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-Aminolevulinate Dehydratase and Increases Lipid Peroxidation in Mice (Mus musculus)
Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, 97105–900, Santa Maria, RS, Brasil
2To whom correspondence should be addressed. E-mail: jbtrocha{at}yahoo.com.br.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-aminolevulinate dehydratase (-ALA-D) activity in mice. The GHbA1c level was significantly higher in mice fed the HF diet compared with those fed the HS diet. Hepatic, renal, and cerebral TBA-RS concentrations in mice fed the HF diet were significantly greater than in mice fed the HS diet. In addition, positive correlations were found between the GHbA1c and TBA-RS levels for hepatic (P < 0.05; r = 0.46), renal (P < 0.003; r = 0.65), and cerebral (P < 0.001; r = 0.69) tissues. The -ALA-D hepatic, renal and cerebral activities of mice fed the HF diet were significantly lower than those of mice fed the HS diet. Furthermore, a negative correlation was found between the GHbA1c level and -ALA-D activity in hepatic (P < 0.001; r = -0.77), renal (P < 0.007; r = -0.60), and cerebral (P < 0.007; r = -0.60) tissues. The results of this study indicate that consumption of a high fat diet promotes oxidative stress related to hyperglycemia, which in turn can stimulate glycation of proteins leading to -ALA-D inhibition in mice.
KEY WORDS: • high fat diet • hyperglycemia • oxidative stress • -aminolevulinate dehydratase • mice
A high fat intake is considered to be an important factor in the development of insulin resistance and obesity. Laboratory mice fed a high fat diet are a model for studying the putative effects of dietary fat in humans (1–3), and there is evidence of reduced insulin-mediated glucose metabolism in muscle and adipose tissues from mice fed high fat diets (4–6). Of particular importance, chronic high fat feeding led to a substantial reduction in glucose transporter 4 expression in both adipose tissue and skeletal muscle (7,8).
Elevated levels of circulating glucose can produce permanent chemical alterations in proteins and increase lipid peroxidation in a variety of experimental models of hyperglycemia (9–12). In line with this, overproduction of reactive oxygen species (ROS) and antioxidant depletion have been associated with the onset of diabetes (13–16). Furthermore, the deleterious effects of hyperglycemia on the properties of physiologically abundant proteins such as hemoglobin, albumin and collagen have been investigated (17–19).
-Aminolevulinate dehydratase (-ALA-D) is an essential enzyme for all aerobic organisms because it participates in the biosynthesis pathway of tetrapyrrole molecules, which constitute prosthetic groups of physiologically important proteins such as hemoglobin and cytochromes (20–22). -ALA-D is a sulfhydryl-containing enzyme; consequently, its activity is highly sensitive to the presence of prooxidant elements, which can oxidize its –SH groups (23–27). Of particular importance is the impairment of the heme synthetic pathway in porphyria. The frequent coexistence of diabetes mellitus and porphyria disease has been reported in humans and experimental animal models (28–31); this can be causally linked to the inhibition of this enzyme that occurs in diabetics (32,33).
The present study was designed to examine 1) the effects of high starch (HS) vs. high fat (HF) feeding on blood glycated hemoglobin levels; 2) the contribution of such diets to oxidative stress in different tissues (brain, liver and kidney) measured by levels of thiobarbituric acid-reactive species (TBA-RS); and 3) the effect of these diets on -ALA-D activity in brain, liver and kidney.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Casein (technical grade), coomassie brilliant blue G, 5-aminolevulinic acid (ALA), DL-dithiothreitol (DTT) and malondialdehyde (MDA) were obtained from Sigma (St. Louis, MO). Mono- and dibasic potassium phosphate, acetic acid, orthophosphoric acid, Tris buffer, glucose, hydrogen chloride, trichloroacetic acid and sodium chloride were obtained from Merck (Rio de Janeiro, RJ, Brazil). Cornstarch and wheat bran were obtained from Arisco (Goiania, GO, Brazil), soybean oil from Sadia (Concordia, SC, Brazil), and lard from Dalia (Encantado, RS, Brazil). The vitamin and mineral complexes were obtained from Indubrás (Contagem, MG, Brazil).
Mice and diets.
Female mice (Mus musculus) (2 mo old), weighing between 30 and 35 g, from our own breeding colony (Animal House-holding, UFSM, Brazil), were maintained in a temperature-controlled room (20–25°C) and natural lighting. Diets and water were consumed ad libitum. The mice were randomly divided into two groups and fed either a high starch (HS) or a high fat (HF) diet. The composition of the diets is shown in Table 1. Food was placed in small metal dishes just before the beginning of the dark cycle. Diets were prepared weekly and stored at 4°C.
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Mice were killed by decapitation. The liver, kidney and brain were quickly removed, placed on ice and homogenized in 7 (liver) and 5 volumes (kidney and brain) of cold 0.2 mmol/L BHT + 150 mmol/L NaCl. The homogenate was centrifuged at 4000 x g at 4°C for 10 min to yield a low speed supernatant fraction, which was used for the biochemical assays. The supernatant fraction used for determination of lipid peroxidation was stored at -20°C for 1 wk.
Biochemical assays.
-ALA-D activity was assayed by the method of Sassa (34) by measuring the rate of product [porphobilinogen (PBG)] formation, except that 84 mmol/L potassium phosphate buffer, pH 6.4, and 2.4 mmol/L ALA were used (35,36). The reaction product was determined using modified Ehrlich’s reagent at 555 nm, with a molar absorption coefficient of 61,000 (mol/L)-1cm-1 for the Ehrlich-PBG salt. Thiobarbituric acid reactive species (TBA-RS) were determined according to Ohkawa et al. (37), as modified by Rossato et al. (38). TBA-RS were quantified by adding the supernatant fraction directly to the reaction medium described above or after a preincubation at 37°C for 60 min. The amount of TBA-RS produced was measured at 532 nm using MDA to construct standard curves. Protein was measured by the method of Bradford (39) using bovine serum albumin as a standard. After collection, blood samples were transferred to polypropylene tubes containing EDTA (12 g/L) and stored on ice. Plasma samples were harvested by centrifugation (1000 x g, 10 min) and frozen until assay. The percentage of glycated hemoglobin A1c (GHbA1c) was determined using the glyc-affinity columns from a Labtest commercial kit (Belo Horizonte, MG, Brazil).
Statistical analysis.
Results are expressed as means ± SD. The effects of the HS and HF diets on TBA-RS concentration and -ALA-D activity were evaluated by a two-way ANOVA. Because no interaction was found, data were then analyzed by one-way ANOVA (SPSS for Windows 8.0, SPSS 1998, Chicago, IL). When the one-way ANOVA was significant, differences were determined using Duncan’s Multiple Range test (SPSS). Body weights of HS- and HF-fed mice were compared by two-tailed Student’s t test for independent samples (SPSS). Correlation coefficients were determined by linear regression. Differences between groups were considered to be significant when P ≤ 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The body weight of the HS-fed mice was less than that of the mice fed HF after the 16-wk experiment (Fig. 1). During the initial 2 wk of feeding, weight gain in mice fed the HF diet was significantly greater than that in mice fed the HS diet (Fig. 1). This difference in body weight persisted from wk 2 through the final feeding period (wk 16).
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The GHbA1c level, a classical index of glycemic stress, was significantly higher in mice fed the HF diet compared with those fed the HS diet for 16 wk (5.434 ± 0.61 and 4.082 ± 0.56%, for the HF and HS diets, respectively, P < 0.05). This suggests that the high fat diet resulted in higher blood circulating glucose levels than the high starch diet during the 16 wk.
Tissues TBA-RS levels.
Basal TBA-RS levels in hepatic, renal and cerebral tissues of mice fed the HF diet mice were significantly increased compared with the levels in mice fed the HS diet (Fig. 2). However, after induction of lipid peroxidation by preincubation of the supernatant fraction at 37°C for 60 min, TBA-RS production increased equally in both groups, and the differences between the HF and HS groups persisted. Of particular importance, positive correlations were found between the percentageage of GHbA1c and TBA-RS levels for hepatic (r = 0.46, P < 0.05, Fig. 3A), renal (r = 0.65, P < 0.003, Fig. 3B) and cerebral (r = 0.69, P < 0.001, Fig. 3C) tissues. This suggests that the variations observed in GHbA1c levels in blood, which reflect the degree of circulating glucose, may be related to an increase in oxidative stress in various tissues.
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-ALA-D activity.
Hepatic, renal and cerebral -ALA-D activities of mice fed the HS diet were significantly lower than those of mice fed the HS diet (Fig. 4).
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-ALA-D inhibition, we tested the effect of DTT on the enzyme activity in both groups. The addition of DTT (2 mmol/L) in the assay did not affect -ALA-D activity in liver, kidney or brain, and the differences between the HF and HS groups persisted. Hence, in vitro DTT did not abolish the inhibition of hepatic, renal and cerebral -ALA-D in mice fed the HF diet (Fig. 4).
A negative correlation was found between the percentage of GHbA1c and -ALA-D activity for hepatic (r = -0.77, P < 0.0001, Fig. 5A), renal (r = -0.60, P < 0.007, Fig. 5B) and cerebral (r = -0.60, P < 0.007, Fig. 5C) tissues. In addition, negative correlations also were found between the TBA-RS concentrations and -ALA-D activities for hepatic (r = -0.59, P < 0.007) and cerebral (r = -0.49, P < 0.03) tissues, but not for renal tissue (r = -0.29, P < 0.22, data not shown).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Hyperglycemia has been shown to generate superoxide radicals from autooxidation of glucose (13,16), which contributes to an increase in cellular lipid peroxidation in studies with erythrocytes in vitro (43) and in diabetic patients (44,45). Consistent with this, a recent work showed that a high fat diet increases the level of MDA in serum, liver, aorta and kidney of Sprague-Dawley rats (46). In our study, oxidative stress, as determined by TBA-RS levels, increased in cerebral, renal and hepatic tissues of mice fed the HF diet compared with those fed the HS diet.
Positive correlations were found between the GHbA1c concentration and TBA-RS levels for hepatic, renal and cerebral tissues. Because the variations in glycemia parallel the levels of GHbA1c in blood, our data clearly indicate that feeding mice a HF diet elevates serum glucose levels, which can trigger oxidative stress in various tissues. The exact mechanism by which elevated blood glucose leads to membrane lipid peroxidation in diabetics is not clear. Nonenzymatic protein glycation is a complex cascade of reactions leading to the so-called advanced glycation end products (10,16,47,48). In general, the nonenzymatic glycation of proteins has been postulated to explain the relationship between hyperglycemia and lipid peroxidation. This hypothesis is based on the observation that glucose can itself attack and bind to the amino groups of proteins by a nonenzymatic process that forms a Schiff’s base compound. Subsequently, this Schiff’s base adduct is converted to stable glycation products, such as glycated hemoglobin. This process generates radicals and highly reactive oxidants from the glycated proteins under physiologic conditions. The formation of ROS beyond the detoxifying capacity of cells could cause oxidative damage to membrane lipids (principally PUFA) in the cells (49).
The higher PUFA content of the HF diet could result in a higher tissue concentration of linoleic acid, one of the precursors of MDA. Thus, there is a question whether oxidative stress actually occurred, or whether this was an artifact of the TBARS assay. In fact, the types and levels of dietary fat affect the susceptibility of membranes to lipid peroxidation (50,51), particularly when tissue autooxidation is assessed in vitro after a period of preincubation (51). In the present study, TBARS were determined both with and without preincubation of the tissues and, as expected, TBARS production increased in liver and brain after preincubation. However, the increase in TBARS was proportional to its basal level, indicating that the PUFA content of membranes is not artifactually exacerbating the quantification of lipid peroxidation in our assay system.
Glycation and carbonylation of proteins can inactivate enzymes, which may play an important role in the long-term effects of hyperglycemia (47). In this work, -ALA-D activity of HF-fed mice was significantly lower than that of HS-fed mice for liver, kidney and brain. A frequent coexistence of diabetes with porphyria diseases, mainly porphyria cutanea tarda, has been reported (33). In line with this, the activities of several enzymes of the heme pathway were diminished in both the diabetic population (32) and diabetic mice (12,30). Importantly, -ALA-D, which is the second enzyme in the heme pathway, may be glycated by glucose and also by several others sugars (52).
Another aspect that must be considered here is the observation that the consumption of high fat diets (especially those rich in saturated fatty acids such as stearic acid) increases iron absorption and deposition in different tissues (53–55). In the present study, lard was used as the major source of fat; thus the HF diet contained 
34 g stearic acid/kg and 60 g/kg palmitic acid (56), another fatty acid that facilitates iron transport (57). Because porphyria cutanea tarda is associated with iron overload (58–60) and hepatic porphyria is associated with lipid and DNA oxidant damage (61), it is very likely that the impaired PBG synthesis observed in our model is similarly associated with altered iron homeostasis, which may have important implications for lipid peroxidation.
The molecular mechanism underlying -ALA-D impairment in diabetes is still not completely understood, but may be caused either by glycation and carbonylation of the active site lysine residue involved in Schiff’s base formation with the first -ALA molecule or oxidation of essential reduced cysteinyl residues of the enzyme (52,62,63). DTT, which acts by reducing disulfide bonds, did not abolish the inhibitory effect of the HF diet on -ALA-D inhibition, suggesting that the hyperglycemia associated with HF diet feeding can cause glycation of the active site lysine. Overproduction of free radicals, whose formation was confirmed by an increase in TBA-RS production, certainly contributes to the formation of adducts between the aldehyde group of glucose and the amino group of lysine in -ALA-D. This labile adduct then undergoes an Amadori rearrangement to the stable ketoamine (17). Furthermore, analogous with other enzymes (47), carbonylation of residues such as lysine and cysteine can also contribute to the -ALA-D inhibition observed in HF-fed mice. Finally, -ALA-D inhibition can result in -ALA accumulation which, under physiologically relevant conditions, can have prooxidant effects (64,65) and can exacerbate the oxidative stress caused by hyperglycemia.
In accordance with this, a negative correlation was found between the percentage of GHbA1c and -ALA-D activity for hepatic, renal and cerebral tissues, suggesting that glycated plasma protein levels could be used as a good predictor of intracellular glycation. In fact, early glycation in cytosolic proteins is closely associated with glycated proteins in plasma during short periods of experimental diabetes (66,67). Most importantly, in vitro glycation of hemoglobin strictly parallels human blood -ALA-D inhibition (63). Thus, -ALA-D inhibition caused by feeding female mice high fat diets is likely to be associated with glycation of this enzyme in the tissues studied (liver, kidney, and brain).
We examined alterations in -ALA-D activity and oxidative stress in the present work in an attempt to better understand the mechanisms underlying the pathogenesis of some of the complications in obesity and diabetes. In summary, the present work demonstrated that a short-term change in the macronutrient proportion of the diet from largely carbohydrate to a marginal predominance of fat significantly elevated HbA1c content, indicating that the HF diet caused a hyperglycemia that is characteristic of insulin resistance. Of particular importance, this study presents evidence for the first time that short-term, high fat consumption has a negative effect on the heme synthesis pathway and on oxidative status associated with protein glycation in mice. Thus, increased oxygen radicals can stimulate the glycation of proteins associated with hyperglycemia, and physiological antioxidants that prevent lipid peroxidation reactions may be able to modulate glycation of cellular proteins in diabetes.
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FOOTNOTES |
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3 Abbreviations used: -ALA-D, -aminolevulinate dehydratase; ALA, 5-aminolevulinic acid; DTT, dithiothreitol; GHbA1c, glycated hemoglobin; HF, high fat; HS, high starch; MDA, malondialdehyde; PBG, porphobilinogen; ROS, reactive oxygen species; TBA, thiobarbituric acid; TBA-RS, thiobarbituric acid-reactive species.
Manuscript received 14 December 2002. Initial review completed 8 January 2003. Revision accepted 17 March 2003.
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