Betaine chemistry,roles, and potential use in liver disease

BackgroundBetaine is the trimethyl derivative of glycine and is normally present in human plasma due to dietary intake and endogenous synthesis in liver and kidney. Betaine is utilized in the kidney primarily as an osmoprotectant, whereas in the liver its primary role is in metabolism as a methyl group donor. In both organs, a specific betaine transporter mediates cellular uptake of betaine from plasma. The abundance of both betaine and the betaine transporter in liver greatly exceeds that of other organs.Scope of reviewThe remarkable contributions of betaine to normal human and animal health are summarized together with a discussion of the mechanisms and potential beneficial effects of dietary betaine supplements on liver disease.Major conclusionsA significant amount of data from animal models of liver disease indicates that administration of betaine can halt and even reverse progression of the disruption of liver function. Betaine is well-tolerated, inexpensive, effective over a wide range of doses, and is already used in livestock feeding practices.General significanceThe accumulated data indicate that carefully controlled additional investigations in humans are merited. The focus should be on the long-term use of betaine in large patient populations with liver diseases characterized by development of fatty liver, especially non-alcoholic fatty liver disease and alcoholic liver disease.     

Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis

Although simple steatosis was originally thought to be a pathologically inert histological change, fat accumulation in the liver may play a critical role not only in disease initiation, but also in the progression to nonalcoholic steatohepatitis and cirrhosis. Therefore, prevention of fat accumulation in the liver may be an effective therapy for multiple stages of nonalcoholic fatty liver disease (NAFLD). Promising beneficial effects of betaine supplementation on human NAFLD have been reported in some pilot clinical studies; however, data related to betaine therapy in NAFLD are limited. In this study, we examined the effects of betaine on fat accumulation in the liver induced by high-sucrose diet and evaluated mechanisms by which betaine could attenuate or prevent hepatic steatosis in this model. Male C57BL/6 mice weighing 20 +/- 0.5 g (means +/- SE) were divided into four groups (8 mice per group) and started on one of four treatments: standard diet (SD), SD+betaine, high-sucrose diet (HS), and HS + betaine. Betaine was supplemented in the drinking water at a concentration of 1% (wt/vol) (anhydrous). Long-term feeding of high-sucrose diet to mice caused significant hepatic steatosis accompanied by markedly increased lipogenic activity. Betaine significantly attenuated hepatic steatosis in this animal model, and this change was associated with increased activation of hepatic AMP-activated protein kinase (AMPK) and attenuated lipogenic capability (enzyme activities and gene expression) in the liver. Our findings are the first to suggest that betaine might serve as a therapeutic tool to attenuate hepatic steatosis by targeting the hepatic AMPK system.     

Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet

Aberrant DNA methylation contributes to the abnormality of hepatic gene expression, one of the main factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Betaine is a methyl donor and has been considered to be a lipotropic agent. However, whether betaine supplementation improves NAFLD via its effect on the DNA methylation of specific genes and the genome has not been explored. Male C57BL/6 mice were fed either a control diet or high-fat diet (HFD) supplemented with 0%, 1% and 2% betaine in water (wt/vol) for 12 weeks. Betaine supplementation ameliorated HFD-induced hepatic steatosis in a dose-dependent manner. HFD up-regulated FAS and ACOX messenger RNA (mRNA) expression and down-regulated PPARα, ApoB and MTTP mRNA expression; however, these alterations were reversed by betaine supplementation, except ApoB. MTTP mRNA expression was negatively correlated with the DNA methylation of its CpG sites at −184, −156, −63 and −60. Methylation of these CpG sites was lower in both the 1% and 2% betaine-supplemented groups than in the HFD group (averages; 25.55% and 14.33% vs. 30.13%). In addition, both 1% and 2% betaine supplementation significantly restored the methylation capacity [S-adenosylmethionine (SAM) concentration and SAM/S-adenosylhomocysteine ratios] and genomic methylation level, which had been decreased by HFD (0.37% and 0.47% vs. 0.25%). These results suggest that the regulation of aberrant DNA methylation by betaine might be a possible mechanism of the improvements in NAFLD upon betaine supplementation.     

Betaine supplementation prevents fatty liver induced by a high-fat diet: effects on one-carbon metabolism

The purpose of this study was to examine the effects of betaine supplementation on the regulation of one-carbon metabolism and liver lipid accumulation induced by a high-fat diet in rats. Rats were fed one of three different liquid diets: control diet, high-fat diet and high-fat diet supplemented with betaine. The control and high-fat liquid diets contained, respectively, 35 and 71 % of energy derived from fat. Betaine supplementation involved the addition of 1 % (g/L) to the diet. After three weeks on the high-fat diet the rats had increased total liver fat concentration, liver triglycerides, liver TBARS and plasma TNF-α. The high-fat diet decreased the hepatic S-adenosylmethionine concentration and the S-adenosylmethionine/S-adenosylhomocysteine ratio compared to the control as well as altering the expression of genes involved in one-carbon metabolism. Betaine supplementation substantially increased the hepatic S-adenosylmethionine concentration (~fourfold) and prevented fatty liver and hepatic injury induced by the high-fat diet. It was accompanied by the normalization of the gene expression of BHMT, GNMT and MGAT, which code for key enzymes of one-carbon metabolism related to liver fat accumulation. In conclusion, the regulation of the expression of MGAT by betaine supplementation provides an additional and novel mechanism by which betaine supplementation regulates lipid metabolism and prevents accumulation of fat in the liver.     

Porphyrin Overproduction by Pseudomonas denitrificans: Essentiality of Betaine and Stimulation by Ethionine

Ethionine supplementation of a defined medium for growth of Pseudomonas denitrificans inhibited vitamin B(12) overproduction and led to the elaboration of a red pigment. The pigment was shown to be coproporphyrin III. Inhibition by ethionine of cobalamin synthesis is probably due to interference of methylation of the corrin nucleus by methionine. Accumulation of coproporphyrin III is thought to result from interference by ethionine with the activity of methionine in the coproporphyrinogenase reaction; this would inhibit formation of heme, the feedback inhibitor and corepressor of delta-aminolevulinate synthetase, thus allowing unregulated synthesis of coproporphyrinogen III and its degradation product, coproporphyrin III. Betaine, known to be required for vitamin B12 overproduction, was found to be an essential requirement for porphyrin overproduction in the presence of ethionine. Low-level production of porphyrin, which occurs in the absence of ethionine, also required betaine supplementation. Betaine is thus required for overproduction of both corrins and porphyrins in P. denitrificans.     

Betaine-induced stimulation of respiration at high osmolarities in a halotolerant bacterium.

It was shown that non-penetrating solutes at high concentrations inhibit the respiration of the halotolerant bacterium Ba1. Betaine relieved the inhibition caused by osmotic stress and exhibited in this respect a considerable structural specificity. The rate of oxidation of various substrates was stimulated to different extents. It stimulated the rates of both respiration and growth to a similar extent, leaving the energy yield essentially unchanged. In cells pre-loaded with labelled glutamate, betaine also stimulated the rate of oxidation of this intracellular substrate. Betaine was accumulated by respiring cells, and the maximum amount taken up was correlated with the osmolarity of the medium. As judged by chromatography, accumulated intracellular betaine underwent no chemical modification, and this accumulated betaine could not be exchanged with the betaine in the medium or released by passive efflux when respiration was inhibited. Intracellular betaine caused no stimulation of respiration, whereas betaine added to the medium increased the respiratory rate to the same extent in cells pre-loaded with betaine as that in the nonloaded cells. The above observations suggest that iso-economic adjustment is not involved in the anti-osmotic effect of betaine, and that betaine exerts its action on the cellular membrane from the outside.     

Betaine is a highly effective organic osmolyte but does not appear to be transported by established organic osmolyte transporters in mouse embryos

Betaine protects early preimplantation mouse embryos against increased osmolarity in vitro, functioning as an organic osmolyte. Betaine is effective at very low external concentrations, with half-maximal protection of 1-cell embryo development to blastocysts at approximately 50 microM, making it one of the best osmoprotectants for mouse preimplantation embryos. We performed studies designed to determine whether known high-affinity organic osmolyte transporters could account for the ability of betaine to act as an organic osmolyte in preimplantation embryos. We found no evidence in 1-cell embryos of transport by a betaine/GABA transporter (BGT1), the osmoregulated betaine transporter found in a number of cell types, as betaine and GABA did not inhibit each other's transport. Instead, all saturable GABA transport in embryos was apparently via the beta-amino acid transporter. We also found that the glycine transporter, GLY, which mediates osmoprotective transport of glycine in early preimplantation embryos, does not appear to transport betaine. Finally, increased osmolarity did not induce any detectable System A amino acid transporter activity, which is osmotically-inducible in other cells and can transport betaine. There does appear, however, to be a saturable betaine transporter in 1-cell mouse embryos, as considerable 14C-betaine transport was measured which was substantially inhibited by excess unlabeled betaine. Our data imply that betaine functions as an organic osmolyte in embryos due to its saturable transport via a mechanism distinct from known osmolyte transporters. We propose that an unidentified high-affinity betaine transporter may be expressed in early embryos and mediate transport of betaine as an organic osmolyte.     

Betaine Elevates Ovarian Antioxidant Enzyme Activities and Demonstrates Methyl Donor Effect in Non-Pregnant Rats

Chronic alcoholism leads to infertility in male and female rats, and antioxidant enzymes form the first line against oxidative stress in organisms. In recent years, betaine has shown beneficial effects on various tissues, and this study has attempted to clarify antioxidant and methyl donor properties of betaine in the rat ovary. For this purpose, the sexually matured Sprague-Dawley female rats were divided into Control, Ethanol (EtOH), Betaine, and Betaine?+?EtOH groups. Administration of betaine in Betaine?+?EtOH group significantly increased CAT activity when compared to the other groups (P?<?0.05). GPx activity increased significantly in Betaine and Betaine?+?EtOH groups as compared to controls (P?<?0.05). Interestingly, GPx and CAT activities insignificantly increased (in order compensatory) in EtOH group to suppress oxidative stress. In contrast, SOD activity decreased insignificantly in EtOH group compared to Betaine?+?EtOH and control groups (P?>?0.05). TBARS concentration (as a lipid peroxidation marker) significantly increased in ethanol-treated rats as compared to controls, while total homocysteine concentration significantly decreased in betaine-treated rats in comparison with EtOH group. Regarding to oestrous cycles, ethanol-treated animals had irregular estral cycle and persistent oestrous phase compared to controls and betaine-treated rats. In conclusion, these results demonstrate for the first time the antioxidant and methyl donor properties of betaine in the rat ovary. Thus, betaine might be used as a potential therapy in hyperhomocysteinemia and partial infertility mediated by oxidative stress in females.     

Betaine Protects Against Rotenone-Induced Neurotoxicity in PC12 Cells

Rotenone is an inhibitor of mitochondrial complex I-induced neurotoxicity in PC12 cells and has been widely studied to elucidate the pathogenesis of Parkinson’s disease. We investigated the neuroprotective effects of betaine on rotenone-induced neurotoxicity in PC12 cells. Betaine inhibited rotenone-induced apoptosis in a dose-dependent manner, with cell viability increasing from 50 % with rotenone treatment alone to 71 % with rotenone plus 100-μM betaine treatment. Flow cytometric analysis demonstrated cell death in the rotenone-treated cells to be over 50 %; the number of live cells increased with betaine pretreatment. Betaine pretreatment of PC12 cells attenuated rotenone-mediated mitochondrial dysfunction, including nuclear fragmentation, ATP depletion, mitochondrial membrane depolarization, caspase-3/7 activation, and reactive oxygen species production. Western blots demonstrated activation of caspase-3 and caspase-9, and their increased expression levels in rotenone-treated cells; betaine decreased caspase-3 and caspase-9 expression levels and suppressed their activation. Together, these results suggest that betaine may serve as a neuroprotective agent in the treatment of neurodegenerative diseases.     

Betaine enhances the cellular survival via mitochondrial fusion and fission factors,MFN2 and DRP1

Betaine is a key metabolite of the methionine cycle and known for attenuating alcoholic steatosis in the liver. Recent studies have focused on the protection effect of betaine in mitochondrial regulation through the enhanced oxidative phosphorylation system. However, the mechanisms of its beneficial effects have not been clearly identified yet. Mitochondrial dynamics is important for the maintenance of functional mitochondria and cell homeostasis. A defective mitochondrial dynamics and oxidative phosphorylation system have been closely linked to several pathologies, raising the possibility that novel drugs targeting mitochondrial dynamics may present a therapeutic potential to restore the cellular homeostasis. In this study, we investigated betaine’s effect on mitochondrial morphology and physiology and demonstrated that betaine enhances mitochondrial function by increasing mitochondrial fusion and improves cell survival. Furthermore, it rescued the unbalance of the mitochondrial dynamics from mitochondrial oxidative phosphorylation dysfunction induced by oligomycin and rotenone. The elongation properties by betaine were accompanied by lowering DRP1 and increasing MFN2 expression. These data suggest that betaine could play an important role in remodeling mitochondrial dynamics to enhance mitochondrial function and cell viability.     

Alleviation of dimethylnitrosamine-induced liver injury and fibrosis by betaine supplementation in rats

Previous studies suggested that betaine intake might antagonize the induction of oxidative stress-mediated acute liver injury through regulation of the sulfur-amino acid metabolism. In this study we examined the protective effects of betaine on chronic liver injury and fibrosis induced by dimethylnitrosamine (DMN). Male rats were supplemented with betaine (1%, w/v) in drinking water from 2 weeks prior to the initiation of DMN treatment (10 mg/(kg day), i.p., 3 days/week, for 1, 2, or 4 weeks) until sacrifice. Induction of liver injury was determined by quantifying serum alanine aminotransferase, aspartate aminotransferase activities, bilirubin levels, hepatic xenobiotic-metabolizing capacity, histopathological changes and 4-hydroxyproline levels. Development of oxidative injury was estimated by malondialdehyde (MDA) levels and total oxyradical scavenging capacity (TOSC) of liver and serum toward hydroxyl, peroxyl radicals, and peroxynitrite. Progressive changes in the parameters of liver injury and fibrosis were evident in the rats challenged with DMN. Elevation of MDA levels in liver was significant before the onset of a change in any parameters determined in this study. Betaine supplementation markedly attenuated the induction of hepatotoxicity and fibrosis by DMN. Elevation of MDA and the reduction of TOSC were also depressed significantly. Development of liver injury corresponded well with the induction of oxidative stress in rats treated with DMN, both of which are inhibited effectively by betaine supplementation. It is suggested that betaine may protect liver from fibrogenesis by maintaining the cellular antioxidant capacity.     

Caffeine potentiates low frequency skeletal muscle force in habitual and nonhabitual caffeine consumers.

The mechanism of action underlying the ergogenic effect of caffeine is still unclear. Caffeine increases the force of muscular contraction during low-frequency stimulation by potentiating calcium release from the sarcoplasmic reticulum. Studies have also suggested an enhancement of lipid oxidation and glycogen sparing as potential mechanisms. Given that several studies have found an ergogenic effect of caffeine with no apparent metabolic effects, it is likely that a direct effect upon muscle is important. Twelve healthy male subjects were classified as habitual (n = 6) or nonhabitual (n = 6) caffeine consumers based on a 4-day diet record analysis, with a mean caffeine consumption of 771 and 14 mg/day for each group, respectively. Subjects were randomly allocated to receive caffeine (6 mg/kg) and placebo (citrate) in a double-blind, cross-over fashion approximately 100 min before a 2-min tetanic stimulation of the common peroneal nerve in a custom-made dynamometer (2 trials each of 20 and 40 Hz). Tetanic torque was measured every 30 s during and at 1, 5, and 15 min after the stimulation protocol. Maximal voluntary contraction strength and peak twitch torque were measured before and after the stimulation protocol. Caffeine potentiated the force of contraction during the final minute of the 20-Hz stimulation (P<0.05) with no effect of habituation. There was no effect of caffeine on 40-Hz stimulation strength nor was there an effect on maximal voluntary contraction or peak twitch torque. These data support the hypothesis that some of the ergogenic effect of caffeine in endurance exercise performance occurs directly at the skeletal muscle level.     

Studies on halotolerance in a moderately halophilic bacterium. Effect of betaine on salt resistance of the respiratory system

The role of betaine as a factor influencing the salt resistance of the respiratory system in resting cells of the moderately halophilic halotolerant bacterium Ba(1) was studied. Betaine accelerated succinate oxidation in cells obtained from low-salt medium, and stimulation of the respiratory rate was stronger the higher the sodium chloride concentration in the assay medium. The stimulatory effect also depended on the ratio of betaine concentration to the amount of bacteria present. Accumulation of labelled betaine by the bacterial cells was demonstrated; like the respiratory stimulation, it was favourably influenced by an increase in the sodium chloride concentration of the medium. In cells harvested from a high-salt medium and washed with 2.0m-sodium chloride, betaine caused no increase in the respiratory rate, nor was the already high salt resistance of the respiratory system further improved by the addition of betaine. When, however, these cells lost their salt resistance as a result of washing in the absence of sodium chloride, betaine was able to restore it to its original level. In contrast with respiration in low-salt-grown bacteria, that in high-salt-grown cells was not affected by betaine, even after they were washed in the absence of sodium chloride, when the sodium chloride concentration was optimum.     

Metabolic engineering of glycine betaine synthesis: plant betaine aldehyde dehydrogenases lacking typical transit peptides are targeted to tobacco chloroplasts where they confer betaine aldehyde resistance

Certain higher plants synthesize and accumulate glycine betaine, a compound with osmoprotectant properties. Biosynthesis of glycine betaine proceeds via the pathway choline betaine aldehyde glycine betaine. Plants such as tobacco (Nicotiana tabacum L.) which do not accumulate glycine betaine lack the enzymes catalyzing both reactions. As a step towards engineering glycine betaine accumulation into a non-accumulator, spinach and sugar beet complementary-DNA sequences encoding the second enzyme of glycine-betaine synthesis (betaine aldehyde dehydrogenase, BADH, EC 1.2.1.8) were expressed in tobacco. Despite the absence of a typical transit peptide, BADH was targeted to the chloroplast in leaves of transgenic plants. Levels of extractable BADH were comparable to those in spinach and sugar beet, and the molecular weight, isoenzyme profile and K _m for betaine aldehyde of the BADH enzymes from transgenic plants were the same as for native spinach or sugar beet BADH. Transgenic plants converted supplied betaine aldehyde to glycine betaine at high rates, demonstrating that they were able to transport betaine aldehyde across both the plasma membrane and the chloroplast envelope. The glycine betaine produced in this way was not further metabolized and reached concentrations similar to those in plants which accumulate glycine betaine naturally. Betaine aldehyde was toxic to non-transformed tobacco tissues whereas transgenic tissues were resistant due to detoxification of betaine aldehyde to glycine betaine. Betaine aldehyded ehydrogenase is therefore of interest as a potential selectable marker, as well as in the metabolic engineering of osmoprotectant biosynthesis.Abbreviations BADH betaine aldehyde dehydrogenase - bp base pairs - FAB-MS fast atom bombardment-mass spectrometry - GAPDH NADP-linked glyceraldehyde-3-phosphate dehydrogenase We thank Dr. G. An for the gift of the vector pGA643 and Mr. Sylvain Lebeurier for help in maintaining plants. This work was supported, in part, by grants from the Natural Sciences and Engineering Research Council of Canada, the Rockefeller Foundation, and the U.S. Department of Agriculture, and by gifts from CIBAGEIGY Biotechnology.     

Evidence for mitochondrial localization of betaine aldehyde dehydrogenase in rat liver: purification, characterization, and comparison with human cytoplasmic E3 isozyme.

Betaine aldehyde dehydrogenase has been purified to homogeneity from rat liver mitochondria. The properties of betaine aldehyde dehydrogenase were similar to those of human cytoplasmic E3 isozyme in substrate specificity and kinetic constants for substrates. The primary structure of four tryptic peptides was also similar; only two substitutions, at most, per peptide were observed. Thus, betaine aldehyde dehydrogenase is not a specific enzyme, as formerly believed; activity with betaine aldehyde is a property of aldehyde dehydrogenase (EC 1.2.1.3), which has broad substrate specificity. Up to the present time the enzyme was thought to be cytoplasmic in mammals. This report establishes, for the first time, mitochondrial subcellular localization for aldehyde dehydrogenase, which dehydrogenates betaine aldehyde, and its colocalization with choline dehydrogenase. Betaine aldehyde dehydrogenation is an important function in the metabolism of choline to betaine, a major osmolyte. Betaine is also important in mammalian organisms as a major methyl group donor and nitrogen source. This is the first purification and characterization of mitochondrial betaine aldehyde dehydrogenase from any mammalian species.     

Creatine but not betaine supplementation increases muscle phosphorylcreatine content and strength performance

We aimed to investigate the role of betaine supplementation on muscle phosphorylcreatine (PCr) content and strength performance in untrained subjects. Additionally, we compared the ergogenic and physiological responses to betaine versus creatine supplementation. Finally, we also tested the possible additive effects of creatine and betaine supplementation. This was a double-blind, randomized, placebo-controlled study. Subjects were assigned to receive betaine (BET; 2?g/day), creatine (CR; 20?g/day), betaine plus creatine (BET?+?CR; 2?+?20?g/day, respectively) or placebo (PL). At baseline and after 10?days of supplementation, we assessed muscle strength and power, muscle PCr content, and body composition. The CR and BET?+?CR groups presented greater increase in muscle PCr content than PL (p?=?0.004 and p?=?0.006, respectively). PCr content was comparable between BET versus PL (p?=?0.78) and CR versus BET?+?CR (p?=?0.99). CR and BET?+?CR presented greater muscle power output than PL in the squat exercise following supplementation (p?=?0.003 and p?=?0.041, respectively). Similarly, bench press average power was significantly greater for the CR-supplemented groups. CR and BET?+?CR groups also showed significant pre- to post-test increase in 1-RM squat and bench press (CR: p?=?0.027 and p?<?0.0001; BET?+?CR: p?=?0.03 and p?<?0.0001 for upper- and lower-body assessments, respectively) No significant differences for 1-RM strength and power were observed between BET versus PL and CR versus BET?+?CR. Body composition did not differ between the groups. In conclusion, we reported that betaine supplementation does not augment muscle PCr content. Furthermore, we showed that betaine supplementation combined or not with creatine supplementation does not affect strength and power performance in untrained subjects.     

Effects of intravenous betaine on methionine-loading-induced plasma homocysteine elevation in rats

An intravenous methionine-loading model was characterized, and the suppressive effect of betaine on plasma homocysteine elevation induced by methionine loading was examined in rats. The plasma homocysteine concentrations significantly increased 5-120 minutes after 0.34 mmol/kg of methionine loading and then returned to the baseline within 240 minutes. Betaine was then intravenously administered at the same time as the methionine loading. The total increment of plasma homocysteine was assessed using the positive incremental area under the plasma homocysteine concentration curve over the 240-minute post-methionine-loading period (DeltaAUC(0-240)). Betaine reduced DeltaAUC(0-240) dose-dependently: 81% of the control by 1.7 mmol/kg of betaine and 33% by 3.4 mmol/kg. The effects of glycine and methylglycine, analogues of betaine, were also investigated. As observed for betaine, methylglycine decreased DeltaAUC(0-240) to 44% of the control, whereas glycine showed no significant effect on DeltaAUC(0-240), indicating that methyl groups of betaine and dimethylglycine were necessary to suppress plasma homocysteine elevation. These results suggest that betaine contributes to the suppression of plasma homocysteine elevation by promoting homocysteine metabolism, and seems to work as a methyl donor.     

Dietary betaine modifies hepatic metabolism but not renal injury in rat polycystic kidney disease

We undertook a morphometric and proton nuclear magnetic resonance ((1)H-NMR) study to test the hypothesis that 1% dietary betaine supplementation would ameliorate renal disease in the heterozygous Han:SPRD-cy rat, a model of polycystic kidney disease (PKD) and progressive chronic renal failure. After 8 wk of pair feeding, betaine had no effect on renal cystic change, renal interstitial fibrosis, serum creatinine, serum cholesterol, or serum triglycerides. (1)H-NMR spectroscopy of renal tissue revealed no change in renal osmolytes, including betaine, or renal content of other organic anions in response to diet. (1)H-NMR spectroscopy of hepatic tissue performed to explore the metabolic fate of ingested betaine revealed that heterozygous animals fed the control diet had elevated hepatic levels of gluconeogenic amino acids, increased beta-hydroxybutyrate, and increased levels of some citric acid cycle metabolites compared with animals without renal disease. Betaine supplementation eliminated these changes. Chronic renal failure in the Han:SPRD-cy rat is associated with disturbances of hepatic metabolism that can be corrected with betaine therapy, suggesting the presence of a reversible methylation defect in this form of chronic renal failure.