and Use Committee. Animals were maintained in accordance with the guidelines of the Animal Care Committee at the University of Massachusetts-Lowell Research Foundation and the NIH guidelines (NRC 1985). Animals were given free access to food and water at all times except when food only was withheld for experimental protocols described below.
Diets and experimental protocol.
In a parallel group design, the monkeys used in this study were randomized into two groups with respect to serum total cholesterol concentrations, which averaged ~5 mmol/L for each group. The two groups were then fed isocaloric semipurified diets containing either 30% (Group 1) or 36% (Group 2) of total energy as fat. At each dietary fat level, the same group of monkeys was sequentially fed three dietary cholesterol concentrations as egg yolk in the following sequence: low (0.01 mg/kJ), medium (0.03 mg/kJ) and high (0.05 mg/kJ) for 30, 32 and 24 wk, respectively. Dietary polyunsaturated and monounsaturated fatty acids were held constant in both groups, and the 6% increase in fat was due to the addition of the saturated fatty acids 12:0 and 14:0. Animals were used as their own controls and remained in their respective dietary fat group throughout the study. The basic design of the study and the variables measured during each of the three sequential phases are shown in Figure 1. It should be noted that the two groups (30 and 36% of energy as fat) each originally contained 10 monkeys; however, 4 monkeys in the 30% energy as fat group died of causes unrelated to the treatment over the duration of the 86-wk study, thereby reducing the number of animals in that group to only 6.
Sample collection and analytical methods.
Food-deprived monkeys were sedated with 10 mg/kg ketamine-hydrochloride (Bristol Laboratories, Veterinary Products, Syracuse, NY), and blood samples were drawn from the femoral vein into tubes containing no anticoagulant. Serum was separated at 1500 × g for 20 min at 4°C; phenylmethylsulfonylfluoride (0.2 mmol/L) and N-ethylmaleimide (1.25 g/L) (Sigma Chemical, St. Louis, MO) were added as proteolytic and lecithin-cholesterol acyltransferase inhibitors, respectively.
LDL apolipoprotein B metabolic studies.
LDL (d = 1.020-1.050 kg/L) for the metabolic studies during each dietary cholesterol phase were obtained from homologous donor animals from within each diet group and isolated from plasma by density gradient ultracentrifugation (Terpstra and Pels 1988 Kinetic analyses.
Kinetic variables were calculated, assuming a biphasic exponential die-away of LDL apo B and a metabolic steady state. The radioactivity in each isopropanol-precipitated apo B sample was expressed as a fraction of the radioactivity in the sample obtained at 10 min after tracer administration. Fractional catabolic rate was calculated as previously described (Nicolosi et al. 1990 Statistical analyses.
Two-way repeated-measures ANOVA (RM-ANOVA) was used to analyze all data, the main effects of dietary cholesterol concentration and percentage of energy as fat were used to determine whether there were differences in serum lipid and apolipoprotein concentrations as well as in LDL kinetic parameters. When significant main effects were detected (P < 0.05), least-square means t tests for unbalanced designs were used to determine significance (Steel and Torrie 1980 Serum lipid, lipoprotein cholesterol and apolipoprotein B concentrations.
As expected, the magnitude of the cholesterolemic response to dietary cholesterol was not the same in all monkeys. Although the average LDL cholesterol concentration for each group increased in a dose-dependent manner during each dietary cholesterol phase, the individual increases in LDL cholesterol in the 30% energy as fat group ranged from 20 to 175% (0.01 mg/kJ vs. 0.03 mg/kJ) and from 25 to 255% (0.03 mg/kJ vs. 0.05 mg/kJ) (Fig. 2, upper panel). The individual increases in LDL cholesterol in the 36% energy as fat group ranged from
LDL apo B metabolism.
As expected, the changes in LDL apo B pool size (Table 4) after an increasing dietary cholesterol challenge at both fat concentrations closely reflected the changes in plasma LDL apo B concentrations (Table 3). At 30% energy as fat, the LDL apo B pool size when monkeys were fed both the medium and high cholesterol diets was 55% (P < 0.05) and 75% greater (P < 0.05), respectively, compared with when they consumed the low cholesterol diets. Similarly, at 36% energy as fat, the LDL apo B pool size in monkeys when fed both the medium and high cholesterol diets was significantly greater compared with when they consumed the low cholesterol diet. Additionally, when monkeys were fed the high cholesterol diet, they had significantly elevated LDL apo B pool sizes compared with when they consumed the medium cholesterol diet (Table 4).
Relationships between LDL metabolism and serum LDL cholesterol and LDL apo B.
As mentioned above, to assess the strength of the linear relationships between the serum concentrations of LDL apo B and LDL cholesterol and their respective kinetic parameters (fractional catabolic rate and production rate), the data from the 30 and 36% energy as fat groups were combined after testing for heterogeneity of slopes. As expected, serum LDL cholesterol was significantly correlated with serum LDL apo B concentrations at all three intakes of dietary cholesterol (low: r = 0.94, P < 0.0001; medium: r = 0.94, P < 0.0001; and high: r = 0.80, P < 0.0002). There were no significant relationships between LDL apo B fractional catabolic rates and the serum concentrations of LDL apo B when the low and medium cholesterol diets were consumed; however, there was a significant inverse correlation between these variables when the high cholesterol diet was consumed (Fig. 3). In addition, LDL apo B production rate was significantly correlated with the serum concentrations of LDL apo B at all three intakes of dietary cholesterol (Fig. 4).
Recent studies in humans have shown that although there is individual variability in response, cholesterol consumption results in a modest dose-dependent rise in serum cholesterol concentrations (McNamara 1995
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
and 1995, Lichtenstein et al. 1994, Schnohr et al. 1994), others have shown that dietary cholesterol has little or no effect on serum lipids (Kestin et al. 1989, Morgan et al. 1993, Vorster et al. 1992). The disparity in these studies may have been due to the considerable individual variability in the response to dietary cholesterol. An earlier meta-analysis (Hopkins 1992) suggested that the underlying explanation for the heterogeneity of the cholesterolemic response in humans was purportedly due to dietary factors such as the total and saturated fat content of the diet as well as the baseline dietary and serum cholesterol concentrations. However, a more recent meta-analysis of 128 cholesterol feeding studies in humans (McNamara 1995) concluded that although the data still show a modest dose-response increase in serum cholesterol concentrations as dietary cholesterol increases (0.07 mmol/L or 2.5 mg/dL per 100 mg of dietary cholesterol per day), the above-mentioned dietary factors play an insignificant role in the response to dietary cholesterol. It appears that genetics (McGill and Kushwaha 1995) as well as age and gender (Clifton and Nestel 1992, Cobb et al. 1993) may contribute more to the individual variability in the response to dietary cholesterol than other dietary factors.
, Spady et al. 1993), it appears that there are distinct species differences that may account for the varying degrees of responsiveness to dietary cholesterol. Species in which the liver accounts for <20% of whole-body cholesterol biosynthesis, such as the guinea pig, cynomolgus monkey, hamster and perhaps humans, appear to be less tolerant to dietary cholesterol apparently due to their inability to suppress hepatic cholesterol biosynthesis (Spady et al. 1993). Hence, alterations in LDL metabolism are likely to occur in these species as dietary cholesterol concentrations increase.
) and guinea pigs (Lin et al. 1994) fed high fat and cholesterol diets indicate that the resulting elevation in LDL cholesterol concentrations was due to the combined effects of both dietary fat saturation and cholesterol in down-regulating hepatic LDL receptors. Other studies in guinea pigs by Lin et al. (1995) demonstrated that elevated high density lipoprotein (HDL) cholesterol concentrations after the consumption of high fat and cholesterol diets were also influenced primarily by dietary cholesterol. Therefore, it appears that both serum LDL and HDL cholesterol concentrations are regulated in part by dietary cholesterol in cholesterol-sensitive species (Spady et al. 1993).
), similarities to humans, such as the variability in the cholesterolemic response coupled with large increases in LDL cholesterol with cholesterol feeding (Rudel and Pitts 1978), make this species a relevant model for studying the metabolic mechanism(s) underlying the response to dietary cholesterol (Turley et al. 1995). However, identification of the mechanism(s) underlying the observed responsiveness are necessary to establish the usefulness of the model. Therefore, in this study, we examined the response to three different dietary cholesterol concentrations (0.01, 0.03 and 0.05 mg/kJ) at 30 and 36% energy as fat by evaluating LDL kinetics in the cynomolgus monkey. Our results indicate that, in this cholesterol-sensitive monkey model, dietary cholesterol significantly affected serum total cholesterol, LDL cholesterol and apolipoprotein (apo) B concentrations in a dose-dependent manner and that these changes were due to cholesterol-induced alterations in LDL apo B fractional catabolic and production (transport) rates.
MATERIALS AND METHODS
Abstract
Introduction
Methods
Results
Discussion
References
View larger version (18K):
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Fig 1.
Diagram of the cholesterol dose response study showing the two groups of monkeys fed in a parallel design through the three dietary cholesterol phases. At each dietary fat level (30 and 36% energy as fat), the same group of monkeys was sequentially fed the three dietary cholesterol concentrations from low to high for 30, 32 and 24 wk, respectively. The dietary fat and cholesterol concentrations and the variables that were measured during each phase are shown. Monkeys were used as their own controls and remained in their respective dietary fat group throughout the study.
). As dietary cholesterol concentrations increased in each sequential phase and additional egg yolk was required, the total fatty acid content of the diet was compensated for by adjusting the quantities of the other oils, especially the MUFA-rich olive oil (see Table 1). Both groups were then sequentially fed the three concentrations of dietary cholesterol (Figure 1) in ascending order. Each monkey received ~200 g diet/d. The fatty acid composition of the diets is presented in Table 2.
View this table:
Table 1.
Composition of semipurified monkey diets
View this table:
Table 2.
Fatty acid composition of semipurified monkey diets
) and triglycerides (TG) (Bucolo and David 1973) were quantified by enzymatic methods, and HDL cholesterol was obtained after heparin-Mn2+ precipitation (Warnick et al. 1985) of VLDL + IDL + LDL. Completeness of precipitation was assessed via agarose gel electrophoresis of the supernatant (Noble 1968). VLDL + IDL + LDL cholesterol was determined by subtracting HDL cholesterol from total cholesterol. Because food-deprived cynomolgus monkeys had negligible amounts of VLDL cholesterol as determined by ultracentrifugation (data not shown), the VLDL + IDL + LDL cholesterol fraction (non-HDL cholesterol) will be referred to as LDL cholesterol for the purpose of brevity. Serum lipid assays were standardized by participation in the Centers of Disease Control and Prevention-National Heart, Lung and Blood Institute Standardization Program. LDL apo B and HDL apo A-I concentrations were measured by radial immunodiffusion as previously described (Chong et al. 1987). The intra- and interassay coefficients of variation for LDL apo B were 5.0 and 5.7%, respectively; for HDL apo A-I, they were 4.1 and 3.0%, respectively. LDL protein determinations were performed by the method of Markwell et al. (1978) with bovine serum albumin as a standard.
). Isolated LDL were dialyzed for 24 h at 4°C against 0.15 mol/L NaCl containing 0.3 mmol/L EDTA and 1 mmol/L NaN3, pH 7.0, under nitrogen. LDL purity was verified by agarose electrophoresis (Noble 1968).
as modified by Bilheimer et al. (1972). Unbound iodine was removed by eluting the sample through a Sephadex G-25M column (PD-10, Pharmacia, Piscataway, NJ) with PBS. Protein-bound radioactivity was assessed by precipitation of an aliquot of the labeled mixture with 1.2 mol/L trichloroacetic acid (TCA). Samples of the labeled 125I-LDL infusion mixture were found to be >98% TCA precipitable with <5% lipid labeling. The specific activity of the 125I-LDL preparations ranged from 3.7 to 6.1 mBq/ng protein. Butylated hydroxytoluene (10 mmol/L) was utilized during iodination to prevent potential oxidative damage to LDL. No LDL oxidation was detected after the labeling procedures, as verified by the relative mobility of labeled LDL compared with fresh LDL on agarose gels (Noble 1968).
), ketamine can induce anorexia; therefore those animals that did not resume eating within 12 h were given an enteral bolus of their regular diet to minimize any effects of extended food deprivation on steady-state kinetics.
). The fractional catabolic rate of serum apo B was subsequently determined by using the counts from the washed, precipitated apo B pellet. The supernatant fraction contained only a small portion of the total radioactivity in each aliquot and remained relatively constant throughout the study.
) by using a curve-peeling computer program in accordance with the general principles defined by Matthews (1957). Serum volume was determined by isotopic dilution from the counts at the 10-min time point. Apo B pool size was calculated as the serum volume × plasma LDL apo B concentrations. Total production (synthetic or transport) rate is equal to the fractional catabolic rate × pool size (mg/kg·d), which is equivalent to the disposal rate in the steady state as described by Slater et al. (1984).
). To assess the strength of the linear relationships between the serum concentrations of LDL apo B and LDL cholesterol and their respective kinetic parameters (fractional catabolic and production rates), the 30 and 36% energy as fat groups were combined after testing for heterogeneity of slopes. Heterogeneity was tested in an analysis of covariance, with the interaction term between the percentage of energy as fat and the particular parameters of interest (Type III sums of squares) (Littell et al. 1991). For all of the serum lipid and apolipoprotein parameters, a reduced model omitting the interaction term was indicated after appropriate testing (i.e., nonsignificant interaction term; 
= 0.05). Pearson's product-moment correlation coefficients were then used to evaluate linear relationships between variables. Homogeneity of variance was determined for all data; to normalize the data and to stabilize the variance, all raw data were transformed to log10 values before statistical analyses were performed. All data are presented as means ± SEM.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
40 to 93% (0.01 mg/kJ vs. 0.03 mg/kJ) and from 3 to 225% (0.03 mg/kJ vs. 0.05 mg/kJ) (Fig. 2, lower panel).
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Fig 2.
The serum LDL cholesterol concentration of each monkey at both 30% (upper panel; n = 6) and 36% (lower panel; n = 10) fat as total energy at each dietary cholesterol concentration. At each dietary fat level (30 and 36% energy as fat), the same group of monkeys was sequentially fed the three dietary cholesterol concentrations from low to high for 30, 32 and 24 wk, respectively. The mean ± SEM, shown below each group, is significantly (P < 0.05) greater at each level. The scale of the y-axis was kept the same in both graphs to avoid exaggerating the response in either group.
View this table:
Table 3.
Serum lipids, lipoprotein cholesterols and apolipoproteins B (apo B) and A-I (apo A-I) concentrations in cynomolgus monkeys fed three dietary cholesterol concentrations within each dietary fat level1
View this table:
Table 4.
Kinetics parameters of LDL apolipoprotein B in cynomolgus monkeys fed three dietary cholesterol concentrations
within each dietary fat level1
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[in a new window]
Fig 3.
Correlations between apolipoprotein B-100 (apo B-100) fractional catabolic rate and serum apo B-100 concentration when cynomolgus monkeys were fed the low (0.01 mg/kJ), medium (0.03 mg/kJ) and high (0.05 mg/kJ) cholesterol diets; p/d, pools/day.
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Fig 4.
Correlations between apolipoprotein B-100 (apo B-100) production rate and serum apolipoprotein B (apo B) concentration when cynomolgus monkeys were fed the low (0.01 mg/kJ), medium (0.03 mg/kJ) and high (0.05 mg/kJ) cholesterol diets.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
). As in human studies, those in non-human primates such as cynomolgus monkeys have also shown that there is considerable individual variability in the response to dietary cholesterol (Hunt et al. 1992, Rudel and Pitts 1978). However, the data reported in this study indicate that the magnitude of the cholesterolemic response appears to be considerably greater than that of humans. This may be due in part to the fact that cynomolgus monkeys are among the most cholesterol-sensitive non-human primate species (Laber-Laird and Rudel 1989). This sensitivity does not, however, preclude the usefulness of this model in the study of the metabolic mechanism(s) underlying the response to dietary fat and cholesterol (Turley et al. 1995).
) have shown that the consumption of high concentrations of dietary cholesterol (0.32 mg/kJ) resulted in increased LDL production and serum LDL cholesterol concentrations. Similar studies in non-human primates (Johnson et al. 1983, Mott et al. 1992) fed high cholesterol (0.17-0.24 mg/kJ) and saturated fat diets have also demonstrated significantly elevated serum LDL cholesterol concentrations as a result of increased LDL production. The findings reported in this study, which utilized a more cholesterol-sensitive species, confirm these earlier reports; however, significantly lower concentrations of dietary cholesterol and less saturated fat diets were consumed. In this study, at 30% energy as fat, the significant elevations in serum LDL cholesterol and LDL apo B concentrations at the medium cholesterol intake were due primarily to a 54% rise (P < 0.05) in LDL apo B production compared with the low cholesterol diet period (Table 4). LDL apo B fractional catabolic rate was unaffected (Table 4) and not related (Fig. 3, middle panel) to serum LDL apo B concentrations at this dietary cholesterol concentration. However, as dietary cholesterol intake increased to the high dose, the significant elevations observed in serum LDL cholesterol and LDL apo B concentrations appeared to be the result of a 24% reduction (P < 0.05) in LDL apo B fractional catabolic rate. LDL apo B fractional catabolic rate however, was significantly related to serum LDL apo B concentrations (Fig. 3, bottom panel). At 36% energy as fat, the significant rise in serum LDL cholesterol and LDL apo B concentrations (Table 3) was again due to significantly declining LDL apo B fractional catabolic rates, but at this more saturated fat concentration, this change was now coupled with rising LDL apo B production rates (Table 4). At both 30 and 36% energy as fat, the lack of a significant fat effect suggests that the type of dietary fat did not appear to play a major role in regulating serum LDL cholesterol and LDL apo B concentrations. In addition, the LDL concentrations of free and esterified cholesterol were not significantly affected by either dietary fat or cholesterol; however, there was a significant cholesterol-induced reduction in LDL triglyceride concentration as dietary cholesterol increased (data not shown). These findings suggest that the dietary cholesterol-induced elevations in LDL cholesterol were the result of increase in particle number.
0.252 × 100) and 20% (0.452 × 100), respectively, of the variation in the concentrations of LDL apo B and LDL cholesterol can be explained by dietary cholesterol-induced changes in LDL receptor activity or LDL apo B fractional catabolic rate. However, during the period of high intake of dietary cholesterol, >30% of the variability can be explained by the LDL apo B fractional catabolic rate, which significantly contributes to rising LDL cholesterol concentrations. In contrast, the role of the LDL apo B production rate appears to diminish with increasing dietary cholesterol concentrations. Again, by using r2 as a measure of the total variance, it can be estimated from the correlation coefficients (r) in Figure 4 that although 65% (0.812 × 100) of the variance in serum LDL apo B concentrations can be explained by LDL apo B production rate when the intakes of dietary cholesterol were low, only 37% (0.612 × 100) can be explained by LDL apo B production rate at the highest intake of dietary cholesterol. Therefore, in this study, when the cynomolgus monkeys consumed the low (0.01 mg/kJ) and medium (0.03 mg/kJ) cholesterol diets, it appears that LDL cholesterol and LDL apo B concentrations were regulated to a greater extent by LDL apo B production rate than by LDL apo B fractional catabolic rate. Hence, in contrast to our earlier findings in cynomolgus monkeys consuming diets more saturated in fat (Stucchi et al. 1995), LDL apo B fractional catabolic rate did not appear to play an important role in mediating LDL cholesterol concentrations when low and medium dietary cholesterol diets were consumed. However, when dietary cholesterol intakes increased to the higher 0.05 mg/kJ, both LDL apo B fractional catabolic rate and LDL apo B production rate mutually contributed to the regulation of serum LDL apo B and LDL cholesterol concentrations. These data additionally suggest that there is a threshold of responsiveness to dietary cholesterol between the medium and high cholesterol intakes in this model. At cholesterol intakes below this concentration, LDL apo B production rate alone regulates LDL cholesterol concentrations; however, above this threshold, LDL apo B fractional catabolic rate plays an increasingly important role.
), was not unexpected on the basis of results of other cholesterol feeding studies in both cynomolgus monkeys (Turley et al. 1995) and hamsters (Spady et al. 1993). These studies suggest that when intakes of dietary cholesterol are low, hepatic cholesterol biosynthesis and LDL production contribute substantially to the maintenance of serum LDL cholesterol concentrations, whereas LDL receptor activity (LDL fractional clearance) plays a lesser role (Spady et al. 1993). However, as cholesterol intake increases, hepatic cholesterol biosynthesis becomes increasingly suppressed. The continued influx of dietary cholesterol to the liver, perhaps as a result of increased cholesterol absorption subsequently down-regulates and suppresses LDL receptor activity (Spady et al. 1993, Turley et al. 1995), which reportedly affects net sterol balance in the liver (Turley et al. 1997). The simultaneous increase in LDL production in concert with reduced LDL clearance mutually contribute to achieving a new steady state, whose the metabolic consequence is an elevation in serum LDL cholesterol concentration. The LDL metabolic studies performed at each intake of dietary cholesterol, from low to high, support the previous studies in cynomolgus monkeys (Turley et al. 1995). Additional studies in these animals (data not shown) have also demonstrated that as cholesterol intake increases, whole-body cholesterol biosynthesis is significantly reduced concomitantly with substantial increases in cholesterol absorption. These cholesterol-induced changes further support and explain the findings of this study and are consistent with the changes in LDL metabolism observed here and by others (Lin et al. 1994, Turley et al. 1995).
demonstrated that when cynomolgus monkeys were fed diets containing 30% energy as fat and 0.05 mg/kJ dietary cholesterol, plasma total and VLDL plus LDL cholesterol were significantly reduced when polyunsaturated fatty acids were substituted for saturated fatty acids. These earlier results are in contrast to the findings in this report in which neither serum total nor VLDL + IDL + LDL cholesterol concentrations increased in the 36% energy as fat group, which was fed 6% more energy as fat than the 30% energy as fat group (Table 1). The differing response to saturated fatty acids between the two studies may be due in part to the fact that in this study, polyunsaturated and monounsaturated fatty acids were the same in the two diet groups (Table 1) and only the percentage of energy from saturated fatty acids varied. In the Brousseau (1993) study, polyunsaturated fatty acids were substituted for saturated fatty acids. Despite the 40% increase in saturated fatty acids in the 36% energy as fat group, which consisted primarily of the cholesterolemic fatty acids 12:0 and 14:0 (Table 2), serum cholesterol concentrations were not significantly different between the two groups, suggesting that the cholesterol effect may be masking the saturated fatty acid response even at the lower cholesterol intakes. Hence, the intake of sequentially higher concentrations of cholesterol at two levels of saturated fats, with constant polyunsaturated and monounsaturated fatty acid levels, resulted in both significant LDL receptor down-regulation and increased production rates at the highest intake of dietary cholesterol (0.05 mg/kJ). These results suggest that, in this cholesterol-sensitive species, the reduction in the LDL fractional catabolic rate was not affected by the addition of saturated fatty acids. However, the increased production rate appears to be the result of a synergistic combination of a significant cholesterol effect coupled with an upward trend (P > 0.05) resulting from dietary saturated fat.
). Hence, under the dietary conditions of this study, cynomolgus monkeys are nearly 20 times more responsive to dietary cholesterol per 4200 kJ than predictions in humans (Hegsted et al. 1993). In contrast, when dietary cholesterol intake is expressed as mg/(kg·d) rather than per 4200 kJ, the monkeys are 14 times more responsive on average to dietary cholesterol than predictions in humans (Hegsted et al. 1993). Therefore, expressing the cholesterolemic response of cynomolgus monkeys compared with humans in either of the aforementioned units still demonstrates that cynomolgus monkeys are hyperresponsive to dietary cholesterol compared with humans. Despite the fact that even the lowest intake of dietary cholesterol (0.01 mg/kJ) represents a substantial amount for this sensitive species, these data still suggest that this model may be useful in identifying metabolic and genetic (Turley et al. 1995) predictors for hyperresponsiveness to dietary cholesterol in humans as well as assessing the metabolic heterogeneity in responses to dietary cholesterol.
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FOOTNOTES |
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Manuscript received 10 April 1997. Initial reviews completed 17 June 1997. Revision accepted 17 March 1998.
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ACKNOWLEDGMENTS |
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The authors thank Lorraine Misner, Donato B. Vespa, Subbiah Yoganathan and Nancy Marchand for technical assistance.
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LITERATURE CITED |
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Abstract
Introduction
Methods
Results
Discussion
References
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1-adrenergic inhibitor, on plasma lipid and lipoprotein levels, low density lipoprotein metabolism and cholesterol absorption in cynomolgus monkeys.
Atherosclerosis
1994;
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