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Department of Nutrition, University of Massachusetts-Amherst, Amherst, MA and * Department of Health and Clinical Sciences, Center for Health and Disease Control, University of Massachusetts-Lowell, Lowell, MA 01854
2To whom correspondence should be addressed. E-mail: Robert_Nicolosi{at}uml.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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concentrations than hamsters in the Low-CO group. Hamsters in the Med-CO group had significantly higher aortic interleukin-1ß concentrations than hamsters in the Med-chol group. In conclusion, the present study suggests that dietary cholesterol and saturated fatty acids could have an effect on atherosclerosis not only beyond their role in affecting plasma lipoproteins but also through increased production of inflammatory cytokines in the arterial wall.
KEY WORDS: • cholesterol • saturated fat • coconut oil • aortic cholesterol • cytokines
Atherosclerosis is the leading cause of death in modern societies (1,2). The effect of fatty acids on plasma lipoproteins has been studied extensively (3–5). As reviewed elsewhere (6), SFAs increase total cholesterol and LDL cholesterol (LDL-C),3 whereas monounsaturated fatty acids and PUFAs decrease LDL-C. A number of epidemiologic studies have shown a clear association between dietary saturated fat and atherosclerosis (7,8). Dietary cholesterol has also been shown to raise total and LDL cholesterol; however, its association with atherosclerosis is rather weak (9,10). In most studies, saturated fat is included with dietary cholesterol, further confounding the results. We recently showed that dietary cholesterol is less atherogenic than saturated fat in hamsters with low- to-medium plasma LDL-C, but is more atherogenic when plasma LDL-C is high (11). These differences in atherosclerosis could not be explained by variations in LDL size or composition.
On the other hand, there is growing evidence suggesting that fatty acids could have a direct role in inflammation. Atherosclerosis is considered by some to be an inflammatory disease (12), and the role of the immune system in the pathogenesis of atherosclerosis is gaining considerable attention (13–15). Oxidized LDL was shown to stimulate an inflammatory response (16–19); a number of cytokines were found present in the atherosclerotic lesions and may contribute to the recruitment of macrophages and the accumulation of cholesterol in the arterial wall (20,21). Interluekin-1 (IL-1), IL-6, and tumor necrosis factor- (TNF-) are the most important proinflammatory cytokines associated with atherosclerosis; they have been studied extensively by numerous investigators (22–24). They are secreted by almost any cell and are expressed early in the inflammatory response. It is not well understood why dietary fat would have an affect on inflammation, but it is possible that susceptibility to oxidation could be responsible (25). The immunomodulating effects of some fatty acids, especially of the monounsaturated and the PUFA, are under investigation (26,27), but there is almost no information available on the effect of SFAs and cholesterol on the production of inflammatory cytokines.
To date, no one has investigated the concentration of cytokines inside the arterial wall. Thus, the current study was conducted to examine the role of a diet high in saturated fat vs. a diet containing cholesterol in the development of atherosclerosis as it relates to aortic cholesterol concentrations and cytokine production.
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MATERIALS AND METHODS |
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Aortic tissue collection and homogenization. At the time of killing, hamsters were anesthetized with an i.p. injection of sodium pentobarbital (62.5 g/L at a dosage of 0.2–0.25 mL/200 g body weight) (Henry Schein) and aortic tissue was obtained for cholesterol and cytokine measurements. Specimens were rinsed with PBS and cleaned of blood and connective tissue; subsequently, they were stored in vials at -80°C for later analysis. A section of thoracic aortic tissue extending from as close to the heart as possible to the branch of the left subclavian artery was used for analytical measurements.
The aorta tissues were dissected into small segments. Due to the small size of aortic tissue in hamsters, the aortic tissues of 3 hamsters with similar plasma non-HDL-C concentrations were pooled and subsequently homogenized in a mortar pestle (glass in glass) homogenizer with the addition of 5 mL of lysis buffer. The lysis buffer contained 10% bovine serum albumin, 0.5% Triton 100, 1% gentamycin, 10% 100 mmol/L HEPES, and 1 vial of protease inhibitor in PBS (reagents from Sigma). The homogenized tissue was centrifuged at 400 x g for 10 min and the supernatant was collected and stored in -80°C.
Aortic lipid extractions. Lysis buffer (1 mL) was added with 4 mL of methanol and the solution was mixed on a vortex. Chloroform (8 mL) was then added to the solution. After mixing, 3 mL of a water solution containing 1.25% KCl and 0.05% H2SO4 was added and centrifuged at 400 x g at room temperature for 10 min. The bottom layer was transferred and the supernatant reextracted with 3 mL of chloroform:methanol (2:1) and centrifuged at 400 x g at room temperature for 10 min. The bottom layer was transferred and pooled with that from the previous step. The chloroform solution was stored at -80°C under N2 until analysis.
Aortic cholesterol measurements. The chloroform solution was placed in a 37°C water bath and completely evaporated under N2. Chloroform (1 mL) with 1% Triton-100 was added and placed in a 37°C water bath and completely evaporated at 37°C under N2. Distilled water (500 µL) was added, mixed on a vortex, and the sample was placed in a shaking water bath at 37°C for 20 min to solubilize the lipid. After incubation, aortic total and free cholesterol concentrations were determined using commercial kits (276 and 274) (Wako Chemicals). Aortic cholesteryl ester concentration was determined as the difference between the total and the free cholesterol concentrations.
IL-1, IL-1ß, TNF-, and IL-6 measurements.
Cytokine concentrations were measured with commercially available kits. The kit (ILIA) for the measurement of IL-1 was purchased from the Endogen; the IL-1ß, TNF-, and IL-6–specific kits (0012, 3001, 0062) were purchased from BioSource International. The assay procedure was conducted as described by the company. In brief, the biotinylated antibody was added first to each well of the precoated plate; then 50 µL of standard or undiluted samples was added in duplicate. In the next step streptavidin-peroxidase was added, followed by tetramethylbenzidine substrate solution. The stop solution was added at the final step and the absorbance was read at 450 nm with an MXR ELISA microplate reader (Revelation).
Statistical analysis. Minitab software was used for all statistical evaluations. Differences between experimental diets and between plasma non-HDL-C concentrations were determined using 2-way ANOVA. When significant differences were found by 2-ay ANOVA, a Student-Newman-Keuls post-hoc test was performed. For between treatment group comparisons, a t test was performed. For within treatment group comparisons for baseline vs. final data, paired t tests were performed. Pearson correlations were used for analyzing possible relationships between aortic cholesterol and plasma cholesterol concentrations and the various cytokines. All values are expressed as means ± SEM and significance was set at P < 0.05.
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RESULTS |
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Before stratification, plasma TC and HDL-C concentrations were significantly lower in the cholesterol-fed hamsters compared with those fed coconut oil, whereas plasma TG concentrations were higher in the cholesterol-fed hamsters than in coconut oil–fed hamsters after 10 wk of feeding (Table 2). Plasma non-HDL-C concentrations and the TC/HDL-C ratio did not differ after 10 wk of feeding (Table 2).
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In the Medium group, those fed the cholesterol-containing diet again had significantly lower plasma TC than hamsters fed the coconut oil–containing diet; however, this decrease was reflected in significantly lower plasma HDL-C concentrations in these hamsters compared with the coconut oil–fed hamsters. This decrease in plasma HDL-C concentrations also produced a significantly higher plasma TC/HDL-C ratio in hamsters fed the cholesterol-containing diet compared with those fed the coconut oil–containing diet.
Total, free, and esterified cholesterol accumulation in the aortic arch was significantly greater in the coconut oil–fed hamsters compared with cholesterol-fed hamsters (P = 0.001) (Table 4). After stratification by plasma non-HDL-C concentrations, hamsters in the Low group fed the coconut oil–containing diet had significantly higher aortic total and esterified cholesterol concentrations than those fed the cholesterol-containing diet (Table 5). No other differences were observed for cholesterol accumulation in the aortic tissue due to the dietary treatments or plasma non-HDL-C concentrations (Table 5). However, hamsters in the Medium group fed the cholesterol-containing diet tended to have less total cholesterol (P = 0.17) and cholesterol ester (P = 0.16) accumulation in the aorta.
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concentrations than those in the Low group fed the coconut oil diet (Table 6). Hamsters in the Medium group fed the coconut oil–containing diet had significantly higher aortic IL-1ß concentrations than the cholesterol-fed hamsters (Table 6). Also, hamsters in the Medium group fed the coconut oil–containing diet had significantly higher aortic IL-1ß concentrations than hamsters in the Low group fed the coconut oil–containing diet (Table 6). Hamsters in the Medium group fed the coconut oil–containing diet had significantly higher aortic TNF- concentrations than hamsters in the Low group fed the coconut oil–containing diet (Table 6). No other cytokines were different between the dietary treatments or plasma non-HDL-C concentrations (Table 6). No correlations, either positive or negative, were observed between the various cytokines and aortic or plasma cholesterol concentrations.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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In the earlier study (11), we fed varying levels of cholesterol or coconut oil to the hamsters to produce varying concentrations of plasma non-HDL-C. In the current study, the same level of cholesterol or coconut oil was fed to the hamsters. Thus, the varying concentrations in plasma non-HDL-C that were observed could be due to various reasons. The terms "high-responders" and "low-responders" has been used to describe animal species that have different concentrations of plasma cholesterol when fed the same amount of cholesterol in the diet. Possible reasons for this observation include differences in body weight accumulation, differences in food consumption, genetic differences, and different levels of cholesterol absorption (32,33). In the current study, although cholesterol absorption was not measured, food consumption and body weight gain were.
The two diets were chosen on the basis of previous research in our laboratory showing that they can similarly increase plasma non-HDL-C levels. Hydrogenated coconut oil was chosen as the source of saturated fat in one diet because it contains 100% saturated fat and has been shown to be hypercholesterolemic in experimental animal models (34,35). The dietary fat in the cholesterol diet was cocoa butter, which is high in stearic acid (18:0). Stearic acid is considered to have a neutral effect on plasma cholesterol concentrations (34,35) and was not found to be particularly atherogenic in rabbits fed cholesterol-rich or cholesterol-free diets (36).
Saturated fat–fed hamsters had higher plasma TC and HDL-C and lower TG concentrations compared with cholesterol-fed hamsters, whereas plasma non-HDL-C concentrations and the TC/HDL-C ratio were essentially the same in the two groups. Interestingly, after the stratification, hamsters in the Medium group, who had higher plasma TC and non-HDL-C concentrations and lower plasma HDL-C concentrations compared with those in the Low group, also gained the most weight, indicative of the important role of weight gain in plasma cholesterol metabolism. Weight gain, as stated previously, is a possible explanation for the different cholesterol responses that were observed in the current study.
Previous studies (20–24) reported an increased concentration in the proinflammatory cytokines in atherosclerotic lesions. In the present study, the cholesterol-fed and the saturated fat–fed hamsters did not differ greatly in their cytokine concentration. Nonetheless, significant differences were observed in the aortic IL-1ß and TNF- concentrations after stratification of the hamsters into Low and Medium plasma non-HDL-C concentration groups. In the Low group, cholesterol-fed hamsters had significantly higher aortic TNF-. Conversely, in the Medium group, the coconut oil–fed hamsters had significantly higher aortic IL-1ß.
It is not absolutely clear how these two diets, which raised plasma non-HDL-C concentrations similarly, could have such a different effect on inflammatory cytokines. Recent reviews summarize how different fatty acids could have a direct effect on transcription and therefore up- or downregulate the expression of a number of molecules (37,38). Additional work was provided in a study by Lee et al. (39), in which it was shown that SFAs could have a direct effect on inflammation by activating nuclear factor (NF)-
B through the Toll-like receptor 4. NF-B is involved in the transcription of many proinflammatory cytokines, including IL-1, IL-6, and TNF-, and its activation could result in increased production of these cytokines. On the other hand, in a recent study by Meerarani et al. (40), it was shown that cholesterol can downregulate linoleic acid–induced NF-B activation, resulting in decreased IL-6 production and attenuated endothelial cell activation. Moreover, it was suggested that cholesterol can act as an antioxidant (41) and thus, by decreasing the prooxidant state in the endothelial cells of the vessel wall, it can downregulate the production of inflammatory mediators. This hypothesis is reinforced by the study of Nicholas et al. (42) who showed that dietary cholesterol could decrease the amount of lipid hydroperoxides in LDL particles from corn oil–fed rabbits. However, there are some studies that contradict this hypothesis. Nevertheless, another study by Schwab et al. (43) showed that dietary cholesterol can increase LDL susceptibility to oxidation.
The decreased aortic TNF- concentration in the coconut oil–fed hamsters in the Low group, is perhaps better explained when considered in combination with the data on aortic cholesterol accumulation. In the present study, aortic cholesterol accumulation was significantly higher in the coconut oil–fed hamsters compared with the cholesterol-fed hamsters. This was true for total, free, as well as esterified cholesterol. The differences were more pronounced after stratification and examination of the plasma non-HDL-C concentration in the Low group. A recent study indicates that macrophages loaded with cholesterol have decreased capability of producing TNF- (44). Thus, the amount of aortic TNF- present in the atherosclerotic plaques could depend on the balance between stimulation of its production by oxidation products and primary cytokines, on the one hand, and the ability of macrophages to respond to these stimuli, on the other hand.
The results on cholesterol accumulation agree with previous studies (11) and are explained at least in part by the differences in aortic IL-1ß concentration. Also, the hamsters that had a greater accumulation of aortic cholesterol had significantly higher plasma TC concentrations, which may account for some of the greater cholesterol accumulation. However, these same hamsters also had higher plasma HDL-C concentrations, which is assumed to be protective in the development of atherosclerosis. Because the hamsters fed the coconut oil diet had higher plasma HDL-C, lower TG, and similar non-HDL-C concentrations but greater cholesterol accumulation in the aortic tissue, other possible mechanism(s) must be involved. Possibly other cytokines, such as monocyte chemoattractive protein-1 and IL-8, which have been implicated in atherosclerosis, could also be responsible for the differences in cholesterol accumulation between the coconut oil–fed and the cholesterol fed-hamsters. Some adhesion molecules, such as vascular adhesion molecule-1 and intracellular adhesion molecule-1, could also be involved (45).
In conclusion, the present study suggests that cholesterol and saturated fat could have an effect on the progression of atherosclerosis beyond their role in affecting plasma lipoproteins. Saturated fat appears to be more atherogenic than dietary cholesterol by increasing the aortic cholesterol accumulation and by increasing IL-1ß concentration in the arterial wall. These findings stress the importance of saturated fat among the dietary factors which can affect the progression of atherosclerosis. Here we report that a diet high in saturated fat increases IL-1ß concentration more than a high-cholesterol diet, whereas other cytokines are not significantly altered in the early development of atherosclerosis. This study suggests that arterial inflammation could explain why a diet high in cholesterol is less atherogenic than a diet high in saturated fat at comparable plasma non-HDL concentrations.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: HDL-C, HDL cholesterol; IL, interleukin; LDL-C, LDL cholesterol; NF-B, nuclear factor B; non-HDL-C, VLDL and LDL cholesterol; TC, total cholesterol; TG, triacylglycerol; TNF, tumor necrosis factor.
Manuscript received 29 July 2003. Initial review completed 15 September 2003. Revision accepted 11 November 2003.
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