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Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011 and * Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801
3To whom correspondence should be addressed. E-mail: kschalin{at}iastate.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • thyroid • glycine N-methyltransferase • homocysteine • retinoic acid • rats
Folate functions as a family of coenzymes that provide one-carbon units for the de novo synthesis of purines and pyrimidines, and for the remethylation of homocysteine to reform methionine (1,2). Methionine has a central role in one-carbon metabolism that is mediated by its conversion to S-adenosylmethionine (SAM).4 SAM is the primary methylating agent in the body, providing methyl groups for >100 biological transmethylation reactions that are critical for cell function and optimal health. For example, methyl group deficiency and a lack of SAM can lead to DNA hypomethylation, thereby resulting in increased expression of oncogenes (3). Because most SAM-dependent methyltransferases are inhibited by the reaction product, S-adenosylhomocysteine (SAH), the ratio of SAM to SAH is an important index of transmethylation potential in the cell (4,5). After transmethylation, SAH can be hydrolyzed to homocysteine. Homocysteine can be remethylated to form methionine by either the folate-dependent enzyme methionine synthase (MS), or by a folate-independent reaction catalyzed by betaine-homocysteine S-methyltransferase (BHMT). Alternatively, homocysteine can participate in the transsulfuration pathway whereby homocysteine and serine are converted to cysteine, 
-ketobutyrate, and ammonia. In addition to providing the necessary cysteine for protein synthesis, the homocysteine-dependent production of cysteine is important for antioxidant defense. Cell culture studies showed that approximately half of the cysteine moiety of glutathione is derived from homocysteine and the transsulfuration pathway (6). Thus, the disruption of one-carbon and sulfur amino acid metabolism can result in compromised health and increased risk for disease.
SAM exerts regulatory control of folate metabolism and methyl group supply from the one-carbon pool through its allosteric inhibition of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) (7,8). Glycine N-methyltransferase (GNMT) catalyzes the conversion of glycine to sarcosine, along with the associated conversion of SAM to SAH. Sarcosine has no known physiologic function, suggesting that GNMT functions to regulate the SAM/SAH ratio. Moreover, GNMT is allosterically inhibited by 5-methyltetrahydrofolate (5-methyl-THF), the product of the reaction catalyzed by MTHFR (9,10). It follows that high levels of SAM inhibit MTHFR activity and the subsequent synthesis of 5-methyl-THF, thereby increasing GNMT activity and allowing excess methyl groups to be disposed of as sarcosine until the SAM/SAH ratio is restored. Conversely, if methyl groups and subsequent SAM levels are low, 5-methyl-THF synthesis will increase, GNMT activity will be inhibited, and methyl groups will be conserved for transmethylation reactions of biological importance.
Our research to date indicates that retinoids disrupt the interrelation between the one-carbon pool and methyl group metabolism (11–14). We demonstrated that retinoid compounds are capable of decreasing the hepatic concentration of SAM and the SAM/SAH ratio (15,16). More recently, we found that the mechanistic basis for altering methyl group metabolism resides in elevated GNMT activity and induction of GNMT protein abundance. All-trans-retinoic acid (RA) was the most potent inducer of active GNMT protein, and this activation was found to be biologically important as shown by the subsequent hypomethylation of DNA (12). Moreover, RA treatment reduced circulating levels of methionine and homocysteine (11). Because the induction of GNMT does not appear to be mediated directly by RA, research efforts have focused on identifying other physiologic or cellular signals that may be involved.
A number of studies showed that thyroid status can perturb hepatic one-carbon metabolism (17–23), and thus may function to regulate the activity of GNMT post-translationally. For example, hypothyroidism decreases the activity of MTHFR. It would be expected that this would lead to diminished synthesis of 5-methyl-THF and, consequently, increased GNMT activity. Conversely, hyperthyroidism increases the enzymatic activity of MTHFR, thereby resulting in 5-methyl-THF accumulation and potentially inhibiting GNMT activity. However, there have been no previous investigations into the direct effects of thyroid status on the regulation of GNMT.
Interestingly, it was observed that large doses of retinol and RA resulted in a sharp decrease in serum thyroid hormone concentrations, a decrease in the half-life of thyroxine (T4), and an increased concentration of triiodothyronine (T3) and T4 in the tissues of rats (24). Thus, it is plausible that treatment with T3 may prevent or reverse some of the anomalies resulting from retinoid administration. Our focus in this study was to determine the following: 1) whether a hypothyroid condition resulted in similar disruption of hepatic methyl group metabolism as RA; and 2) whether treatment with T3 could prevent the effects of RA on methyl group and homocysteine metabolism.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Animals and diets. All animal experiments were approved by and conducted in accordance with guidelines established by Iowa State University Laboratory Animal Resources. Male Sprague-Dawley (Harlan Sprague Dawley) rats (50–74 g) were housed in plastic cages in a room with a 12-h light:dark cycle and consumed water and a control diet (14) ad libitum. The control diet consisted of (g/kg diet): cornstarch, 402; glucose monohydrate, 393; casein, 100; AIN 93 mineral mix, 40; AIN 93 vitamin mix, 10; corn oil, 50; choline bitartrate, 2; and L-methionine, 3. For experiment series 1, rats were randomly assigned to 1 of 4 treatment groups (n = 6): control, RA, PTU, and PTU + RA. PTU was used to induce a hypothyroid state and was administered at 0.5 g/L drinking water for 15 d (18). Rats were administered a daily dose of either corn oil vehicle or corn oil containing RA (30 µmol/kg body weight) for a total of 5 d beginning on d 10. For experiment series 2, rats were randomly assigned to 1 of 4 treatment groups (n = 6): control, RA, T3, and T3 + RA. Corn oil or corn oil containing RA (30 µmol/kg body weight) was administered for a total of 7 d. For the hyperthyroid treatment, rats were injected daily (i.p.) with either 50 µg T3/100 g body weight or vehicle (0.01 mol/L sodium hydroxide) for a total of 4 d beginning on d 3. This experimental design was based on previous studies designed to provide saturating levels of T3 and RA (11,14,16,19,26). After the treatment period in each of the experimental series, rats were anesthetized with ketamine:xylazine (90:10 mg/kg body weight) 4–5 h into the light cycle, and blood and liver samples were immediately collected. Rats were killed by exsanguination.
GNMT activity. The enzymatic activity of GNMT was assayed as described by Cook and Wagner (27) with minor modifications. Liver tissue samples were homogenized in 4 volumes of ice-cold buffer containing 10 mmol/L sodium phosphate (pH 7.0), 0.25 mol/L sucrose, 1 mmol/L EDTA, 1 mmol/L sodium azide, and 0.1 mmol/L PMSF. After centrifugation at 20,000 x g for 30 min, the resulting supernatant was removed and 2-mercaptoethanol was added to a final concentration of 10 mmol/L. The substrate mixture for the assay consisted of 0.1 mol/L Tris buffer (pH 9.0), 5 mmol/L dithiothreitol, 1 mmol/L glycine, and 1 mmol/L S-adenosyl-L-[methyl-3H]methionine (4.77 MBq/mmol). The reaction was initiated upon addition of 250 µg of sample protein. The assay was linear with respect to time and protein concentration. Total soluble protein in the tissue extract was determined using a commercial kit (Coomassie Plus, Pierce) according to the method of Bradford (28) with bovine serum albumin (BSA) as a standard.
GNMT and CBS abundance.
For the measurement of relative protein abundance of GNMT and CBS, 75 µg of total protein was denatured in Laemmli sample buffer, loaded onto a 10–20% gradient SDS polyacrylamide gel and run using a Tris-glycine buffer system. Separated proteins were transferred electrophoretically to nitrocellulose and blocked for 1 h with Tween Tris-buffered saline (TTBS) buffer [20 mmol/L Tris (pH 7.5), 500 mmol/L NaCl, 500 µL/L Tween 20] containing 50 g/L nonfat dry milk. After subsequent washing with TTBS, membranes were incubated overnight at 4°C with GNMT antibodies (1:3,000) or CBS antibodies (1:20,000) in TTBS containing 10 g/L BSA. GNMT and CBS protein monomer (
32 and 63 kDa, respectively) were detected using a goat anti-mouse (1:5,000) and a goat anti-rabbit (1:10,000) secondary antibody, respectively, in TTBS. After chemiluminescence detection and subsequent exposure to Kodak X-Omat AR film, the relative density of the protein bands was quantified using SigmaGel software (SPSS).
Total homocysteine and glutathione. Plasma total homocysteine and glutathione levels were measured using the method described by Ubbink et al. (29) with minor modifications. Whole-blood samples were collected by cardiac puncture using heparinized syringes. Plasma was immediately obtained by centrifugation at 400 x g for 5 min and stored at –20°C before analysis of homocysteine. The plasma sample was thawed and treated with 100 mL/L tri-n-butyl phosphine in dimethylformamide to release protein-bound homocysteine and reduce mixed disulfides. After incubation at 4°C for 30 min, 100 g/L trichloroacetic acid containing 1 mmol/L EDTA was added to precipitate protein. After centrifugation at 1000 x g for 5 min, the supernatant was removed followed by the addition of 20 µL of 1.55 mol/L sodium hydroxide, 250 µL of 0.125 mol/L borate buffer containing 4 mmol/L K2EDTA (pH 9.5), and 100 µL of ammonium 7-fluorobenzo-2-oxa-1,3-diazole-4-sulfonate. Homocysteine and glutathione were separated by reversed-phase HPLC using a Waters C18 µBondapak column in conjunction with fluorometric detection (excitation: 385 nm; emission: 515 nm). An internal standard of N-acetylcysteine and standard curves were used to quantify plasma homocysteine and glutathione concentrations.
MS and BHMT analysis. Liver samples were homogenized in 4 volumes of ice-cold phosphate buffered (10 mmol/L, pH 7.0) sucrose (0.25 mol/L) containing 1 mmol/L EDTA, 1 mmol/L sodium azide, and 0.1 mmol/L PMSF. For both enzyme assays, DL-homocysteine solutions (100 mmol/L) were freshly prepared for each experiment. In brief, a thiolactone derivative (15.4 mg) was dissolved in 400 µL of 2 mol/L sodium hydroxide; after 5 min at room temperature, the solution was neutralized with 600 µL of a saturated monopotassium phosphate solution. For MS, samples consisting of 600 µg total protein were incubated at 37°C for 1 h in a reaction mixture containing sodium phosphate buffer (500 mmol/L, pH 7.5), cyanocobalamin (1.3 µmol/L), dithiothreitol (1 mol/L), SAM (10 mmol/L), 2-mercaptoethanol (82.4 mmol/L), homocysteine (100 mmol/L), and 15 mmol/L 5-[methyl-14C]-THF (6.44 kBq/µmol). The reaction was terminated by the addition of ice-cold water. Samples were applied to a AG 1-X8 column (10 x 100 mm, Bio-Rad), eluted in deionized water (3 mL total), and subjected to liquid scintillation counting. BHMT activity was measured as described in detail by Garrow (30). The standard BHMT assay contained 5 mmol/L DL-homocysteine, 2 mmol/L [methyl-14C] betaine (3.7 kBq), and 40 µg total protein.
Cell culture. Rat hepatoma H4IIE cells and pancreatoma AR42J cells (American Type Culture Collection) were grown separately in 150-cm2 flasks to 70–75% confluence under 5% CO2 in a humidified incubator at 37°C in DMEM containing 100 mL/L fetal bovine serum, penicillin (100,000 U/L) and streptomycin (100 mg/L). Cell lines were given fresh media immediately before treatments. Cells were treated with vehicle alone, or with various combinations of DEX (0.1 µmol/L), RA (10 µmol/L), and T3 (2 µmol/L). After a 72-h incubation period in the presence of the various treatment reagents, cells were detached with 2.5 g/L trypsin/1 mmol/L EDTA, washed twice in HBSS, and lysed on ice in a buffer containing 10 mmol/L HEPES (pH 7.0), 10 mmol/L sodium pyrophosphate, 50 mmol/L sodium fluoride, 50 mmol/L ß-glycerophosphate, 5 mmol/L EDTA, 1 mmol/L sodium orthovanadate, 2 mmol/L benzamidine, 10 mg/L leupeptin and pepstatin, 250 mg/L soybean trypsin inhibitor, 0.2 mmol/L PMSF, 24 mg/L p-nitroguanidinobenzoate, and 5 mL/L Nonidet P-40. Lysates were centrifuged at 16,000 x g for 8 min after which supernatants were removed and stored at –70°C for subsequent analysis of GNMT protein abundance.
Statistical analysis. The means of each treatment group were subjected to a two-way ANOVA (P < 0.05) and compared using Fisher’s least significant difference test (31). All statistical analysis were performed using SigmaStat2.0 (SPSS, Chicago, IL).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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70% of the control values. The administration of RA did not affect weight gain. GNMT activity was not induced in hypothyroid rats. The administration of RA increased the hepatic activity of GNMT 72 and 69% in euthyroid and hypothyroid rats, respectively (Fig. 1). PTU treatment had no effect on GNMT activity, indicating that the effect of RA on methyl group metabolism was not mediated by a hypothyroid condition.
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25%) the circulating concentrations of total glutathione, regardless of thyroid status (Fig. 5A). The marked changes in plasma homocysteine concentrations resulting from T3 and/or RA treatment were not associated with similar alterations in the abundance of CBS, a key enzyme in homocysteine catabolism (Fig. 5B).
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70% for both hyperthyroid groups irrespective of RA administration.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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On the basis of earlier reports demonstrating that retinoid administration lowered thyroid hormone levels and thyroid status influenced the hepatic folate-dependent one-carbon pool (16,17,20,21,24,32,33), we initially hypothesized that a mediating signal in the ability of RA to alter GNMT may be a reduction in the circulating levels of thyroid hormones, and subsequent treatment with T3 would restore the anomalies associated with RA administration. It was evident from our earlier work that induction of GNMT protein by RA and/or DEX could be accomplished directly in a cell culture model, indicating that at least part of this regulation was not dependent on hormone action (14). Although hypothyroidism did not modulate GNMT activity, the RA-mediated increase in hepatic GNMT activity was completely abolished by subsequent treatment with T3. To date, T3 treatment represents the first known factor, nutritional or hormonal, that can abrogate the effects of RA on GNMT regulation.
An interesting finding in our studies was that although T3 prevented the RA-mediated increase in GNMT activity, the abundance of GNMT protein remained partially elevated, thus indicating that the restoration of normal GNMT activity by T3 may be accomplished, at least in part, by a post-translational mechanism. This was supported by cell culture studies demonstrating that T3 had no effect on modulating GNMT protein abundance. GNMT was shown to be post-translationally regulated by phosphorylation and the allosteric binding of 5-methyl-THF, which function to activate and inhibit the enzymatic activity of the protein, respectively (9,10). This latter inhibitory mechanism represents a plausible explanation for our findings with RA- and T3-treated rats. A hyperthyroid condition was reported to result in an increase in the hepatic activity of MTHFR, whereas the activity of MS was reduced (17,21,32–34). It would be predicted that these changes in one-carbon pool enzymes may result in the accumulation of 5-methyl THF, thereby potentially inhibiting the activity of GNMT. However, it is also clear from our studies that the abundance of GNMT in RA-treated rats administered T3 was not elevated to the same extent as in those administered RA alone, indicating that there are likely multiple mechanisms involved, such as transcriptional control. It is well documented that T3 and RA can compete for heterologous regulation of specific transcription factors and subsequent response elements (26,35).
An unexpected and novel finding in our studies was the marked hyperhomocysteinemia exhibited by hyperthyroid rats. In contrast, rats administered RA before treatment with T3 did not have elevated plasma homocysteine concentrations. This is consistent with previous studies demonstrating that RA treatment lowers the circulating levels of homocysteine as well as methionine (11). We found similar results in preliminary studies that consisted of RA administration after treatment with T3, thus indicating that RA can prevent or reverse the hyperhomocysteinemia associated with hyperthyroidism (K.A. Tanghe and K.L. Schalinske, unpublished observations).
It appears that regulation of homocysteine metabolism by both RA and T3 may be the result of changes in the activity of the key hepatic remethylation enzymes, MS and BHMT. The hyperhomocysteinemia resulting from a hyperthyroid condition may be related to a marked reduction in folate-independent remethylation (i.e., BHMT), whereas lowering normal or high plasma homocysteine levels by RA could be achieved from upregulation of folate-dependent remethylation (i.e., MS). This is in agreement with earlier studies demonstrating that T3 diminished the activity of MS and BHMT (21,34). In contrast, the catabolism of homocysteine via the hepatic transsulfuration pathway, based on the abundance of CBS, does not appear to be a contributing factor. However, because a number of allosteric factors, such as SAM, can regulate both the remethylation and transsulfuration pathways (17,18,36), direct measurements of metabolic flux in vivo are required to arrive at any definitive conclusions about the relative contributions of these pathways to homocysteine homeostasis. In support of this possibility, we showed previously that in the liver, retinoid compounds diminish SAM concentrations and enhance the catabolism of methionine to taurine, at the expense of glutathione synthesis (15,37). Glutathione synthesis is highly dependent on the transsulfuration pathway (6), and in this study, we found that circulating levels of glutathione were also diminished by RA. T3 treatment had no effect on plasma glutathione levels, in contrast to earlier reports that showed significant elevations in hyperthyroid rats (38). Although the liver is a key organ in methyl group and homocysteine metabolism, as well as the synthesis of glutathione, the contribution of extrahepatic tissues to the circulating levels of homocysteine and glutathione cannot be overlooked. For example, the kidney contributes extensively to the metabolism of homocysteine. Hyperhomocysteinemia was reported under diabetic conditions characterized by renal dysfunction, whereas plasma homocysteine concentrations were lowered in the absence of renal insufficiency (39,40). Similarly, the effects of thyroid hormone and RA on folate, methyl group, and homocysteine metabolism differ in liver and kidney (18,41). It will be important in future research to evaluate the contribution of different tissues to homocysteine and glutathione metabolism as a function of thyroid status and RA administration.
In conclusion, we showed that a significant interaction exists between RA and thyroid status with respect to modulating GNMT function and the metabolism of homocysteine. Our findings complement the recent studies of Brosnan and co-workers directed at examining homocysteine metabolism in the hypothyroid rat (18). They reported that hypothyroidism, via PTU treatment or thyroidectomy, resulted in hypohomocysteinemia. They found that the reduction in plasma homocysteine concentrations was due primarily to an increase in hepatic catabolism of homocysteine by transsulfuration (i.e., CBS and 
-cystathionase), and treatment of thyroidectomized rats with T3 restored these metabolic anomalies. Although there was a significant decrease in the hepatic activity of MTHFR, no changes were observed in the hepatic activities of MS, BHMT, or GNMT. Thus, it is clear that both RA and thyroid status have profound effects on the metabolism of methyl groups and homocysteine in rats. Moreover, it appears that these factors have the ability to interact to attenuate their individual effect.
The relevance of these findings for humans is not clear. It was shown in a number of animal models, including humans, that vitamin A alleviates some of the symptoms associated with a hyperthyroid condition (42,43). We reported that the ability of RA to induce GNMT and modulate methyl group/homocysteine metabolism can be achieved rapidly and in clinically relevant doses (11). However, it is well documented that humans exhibit an opposing response compared with rats with respect to thyroid status and homocysteine metabolism. For humans, hyperhomocysteinemia is associated with a hypothyroid state (44–46). Future studies are warranted to elucidate and understand this species-specific difference.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported in part by the Iowa Agriculture and Home Economics Experiment Station; the Iowa State University Office of Biotechnology; the United States Department of Agriculture NRI 01–35200-09854 (K.L.S.); the American Institute for Cancer Research 00B078REV (K.L.S.); the Cancer Research and Prevention Foundation (K.L.S.); and the National Institutes of Health DK52501 (T.A.G.).
4 Abbreviations used: BHMT, betaine-homocysteine S-methyltransferase; BSA, bovine serum albumin; CBS, cystathionine ß-synthase; DEX, dexamethasone; GNMT, glycine N-methyltransferase; MS, methionine synthase, MTHFR, 5,10-methylenetetrahydrofolate reductase; 5-methyl-THF, 5-methyltetrahydrofolate; PMSF, phenylmethylsulfonyl fluoride; PTU, propylthiouracil; RA, all-trans-retinoic acid; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; T3, triiodothyronine; T4, thyroxine; TTBS, Tween Tris-buffered saline.
Manuscript received 18 June 2004. Initial review completed 22 July 2004. Revision accepted 6 August 2004.
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LITERATURE CITED |
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