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Laboratory of Nutritional Biochemistry, Nagoya University, Nagoya 464-8601, Japan
3 To whom correspondence should be addressed. E-mail: hirooda{at}agr.nagoya-u.ac.jp.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • sulfur-containing amino acids • methionine • cystine • taurine • cholesterol
Abnormality of lipid metabolism is known to be associated with lifestyle-related diseases such as metabolic syndrome. It is necessary to normalize cholesterol metabolism in blood for prevention and treatment of atherosclerosis. It has been shown that HDL4 (high-density lipoprotein)-cholesterol is negatively correlated with risk of coronary heart disease. Although the effect of dietary lipid and carbohydrate on cholesterol metabolism has been extensively investigated, the effect of dietary protein has not been studied in great detail. It is only known that vegetable protein reduces plasma level of cholesterol as compared with animal protein by an unknown mechanism (1–4). Some investigators have found that the source of the protein is not always important and that amino acids themselves and their balance as well as peptides are responsible for the protein effect on lipid metabolism (5–7). SAAs (sulfur-containing amino acids) among amino acids are some of the most potent modulators of lipid metabolism (8). Methionine increased HDL-cholesterol (9). Cystine effectively reduced VLDL (very low-density lipoproteins)-cholesterol (8). Taurine reduced VLDL cholesterol and tended to elevate HDL-cholesterol (10,11). SAAs seem to elevate HDL-cholesterol and to decrease VLDL cholesterol. These data indicate that intake of dietary SAAs has some beneficial functions for the prevention or treatment of atherosclerosis. In this review, we have tried to 1) establish the role of amino acids as one of the major modulators for cholesterol metabolism, 2) establish a feasible index for improvement of lipid metabolism by SAAs, and 3) explore the mechanism of the action.
Sulfur-containing amino acids and HDL-cholesterol
It is well known that soy protein reduces the plasma level of cholesterol and risk of atherosclerosis (1–4). Soy protein reduces HDL-cholesterol as well as VLDL-cholesterol as compared with casein in rats fed a cholesterol-free diet (9). Most of the cholesterol in plasma exists as HDL-cholesterol in rats because of cholesterol ester transfer protein deficiency (12). Therefore, changes in plasma cholesterol in rats fed a cholesterol-free diet occur in the HDL fraction (5,12–14). Supplementation of methionine to soy protein elevated plasma cholesterol to a similar level to the plasma cholesterol in rats fed casein (9). Addition of methionine to casein also increased serum cholesterol in rats (15). Methionine-supplementation increased HDL-cholesterol and apolipoprotein A-I (apo A-I) in blood (13). Moreover, hepatic mRNA levels and transcription rates of apo A-I gene were increased by the addition of methionine to soy protein (13). Egg white protein, which contains more SAAs than other proteins, increased HDL-cholesterol in humans, mice, and rats compared to casein (7,16). Therefore, the stimulation of apo A-I gene by methionine might be responsible for the increased HDL-cholesterol resulting from the addition of methionine to the diet.
The feeding of xenobiotics, such as polychlorinated biphenyls (PCB), 2,6-di-tert-2,2-butyl-p-cresol (BHT), or phenobarbital, to rats causes an increase in plasma cholesterol, tissue ascorbic acid level, and the activity of hepatic drug-metabolizing enzymes (12,17). Hypercholesterolemia induced by xenobiotics is a novel type of hyper-
-lipoproteinemia, which is thought to result from activation of cholesterol synthesis and apo A-I gene expression (12). This type of hypercholesterolemia can be a useful model for investigating HDL metabolism because amplified HDL-cholesterol enables us to detect small changes in HDL metabolism. In rats fed PCB, addition of methionine strongly elevated HDL-cholesterol (14), although supplementation of cystine was less effective on HDL-cholesterol levels than methionine (18). As mentioned below, taurine also tended to increase HDL-cholesterol (11). On the other hand, supplementation of methionine and lysine increased total and LDL (low-density lipoproteins)-cholesterol levels in plasma in rabbits (19). In contrast to rodents, feeding casein to rabbits markedly elevated plasma LDL-cholesterol (20). Moreover, changes in plasma cholesterol in humans and rats are more moderate than those in rabbits (20). Because each species has different cholesterol and lipoprotein metabolism, more comparative study about SAA effects is required to determine the precise actions of SAAs on HDL-cholesterol.
These data suggested that the ingestion of SAAs can lead to an increase in blood HDL-cholesterol levels. It seems that HDL-cholesterol is elevated by SAAs through an increase of apo A-I gene expression in the liver. The magnitude of the action was different among SAAs. Relatively small amounts of methionine increased serum cholesterol in rats, but excess methionine caused growth retardation and reduction of serum cholesterol (15). Excess amounts of cystine in the diet also caused growth retardation, but elevated plasma cholesterol (21). Increased HDL-cholesterol by SAAs might be beneficial for prevention of atherosclerosis. Because it is known that excess amounts of SAAs show side effects (22), an adequate SAA intake should be determined.
Sulfur-containing amino acids and VLDL-cholesterol
Feeding of a high-cholesterol diet suppresses cholesterol biosynthesis and increases VLDL-cholesterol in rats (23). Although VLDL is mainly transformed to LDL in humans, most of the remnant VLDL returns to the liver, and a small portion of VLDL changes to LDL in rats. Seidel et al. (24) identified the significance of SAAs in cholesterol metabolism in rats fed a high-cholesterol diet. Egg white protein, which contains more SAAs than other proteins, reduced VLDL-cholesterol and triglyceride efficiently in rats fed a high-cholesterol diet (7). Both methionine and cystine reduced the serum level of cholesterol (24). Sugiyama et al. (8) reported that cystine effectively reduced plasma cholesterol in rats fed a high-cholesterol diet. However, they observed that the addition of methionine increased plasma cholesterol in rats fed a high-cholesterol diet (8). Because the reason for the differences in methionine effects is unclear, changes in VLDL metabolism by methionine should be investigated in detail. Supplementation of methionine and cystine reduced the plasma level of VLDL- and LDL-cholesterol in another type of hypercholesterolemia, which was induced by implantation of hepatoma cells (25). This animal model for hypercholesterolemia showed an increase in VLDL- and LDL-cholesterol because of the reduction of lipoprotein lipase activity (25). Taurine, an endproduct of SAAs, strongly induced CYP7A1 gene expression and reduced VLDL cholesterol in rats fed a high-cholesterol diet (10). These results suggested that VLDL-cholesterol was decreased by SAAs through the induction of CYP7A1 gene expression in the liver. Decreased VLDL-cholesterol by SAAs might be beneficial for prevention of atherosclerosis. It was actually demonstrated that dietary taurine significantly reduced atherosclerotic lesions in apo E-deficient mice (26). Excess amounts of some SAAs show toxic effects (15,22), although taurine has not been shown to have strong toxicity. Adequate SAA intake should be determined before SAAs are used to ameliorate high plasma LDL and VLDL levels.
Relative availability of sulfur-containing amino acids controls lipid metabolism
As mentioned above, the content of SAAs in a diet significantly affects plasma lipid levels. However, SAAs content only partly explains how dietary protein affects plasma lipid levels. For example, wheat gluten has a cholesterol-lowering effect, but the mechanism of the effect is not understood (27). The first limiting amino acid of wheat gluten is lysine, and wheat gluten contains SAAs at a nearly adequate level for maximum growth. We hypothesized that the hypocholesterolemic effect of gluten can be explained in part by the balance between SAAs and the first limiting amino acid. SAAs seem to be in excess compared to lysine in rats fed a wheat gluten diet. Rats fed a wheat gluten diet showed a high level of taurine in urine and liver (28). Moreover, CYP7A1 gene expression was induced by feeding wheat gluten but not by feeding casein only (29). It is postulated that SAAs are in relative excess in wheat gluten because of the shortage of lysine, and that this relative excess in SAAs reduces plasma cholesterol through the activation of CYP7A1 gene expression. From this hypothesis, we proposed that the relative availability of SAAs (RASAA) could be an index for cholesterol metabolism. RASAA is calculated using as the following formula:
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Based on preliminary, unpublished data (H. Oda), higher RASAA is associated with lower plasma cholesterol levels in rats fed a high-cholesterol diet. Plasma triglyceride also shows a negative correlation with RASAA. On the other hand, higher RASAA shows a higher level of CYP7A1 mRNA in the liver. These suggest that the balance of SAAs (RASAA) is more important for lipid metabolism than the content of SAAs.
Possible mechanism of sulfur-containing amino acids function on lipid metabolism
Although we still do not know the mechanism of SAAs' action, there are some possibilities:
The redox state of glutathione changes enzyme activity and transcriptional activity.
Dietary SAAs other than taurine determine the hepatic level of glutathione. The concentration and ratio of the reduced form (GSH) to the oxidized form (GSSG) of glutathione regulate protein functions including enzyme activity, stability of proteins, activity of transcription factors (c-Fos, c-Jun) (30), and steroid hormone receptor functions. NF-
B is known to be activated by many extracellular stimuli (31). Phosphorylated I-B by activated IKK (I-B kinase) is degraded by the proteasome pathway. Released NF-B then goes into the nucleus to bind to the B site of target genes (31). This signal transduction pathway is also inhibited strongly by GSH (31). In cholesterol metabolism, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase and CYP7A1, which are rate-limiting steps in cholesterol synthesis and degradation, respectively, are activated by GSH. The activity of HMG-CoA reductase is dependent not only on the ratio of [GSH]/[GSSG] but also on the amount of GSH in vitro (32). The activity of CYP7A1 is dependent on the concentration of SH groups (33). Therefore, when cholesterol synthesis is suppressed by feeding a high-cholesterol diet, higher hepatic GSH content resulting from feeding higher amounts of SAAs might enhance cholesterol degradation.
SAAs might change posttranslational modification of some regulatory proteins.
Taurine, one of SAAs, is synthesized mainly in the liver as an endproduct of SAA catabolism. As mentioned above, dietary taurine effectively reduced VLDL-cholesterol in rats fed a high-cholesterol diet (10), and HDL-cholesterol tended to be elevated by dietary taurine (11). Dietary taurine strongly induced the activity and gene expression of CYP7A1 in the liver (10). The gene expression of HNF-4 (hepatocyte nuclear factor) and LXR (liver X receptor) was not changed by taurine treatment (34). These results suggest that taurine exerts its effect through posttranslational modification of regulatory proteins such as those associated with phosphorylation/dephosphorylation or ligand binding to nuclear receptors.
SAAs stimulate gene expression directly or indirectly. As mentioned above, CYP7A1 is a target gene of SAAs. Apo A-I appears to be a target gene of SAAs too. Kilberg et al. summarized amino acid–dependent control of transcription in mammalian cells (35). Although several genes controlled by amino acids are listed in their review, CYP7A1, apo A-I, and SAA-related genes are not in the list. Because we do not know any other target genes of SAAs, a preliminary DNA microarray analysis was performed, and it was found that each SAA changed the expression of >100 genes (H. Oda, unpublished data). Detailed analysis of the DNA microarray with bioinformatics might reveal interaction of the expression of signal transduction pathways of SAAs and the specific target genes of each SAA. Because supplementation of SAAs to diets can lead to an increase in plasma level of homocysteine, it is important to observe the effect of SAAs on enzymes involved in homocysteine metabolism. Homocysteine is thought to be a potent risk factor for atherosclerosis (36). Plasma homocysteine is inversely associated with the plasma level of folate, which is a cofactor of methionine synthase to convert from homocysteine to methionine (37). Betaine homocysteine methyltransferase (BHMT) catalyzes a methyl transfer from betaine to homocysteine, forming dimethylglycine and methionine. Although the significance of BHMT in homocysteine metabolism is not clear, it is known that the relative contribution of BHMT to homocysteine remethylation can be influenced by diet (38). Orally administered betaine resulted in lowered plasma level of homocysteine in healthy humans (39). Supplementaion of SAAs should be done carefully to prevent the increase in plasma homocysteine because methionine is a precursor of homocysteine. The induction in BHMT might be protective against an increase in plasma homocysteine. We are at present investigating the relation among plasma homocysteine, BHMT, and supplementation of SAAs.
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FOOTNOTES |
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2 Supported in part by a Grant-in-Aid for Scientific Research (15580104) from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan.
4 Abbreviations used: apo, apolipoprotein; BHMT, betaine homocysteine methyltransferase; BHT, 2,6-di-tert-2,2-butyl-p-cresol; CYP7A1, cholesterol 7-hydroxylase; GSH, reduced form of glutathione; GSSG, oxidized form of glutathione; HDL, high-density lipoproteins, HMG-CoA, 3-hydroxyl-3-methylglutaryl coenzyme A; HNF, hepatocyte nuclear factor; IKK, I-B kinase; LDL, low-density lipoproteins; LXR, liver X receptor; PCB, polychlorinated biphenyls; RASAA, relative availability of sulfur-containing amino acids; SAAs, sulfur-containing amino acids; VLDL, very low-density lipoproteins.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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