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2
Departments of
*
Foods and
Biological Sciences, Universidade Federal de Ouro Preto, Ouro Preto, Brazil and
**
Department of Physiology, EPM, Universidade Federal de São Paulo, São Paulo, Brazil
2To whom correspondence should be addressed. E-mail: lpedrosa{at}nupeb.ufop.br.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • iron overload • hypercholesterolemia • blood pressure • rats
Iron is an essential element and its deficiency is a nutritional problem in both developed and developing countries. Consequently, many types of dietary iron supplementation are used. Some researchers have suggested that the general population is consuming excess iron due to these supplements. They found that several types of diseases are provoked by short- or long-term exposure to iron in quantities above the capacity of the organism to protect itself against iron’s reactivity and that iron’s role in pathological processes is related to its ability to catalyze reactions that lead to the formation of oxygen free radicals (1
,2
).
There is considerable evidence to support the role of oxidative stress in the development of atherosclerosis and related cardiovascular diseases (CVD).3 The development of atherosclerosis involves lipid deposits on the inner walls of arteries, with subsequent inflammation and scarring. The fat deposits are composed mainly of cholesterol and cholesterol esters, which are associated with foam cells and macrophages on the artery walls (3
). Epidemiologic and experimental data show a clear correlation between increased atherosclerosis and plasma cholesterol levels. Increased levels of LDL are considered the principal causal factor (4
). This becomes part of the atherosclerotic process after oxidative modification (5
). Therefore, iron could be involved in the pathology of atherosclerosis by promoting an oxidative modification of LDL, thus increasing their atherogenic potential. In vitro studies have shown that iron and copper are necessary for the oxidation of LDL in endothelial cells (6
) and macrophages (7
). Iron can also increase the peroxidation of LDL by lowering the antioxidant levels in plasma (8
).
Epidemiologic and animal studies have provided conflicting evidence for the role of iron in atherosclerosis and coronary disease. For example, epidemiologic data of Salonen et al. (9
) indicate that high levels of stored iron as measured using serum ferritin are an independent risk factor for acute myocardial infarction. However, others have found that transferrin is an independent negative risk factor for myocardial infarction and ferritin was not found to contribute to the risk (10
). Surprisingly, some studies have suggested an inverse association between iron stores and mortality from CVD (11
,12
), and a significant inverse relationship between iron overload, resulting from hemochromatosis or multiorgan siderosis, and the prevalence of coronary atherosclerosis has been reported (13
). Animal studies on the role of iron in experimental atherosclerosis are limited and also have yielded conflicting results. Although one study suggested that excessive iron loading in hypercholesterolemic rabbits was beneficial and significantly reduced lesion formation (14
), a similar study suggested a detrimental role for iron loading in the same model (15
). Considering that the role of iron in CVD remains unclear, the effect of excess iron on the various risk factors for this disease must be assessed.
Iron excess induces cellular injury and functional abnormalities in hepatocytes by the process of lipid peroxidation (16
). Because the liver has a central role in the maintenance of lipid homeostasis, excess iron may alter the concentration of serum lipids, which could reduce or increase the risk of atherosclerosis. Lipid peroxidation may also damage membranes in other cells, altering important elements of control for blood pressure and heart rate. Given that increased LDL cholesterol (LDL-C), decreased HDL cholesterol (HDL-C) and alterations of systolic blood pressure (SBP) have been implicated as risk factors for atherosclerosis and related CVD, the present study was designed to determine whether excess iron alters serum lipids and SBP in control and hypercholesterolemic rats. Because hypercholesterolemia can result in atherogenesis, which is considered a chronic inflammatory disease (17
), and evidence exists for a connection between iron metabolism and an inflammatory response (18
), we also analyzed the effect of a hypercholesterolemic diet on serum iron levels, total iron-binding capacity (TIBC) and transferrin saturation (TS).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The experiment was conducted with female Fischer rats (n = 32) weighing 
100 g. The rats were divided into four groups. The control group (C) was fed the control diet, the CI group was fed the control diet and given iron dextran by intraperitoneal (i.p.) injections, the hypercholesterolemic group (H) was fed a 1 g/100 g cholesterol diet, and the HI group was fed the cholesterol diet and given iron dextran injections. The rats were housed in metabolic cages. They were maintained at 24°C at constant humidity (55%) with a 12-h light:dark cycle. They consumed food and water ad libitum for 8 wk. Food intake and weights were recorded daily, from d 35 to 44. The injections of iron dextran, 100 g/L, (Sigma, St. Louis, MO) were given during wk 6 at a total dose of 50 mg, divided into 10 mg/d doses for 5 d. This dose causes iron overload in mice (19
,20
). Rats of groups C and H were administered 0.1mL of sterile saline i.p. All injections were done early in the day during wk 6. This week was chosen because after 1 mo of consuming a high cholesterol diet, rats develop hypercholesterolemia (21
). Rats were killed 2 wk later because after i.p. injection, iron dextran is taken up by the reticuloendothelial system; part of the iron is transferred to transferrin and part is removed from circulation within 48 h, thus increasing liver and spleen stores (22
). By killing rats at wk 8, we were sure that the injected iron would have had time to increase iron stores in the tissues.
After overnight food deprivation, the rats were anesthetized with an i.p. injection of pentobarbital (Sigma), at a dosage of 60 mg/kg body; blood was collected through the brachial plexus and centrifuged at 2000 x g for 10 min. The liver was infused with 9 g/L NaCl, removed and frozen at -20°C for subsequent iron and fat measurements. The spleen was also frozen for subsequent iron measurements. We followed the general guidelines for the care and use of laboratory animals recommended by the Canadian Council on Animal Care 1984 (23
).
Diet composition.
The control diet contained (g/kg) casein (Isofar, Duque de Caxias, Brazil), 120; salt mixture,4 50; vitamin mixture,5 10; soybean oil, 80 (Sadia, São Paulo, Brazil); choline (Labsynth, Diadema, Brazil), 0.4; cellulose 10 (Merck, Darmstadt, Germany); cornstarch, 729.6 (Unilever Bestfoods, Mogi-Guaçu, Brazil). Total energy was 17.21kJ/kg (24
). The hypercholesterolemic diet was the same except for soybean oil, 250; cellulose, 130; cornstarch, 429.6; cholesterol, 10, with total energy 18.59kJ/g. This diet was chosen because diets rich in fat and cholesterol have been used to produce hyperlipidemia in animals (21
). More fiber was added to reduce the difference in energy between this diet and the control diet.
Assays.
Serum iron concentrations and TIBC (as well as UIBC) were determined in nonhemolyzed serum samples by spectrophotometric analysis using commercially available kits (#38 and 41, respectively; Labtest, Belo Horizonte, Brazil), and employing an iron standard of 89.5 µmol/L. Iron TS was determined from the serum iron/TIBC ratio. Serum triglycerides and cholesterol were determined by commercially available enzymatic methods (#59–4/50 and 60–2/100, respectively; Labtest) using glycerol and cholesterol as standards, respectively. After precipitation of VLDL and LDL with phosphotungstenic acid and magnesium chloride, HDL-C was measured in the supernatant (#13 Labtest). The VLDL- and LDL-C concentrations were calculated using the Friedewald equation: LDL-C = total cholesterol – (HDL-C + VLDL-C), and VLDL-C = triglycerides/2.175, according to the HDL-C manufacturer’s instructions (Labtest). Urea, total protein, serum albumin, alanine aminotransferase and aspartate aminotransferase were determined with commercially available kits (#27, 18, 19–250, 253 and 52, respectively; Labtest), and external standards of urea, protein and albumin, respectively, were used. To measure enzymatic activity, a calibration curve was utilized that correlated the obtained readings with the U/L standardized values, which were supplied by the manufacturer. Serum nitric oxide (NO) was measured by the concentration of nitrate, the stable end product, using the Griess reagent, after bacterial nitrate reductase treatment, as previously described (25
). Sodium nitrate was used as the standard.
Iron levels in the organs.
Liver and spleen samples were digested in HNO3 at 100°C. After the acid was evaporated, the iron was quantified by colorimetric analysis using ortophenantroline (24
). An external iron standard (89.5 µmol/L) was used.
Fecal lipids.
Total lipids were analyzed, following the methodology proposed by AOAC (24
). During wk 7, feces were collected daily, dried in an air draft oven at 60°C for 60 min, weighed and kept at -20°C until analyzed; 5 g of each sample was dried in an oven at 105°C for 2 h and lipids were measured in a Sohxlet apparatus (24
)
Liver lipids.
Total lipids were analyzed following the methodology proposed by AOAC (24
); 1 g of liver was ground in a porcelain mortar, using 12 g of clean sand, and then dried at 105°C for 2 h. All of the resulting powder was placed in a cellulose cartridge, the lipids extracted with petroleum ether for 6 h and measured in a Soxhlet apparatus.
Determination of systolic blood pressure and heart rate.
We measured SBP and heart rate using the Kent RTBP2000 series Rat Tail System (Kent Scientific, Litchfield, CT) in conscious, restrained rats with a photoelectric sensor and a tail-cuff sphygmomanometer. At 30 min before the measurements, the rats were placed in a preheated restrainer, with the tail exposed. The tail cuff was pushed up to the base of the tail and fit closely but freely on the tail and the pulse sensor was placed just behind the tail cuff. The cuff was then inflated and deflated automatically within 90 s. Readings were taken for 30 min. The pressure in the occlusion cuff and the pulse signal were monitored and recorded in a PowerLab/400 (Software Chart, Castle Hill, Australia) system. The initiation of the pulse signals, after the inflation peaks, was correlated with the pressures in the occlusion cuff to obtain the mean SBP readings for each rat.
Statistical analysis.
Values are expressed as means ± SD. Statistical analysis of the data was carried out using MINITAB 13 Statistical Software (State College, PA). Data were tested by two-way ANOVA. When interactions were significant, Tukey’s test was done to determine the specific differences between means. A difference of P < 0.05 was considered significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The rats of group CI had higher levels of serum iron and greater TIBC and TS than the control group (P < 0.05, Table 1
). The UIBC did not differ between groups C and CI (Table 1)
. Diet did not affect serum iron but UIBC and TIBC were higher in group H than in group C (P < 0.05). TS was lower in group H than in group C. Diet and iron dextran interacted to affect serum iron, UIBC and TIBC. Group HI had a lower serum iron concentration than group CI but did not differ from group H (P < 0.05). UIBC was higher in group H, intermediate in group HI and lower in groups C and CI. TIBC was higher in group H, intermediate in groups HI and CI and lower in C.
|
. Diet and iron dextran interacted to affect liver total iron; group HI had higher total iron in the livers than group CI (P < 0.05). The spleens of groups CI and HI had greater (P < 0.01) total iron than groups C and H. Diet did not affect spleen total iron levels (P < 0.05). Serum cholesterol, triglycerides and lipoprotein profiles.
Group H had about twice the serum cholesterol and half the triglycerides of the control group (C) (Table 2
). Iron injections lowered the concentration of cholesterol but not that of triglycerides. In rats fed cholesterol and injected with iron (HI), the serum cholesterol levels were 40% lower than in group H. There were no differences in serum triglycerides between groups HI and H (Table 2)
. The high cholesterol diet increased LDL-C and reduced HDL-C. Iron also affected LDL-C and HDL-C by decreasing the former and increasing the latter. Iron and diet did not interact to affect these variables (Table 2)
.
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Iron did not affect final body weight or weight gain, whereas dietary cholesterol increased both. Food intake was affected by cholesterol, iron and their interaction with intake greatest in group H, least in group C and intermediate in the others (P < 0.05, Table 3
). Absolute and relative liver weights were increased by iron dextran but differences were significant only in rats fed the hypercholesterolemic diet. Cholesterol, iron and their interaction affected fat in the liver; H and HI groups had higher fat content in the liver compared with those fed the control diet (P < 0.05, Table 3
). The fat level in the livers of group HI was lower than that of group H.
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, which was higher for group H than for group C. Iron alone had no effect. Iron and its interaction with diet affected fecal amounts with the greatest excretion in group H, the least in group C and intermediate amounts in the other groups (P < 0.05, Table 3
). Serum metabolites and enzymes.
The groups did not differ in the serum variables measured except for alanine aminotransferase activity, which was increased by dietary cholesterol (17.1 ± 4.5, 18.3 ± 6.7, 54.8 ± 38.5 and 46.3 ± 19.7 U/L for groups C, CI, H and HI, respectively).
Systolic pressure and heart rate.
After 8 wk, the groups did not differ (P < 0.05) in SBP (130.6 ± 19.7, 127.77 ± 17.6, 126.35 ± 9.8 and 125.1 ± 14.7 mm Hg for groups C, CI, H and HI, respectively) or heart rate (386.9 ± 31.8, 389.3 ± 24.33, 395.0 ± 28.7 and 387.8 ± 31.7 bpm for groups C, CI, H and HI, respectively).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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2.5-fold, as measured by total liver iron levels, compared with the corresponding values in control rats. The levels of hepatic iron observed in the present study were moderate compared with patients with symptomatic hemochromatosis, who have 16- to 30-fold increases in liver iron levels (26
). This level was also below the critical threshold (>22-fold increase) in which hepatocellular injury has been observed (27
).
Our data suggest that the cholesterol diet altered the metabolism of iron. In HI rats, the levels of serum iron were reduced and those of liver iron were increased compared with CI rats. Because iron dextran disappears from the circulation within 48 h and is distributed in various tissues (22
) and because released iron can return to circulation bound to transferrin, our results indicate that the iron in HI rats was released more slowly into circulatory system. These results confirm those of Dabbagh et al. (8
), who found that the levels of serum iron in rats fed cholesterol and treated with penta-carbonyl iron did not differ from those fed only the high cholesterol diet. It is possible that this alteration in iron metabolism is related to oxidative stress caused by diet and excess iron. In both situations in which an increase in reactive species has been observed (28
–30
), the protective capacity of the antioxidant systems could be exceeded. Down-regulation of iron regulatory protein (IRP) activity may be a common response to increased formation of superoxide anion and H2O2 (31
). IRP binds to iron responsive elements (IRE) and stabilizes the mRNA for the transferrin receptor while decreasing the translation of mRNA for ferritin (31
). Therefore, lower IRP activity could increase ferritin synthesis, thus reducing the release of iron from the liver into the circulatory system.
Atherosclerosis is very unusual in most strains of rats, even when they have sustained high blood lipid levels (32
). Our results suggest that changes in iron homeostasis due to high fat and cholesterol diets could be one of the reasons for this phenomenon. Iron binding by tranferrin or ferritin can limit its participation in the formation of free radicals and therefore, reduce LDL oxidation. This hypothesis is supported by Van Lenten et al. (33
), who found that fatty streak-resistant C3H/HeJ mice fed an atherogenic diet had a higher level of liver apoferritin and a lower concentration of free iron than fatty streak-susceptible C57BL/6J mice.
When we studied the effect of iron overload on plasma lipid levels, we found that excess iron reduced plasma cholesterol. Our results for total cholesterol were similar to those of Dabbagh et al. (34
), who found that iron dextran had a hypocholesterolemic effect on rabbits fed a 1% cholesterol-enriched diet and of Maioli et al. (35
), who showed that patients with ß-thalassemia major, a condition that can lead to iron overload when the patient undergoes repeated blood transfusions, had reduced cholesterol. Other studies had results contrary to ours, e.g., Araújo et al. (15
) treated rabbits with iron dextran and did not find differences in plasma cholesterol between groups fed a high cholesterol and a control diet.
Differences in lipid and plasma lipoprotein metabolism among various species make it difficult to compare the various animal models. Rabbits, for instance, do not have hepatic lipase or a protein analogous to human apolipoprotein-AII. Rats and mice, unlike humans and other species, do not have plasma cholesteryl ester transfer proteins. Thus, most of the serum cholesterol is present as part of HDL (36
). Despite the differences in lipid metabolism between humans and rats, this is an extensively used model for both nutrition and cardiovascular physiology, and that is why we used rats in the present work.
When only experiments with rats are considered, there is consensus that excess iron increases HDL-C as was observed by Dabbagh et al. (8
) with rats that consumed a diet containing cholesterol and by Brunet et al. (37
) with rats that were fed a diet without cholesterol. Both Brunet et al. (37
) and Dabbagh et al. (8
) found an increase in total cholesterol and triglycerides, whereas the present work showed a reduction in serum cholesterol and no effect on serum triglycerides. The divergence between our results and these earlier studies may be explained by the difference in the levels of iron overload. Dabbagh et al. (8
) and Brunet et al. (37
) found 12.5 and 30-fold increases, respectively, in liver iron levels, compared with a 2.5-fold increase in the present work. The rats in group HI had a lower food intake than those in group H, which may have contributed, at least in part, to the lower levels of serum cholesterol and liver fat. On the other hand, hypocholesterolemia could be a consequence of liver damage, which is associated with disturbances in lipid metabolism (38
). However, the hypocholesterolemic effect that we observed apparently was not due to liver damage because we found no alterations due to iron in the activities of alanine aminotransferase and aspartate aminotransferase or in the concentrations of urea, albumin and plasma proteins in the rats treated with iron compared with the controls. A higher activity of alanine aminotransferase was found for group H, and treatment with iron did not change this profile.
There was a large accumulation of fat in the livers of H and HI rats compared with C and CI, respectively, with group HI having a lower level of liver fat than group H. Based on these and previously reported data, we propose that iron and a high cholesterol diet interact to increase the intracellular oxidative stress, perhaps exceeding the protective capacity of antioxidant systems. Oxidative stress has been related to lipid peroxidation and membrane damage, oxidation of glutathione, and consequently, ATP and NADPH depletion that would cause marked disruption in lipid synthesis and transport (39
). Membrane peroxidation may alter the activity of liver enzymes involved in cholesterol metabolism and lipoprotein formation, resulting in a lower total serum cholesterol concentration. A reduction in 3-hydroxy-3-methylglutaryl CoA-reductase and cholesterol-7-
-hydroxylase and an increment of acyl-CoA:cholesterol acyltransferase activities have been observed in rats treated with iron (37
). Furthermore, an ATP deficiency would also favor fatty acid oxidation, which would reduce the fat content in the liver of the animals receiving the hypercholesterolemic diet and iron. More studies are required to confirm this hypothesis. Investigations into the effect of iron on lipase activities, LDL and HDL receptors and other enzymes involved in lipoprotein metabolism are also warranted to explain the alteration in the distribution of cholesterol due to excess iron.
Although alterations in lipid metabolism can change membrane structure and function, contributing to abnormalities in blood pressure (40
), and oxidative stress has been implicated in the etiology of hypertension in humans (41
), we found no changes in blood pressure, heart rate or in NO concentrations due to excess iron.
In conclusion, our results show that excess iron lowers plasma total cholesterol. Iron injections also caused a redistribution of cholesterol among the various lipoprotein fractions, with an increase in HDL-C and a reduction in LDL-C, both in rats fed a normal diet and in those fed a high cholesterol diet. These alterations did not affect SBP or heart rate. Moreover, a high cholesterol diet influences iron homeostasis in Fischer rats. Thus, when risk factors such as cholesterol, lipoprotein levels and blood pressure are considered, our results do not support the hypothesis that iron levels increase the risk of CVD. Nevertheless, due to differences in lipoprotein metabolism among animal species, further studies are required with other animal models to clarify the relationships among iron status, hyperlipidemic diets and lipoprotein metabolism.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: CVD, cardiovascular disease; HDL-C, HDL cholesterol; i.p., intraperitoneal; IRE, iron-responsive element; IRP, iron regulatory protein; LDL-C, LDL cholesterol; NO, nitric oxide; SBP, systolic blood pressure; TIBC, total iron binding capacity; TS, transferrin saturation; UIBC, unsaturable iron-binding capacity; VLDL-C, VLDL cholesterol. Rat groups: C, control; CI, control with iron; H, hypercholesterolemic; HI, hypercholesterolemic with iron.
4 Salt mixture (24
) (expressed in g/kg of mixture): NaCl, 139.3; KI, 0.79; MgSO4 · 7H2O, 57.3; CaCO3, 381.4; MnSO4 · H2O, 4.01; FeSO4 · 7H2O, 27.0; ZnSO4 · 7H2O, 0.548; CuSO4 · 5H2O, 0.477; CoCl2 · 6H2O, 0.023; KH2PO4, 389.0. The salts were purchased from Reagen, Rio de Janeiro, Brazil.
5 Vitamin mixture (24
) (expressed in mg/kg of mixture): retinyl acetate, 690; cholecalciferol, 5; p-aminobenzoic acid, 10,000; inositol, 10,000; niacin, 4000; D-calcium pantothenate, 4000; riboflavin, 800; thiamine HC1, 500; pyridoxine, 500: folic acid, 200; biotin, 40; cyanocobalamin, 3; dl--tocopherol, 6700; sufficient sucrose to bring to l kg. The vitamins were purchased from Merck, Darmstadt, Germany.
Manuscript received 30 April 2002. Initial review completed 4 June 2001. Revision accepted 27 September 2002.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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