Effects of betaine supplementation on hepatic metabolism of sulfur-containing amino acids in mice
Introduction
In mammals, the liver plays a central role in the metabolism of sulfur-containing amino acids because nearly one-half of the daily methionine intake is metabolized there [1]. Methionine metabolism occurs primarily via the transsulfuration pathway, which results in transfer of methionine sulfur to serine to form cysteine (Fig. 1). The first step in transsulfuration reactions is the formation of S-adenosylmethionine (SAM) that is catalyzed by methionine adenosyltransferase (MAT). SAM serves as the methyl donor for various biological methylation reactions, and the co-product, S-adenosylhomocysteine (SAH), is hydrolyzed to yield homocysteine that is either remethylated to methionine or condensed with serine into cystathionine. The transsulfuration of homocysteine to cysteine via cystathionine is mediated by the consecutive actions of cystathionine β-synthase (CβS) and cystathionine γ-lyase (CγL). Cysteine is irreversibly metabolized in liver to yield either taurine, inorganic sulfate, or glutathione (GSH). Cysteine dioxygenase (CDO) catalyzes the oxidation of this amino acid to cysteine sulfinate that is mainly converted to taurine via hypotaurine by the activity of cysteine sulfinate decarboxylase (CDC). Synthesis of GSH is mediated by γ-glutamylcysteine ligase (GCL) and GSH synthetase, consecutively.
Betaine, an oxidative metabolite of choline, is involved in the synthesis of methionine from homocysteine in liver. This reaction, catalyzed by betaine homocysteine methyltransferase (BHMT), has an important role in the maintenance of hepatic methionine, especially when the dietary intake of this amino acid is limited [2]. It was shown that betaine intake increased the hepatic SAM concentrations in experimental animals [3], and also reduced the homocysteine levels in human with homocystinuria [4]. Recently, it has been demonstrated that betaine supplementation prevents a rise in plasma homocysteine concentrations after methionine intake in persons with normal to mildly elevated homocysteine levels [5], [6]. But little published information is available concerning its effect on the transsulfuration reactions beyond homocysteine.
Our previous study indicated that acute betaine treatment to mice resulted in time-dependent changes in the hepatotoxicity induced by chloroform, which was associated with alterations in the hepatic GSH levels [7]. Recently, we have demonstrated that the changes in hepatic GSH in animals treated with betaine may be explained by its effect on the cysteine availability in liver [8]. In that study an acute dose of betaine rapidly enhanced metabolic reactions in the methionine cycle, but inhibited cystathionine synthesis and hepatic uptake of cysteine, leading to a decrease in the cysteine availability for GSH synthesis. Reduction in GSH was reversed slowly with the induction of cysteine synthesis and GCL activity. However, the effects of repeated betaine treatment on hepatic cysteine and GSH remained unknown. Inhibition of the transsulfuration reactions from homocysteine to cysteine may lead to a decrease in the synthesis of GSH, which would produce an important impact on normal biochemistry and physiology of mammals. Therefore, it was of significance to ascertain the changes in the hepatic metabolism of sulfur amino acids in animals supplemented with betaine.
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Animals and treatments
Male ICR mice, weighing 20–25 g, were obtained from Dae-Han Laboratory Animal (Seoul, Korea). The use of animals was in compliance with the guidelines established by the Animal Care Committee of this institute. Animals were acclimated to temperature (22±2 °C) and humidity (55±5%) controlled rooms with a 12-hr light/dark cycle (light: 0700–1900, dark 1900–0700) for at least 1 week prior to use. Laboratory chow and tap water were allowed ad libitum. Betaine-dissolved tap water (1%) replaced regular
Changes in major sulfur amino acid metabolites and liver/kidney physiology
The hepatic concentrations of major metabolites and products in the transsulfuration pathway were monitored in mice supplemented with betaine for 3 weeks (Fig. 2). The methionine, SAM, and SAH levels in liver were elevated significantly, while taurine was reduced after 1 week of betaine intake. However, hepatic cysteine or its metabolic product, GSH, was not affected. The changes in methionine, SAM, SAH, and taurine were further augmented as the supplementation period was extended to 2 weeks,
Discussion
In the present study, dietary betaine supplementation produced significant changes in the metabolism of sulfur amino acids in liver, which were stabilized in 2 weeks after initiation of its administration to mice. The hepatic levels of methionine, SAM and SAH were increased significantly, whereas homocysteine and cystathionine were reduced. The hepatic MAT activity was markedly elevated. Betaine supplementation depressed the CDO activity resulting in reduction of taurine generation. It should
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2018, BiochimieCitation Excerpt :GB increased the expression of the genes for methionine adenosyltransferase-1 (MAT1), methyl tetrahydrofolate reductase (MTHFR), glycine N-methyl transferase (GNMT), S-adenosyl homocysteine (SAH) hydrolase, betaine homocysteine methyl transferase (BHMT) in rat and mouse [80–82]. Also, there are changes in activity in the enzymes MS, BHMT, MAT1, GNMT, cystathionine β-synthase (CBS) [79–85]. Higher expression and activity of these enzymes caused by GB contributes to maintain low homocysteine levels in liver.