High homocysteine induces betaine depletion

Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any Hcy interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of cystathionine β-synthase (CBS) deficiency. S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), methionine, betaine and dimethylglycine (DMG) were quantified by ESI—LC–MS/MS. mRNA expression was quantified using quantitative real-time (QRT)-PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease in the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte.     

Betaine improves growth, but does not induce whole body or hepatic palmitate oxidation in swine (Sus scrofa domestica)

Dietary betaine may reduce carcass fat in growing pigs. We explored the effects of betaine on short-term growth and in vivo and in vitro fatty acid oxidation. Pigs were housed in metabolism crates and fed diets containing either 0% (control), 0.125% or 0.5% betaine at 80% of ad libitum energy intake. Fatty acid oxidation was measured during intravenous infusions of 1-(13)C-palmitate and in hepatocytes incubated in the presence or absence of betaine and carnitine. CO2 and palmitate isotopic enrichments were determined by mass spectrometry. Pigs consuming 0.125% and 0.5% betaine for at least 9 days had growth rates that were 38% and 12% greater than controls, respectively. Feed efficiency was also improved with betaine. Fasting increased palmitate oxidation rates 7-8-fold (P < 0.01), but betaine had no effect in either the fed or fasted state (P > 0.1). For hepatocytes, carnitine but not betaine enhanced palmitate oxidation. This response suggests that previously observed reduction in adipose accretion must be via a mechanism other than oxidation. Betaine had no effect on plasma non-esterified fatty acids or urea nitrogen. Under the confinement conditions in this study, dietary betaine improved animal growth responses, but it had no apparent effect on either whole body or hepatic fatty acid oxidation.     

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.     

Control of choline oxidation in rat kidney mitochondria

Choline is a quaternary amino cationic organic alcohol that is oxidized to betaine in liver and kidney mitochondria. Betaine acts as an intracellular organic osmolyte in the medulla of the kidney. Evidence is provided that kidney mitochondria have a choline transporter in their inner membrane. The transporter has a Km of 173 ± 64 μM and a Vmax of 0.4 ± 0.1 nmol/min/mg mitochondrial protein (at 10 °C). Uptake of choline is not coupled to betaine efflux. Transporter activity demonstrates a dependence on membrane potential and choline transport is inhibited by hemicholinium-3. Steady-state oxygen consumption due to choline oxidation in kidney mitochondria was measurable at 37 °C (125 ± 6 pmolO₂/min/mg mitochondrial protein), in the absence of other mitochondrial electron transport chain substrates and the choline transporter was shown to be the major site of control (96 ± 4%) over choline oxidation flux in isolated kidney mitochondria. We conclude that the choline transporter in rat kidney mitochondria is the major site of control over the production of the organic osmolyte, betaine.     

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.     

Plasma dependent and independent accumulation of betaine in male and female rat tissues

Tissue betaine is an intracellular osmolyte that also provides a store of labile methyl groups. Despite these important biological roles, there are few data regarding tissue betaine content. We measured the betaine concentration of plasma and various tissues (brain, heart, lungs, liver, kidney, spleen, intestine, reproductive tissues, skeletal muscle and skin) in male and female rats and assessed whether there were any gender-specific differences in betaine content or distribution and whether there was any relationship between tissue accumulation and plasma levels. Betaine was highest in the liver and kidney with values ranging from 1.6 to 9.5 mmol/l and 2.0 to 5.4 mmol/l, respectively. Plasma betaine concentrations were significantly lower than tissue levels except in the brain (? 25 % of plasma) and skeletal muscle (similar to plasma). Regression analysis of the combined male and female data revealed a significant plasma-related accumulation of betaine in the heart, skin and skeletal muscle, while the lung, liver, kidney, spleen, and intestine showed significant plasma-related and plasma-independent accumulations of betaine. The betaine content of the skin, liver and kidney was not significantly different between males and females, but in plasma and all tissues analyzed it was significantly higher in males (P<0.01).     

Alterations in the metabolomics of sulfur-containing substances in rat kidney by betaine

Earlier studies have shown that betaine administration may modulate the metabolism of sulfur amino acids in the liver. In this study, we determined the changes in the metabolomics of sulfur-containing substances induced by betaine in the kidney, the other major organ actively involved in the transsulfuration reactions. Male rats received betaine (1 %) in drinking water for 2 weeks before killing. Betaine intake did not affect betaine–homocysteine methyltransferase activity or its protein expression in the renal tissue. Expression of methionine synthase was also unchanged. However, methionine levels were increased significantly both in plasma and kidney. Renal methionine adenosyltransferase activity and S-adenosylmethionine concentrations were increased, but there were no changes in S-adenosylhomocysteine, homocysteine, cysteine levels or cystathionine β-synthase expression. γ-Glutamylcysteine synthetase expression or glutathione levels were not altered, but cysteine dioxygenase and taurine levels were decreased significantly. In contrast, betaine administration induced cysteine sulfinate decarboxylase and its metabolic product, hypotaurine. These results indicate that the metabolomics of sulfur-containing substances in the kidney is altered extensively by betaine, although the renal capacity for methionine synthesis is unresponsive to this substance unlike that of the liver. It is suggested that the increased methionine availability due to an enhancement of its uptake from plasma may account for the alterations in the metabolomics of sulfur-containing substances in the kidney. Further studies need to be conducted to clarify the physiological/pharmacological significance of these findings.     

Corticoadrenal activity regulates in rat betaine-homocysteine <Emphasis Type="Italic">S</Emphasis>-methyltransferase expression with opposites effects in liver and kidney

Betaine-homocysteine S-methyltransferase (BHMT) is an enzyme that converts homocysteine (Hcy) to methionine using betaine as a methyl donor. Betaine also acts as osmolyte in kidney medulla, protecting cells from high extracellular osmolarity. Hepatic BHMT expression is regulated by salt intake. Hormones, particularly corticosteroids, also regulate BHMT expression in rat liver. We investigated to know whether the corticoadrenal activity plays a role in kidney BHMT expression. BHMT activity in rat kidneys is several orders of magnitude lower than in rat livers and only restricted to the renal cortex. This study confirms that corticosteroids stimulate BHMT activity in the liver and, for the first time in an animal model, also up-regulate the BHMT gene expression. Besides, unlike the liver, corticosteroids in rat kidney down-regulate BHMT expression and activity. Given that the classical effect of adrenocortical activity on the kidney is associated with sodium and water re-absorption by the distal tubule leading to volume expansion, by promoting lesser use of betaine as a methyl donor, corticosteroids would preserve betaine for its other role as osmoprotectant against changes in the extracellular osmotic conditions. We conclude that corticosteroids are, at least in part, responsible for the inhibition of BHMT expression and activity in rat kidneys.     

Effects of betaine on performance and body composition: a review of recent findings and potential mechanisms

Betaine is a methyl derivative of glycine first isolated from sugar beets. Betaine consumed from food sources and through dietary supplements presents similar bioavailability and is metabolized to di-methylglycine and sarcosine in the liver. The ergogenic and clinical effects of betaine have been investigated with doses ranging from 500 to 9,000 mg/day. Some studies using animal models and human subjects suggest that betaine supplementation could promote adiposity reductions and/or lean mass gains. Moreover, previous investigations report positive effects of betaine on sports performance in both endurance- and resistance-type exercise, despite some conflicting results. The mechanisms underlying these effects are poorly understood, but could involve the stimulation of lipolysis and inhibition of lipogenesis via gene expression and subsequent activity of lipolytic-/lipogenic-related proteins, stimulation of autocrine/endocrine IGF-1 release and insulin receptor signaling pathways, stimulation of growth hormone secretion, increased creatine synthesis, increases in protein synthesis via intracellular hyper-hydration, as well as exerting psychological effects such as attenuating sensations of fatigue. However, the exact mechanisms behind betaine action and the long-term effects of supplementation on humans remain to be elucidated. This review aims to describe evidence for the use of betaine as an ergogenic and esthetic aid, and discuss the potential mechanisms underlying these effects.     

Intestinal uptake of betaine in vitro and the distribution of methyl groups from betaine, choline, and methionine in the body of broiler chicks

The efficiency of betaine absorption into small intestinal slices of broiler chicks was studied in vitro with 14C-labeled betaine. The relative proportion of Na+-coupled betaine uptake, as well as the total uptake capacity was larger in the duodenum than in the jejunum. Dietary betaine increased the Na+-coupled uptake in the duodenum. In in vivo-experiments, methyl-14C-labeled betaine, methionine, or choline was fed to broiler chicks. Betaine appeared in the blood more rapidly, and reached a higher total concentration than choline or methionine. The data suggest that choline and methionine were associated with plasma lipoproteins whereas betaine remained free in the plasma. The label distribution in liver, kidney, and intestinal tissues was studied 24 h after label ingestion. Most of the label from betaine was found in the aquaeous phase in the muscle, while in the liver and jejunum the label from betaine was distributed more evenly between the aquaeous, lipid, and protein phases. Label from choline accumulated in the lipid fraction, particularly so in the liver, whereas label from methionine showed a more variable distribution pattern. The distribution results are interpreted in terms of specific roles of betaine, choline, and methionine in methyl group metabolism.     

Preliminary Investigation on the Effect of Dietary Supplemental Biotin and Palm Kernel Oil on Blood,Liver and Kidney Lipids in Chicks

Abstract

A total of 480 day-old broiler chicks were used in two trials conducted to investigate the performance and lipid contents of blood, liver and kidneys of birds when fed varying levels of palm kernel oil (0% and 2%) and biotin (40, 80, 120, 160, 200 and 240 mcg/kg feed) in a 2 × 6 factorial experimental design. The results showed that blood, liver and kidney lipid concentrations were significantly affected by dietary biotin treatments. While total lipid, free fatty acid, triglyceride and cholesterol contents were negatively correlated with dietary biotin level, phospholipid concentrations were positively correlated. Biotin-deficient chicks had significantly higher total lipid, free fatty acid, triglyceride and cholesterol but lower phospholipid contents in their blood and the two organs. Supplementation of the diet with 2% palm kernel oil significantly elevated blood phospholipid concentration, but depressed the accumulation of the other lipid fractions in both organs and the blood of birds. Blood, liver and kidney cholesterol concentrations were not affected by 2% fat supplementation. Observation on the lipid parameters coupled with the results on feed utilisation appeared to suggest that a minimum of 120 mcg of the vitamin per kilograme of diet was required by broiler chicks for optimum performance.     

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.     

System A amino acid transporter SNAT2 shows subtype-specific affinity for betaine and hyperosmotic inducibility in placental trophoblasts

Betaine uptake is induced by hypertonic stress in a placental trophoblast cell line, and involvement of amino acid transport system A was proposed. Here, we aimed to identify the subtype(s) of system A that mediates hypertonicity-induced betaine uptake. Measurement of [¹⁴C]betaine uptake by HEK293 cells transiently transfected with human or rat sodium-coupled neutral amino acid transporters (SNATs), SNAT1, SNAT2 and SNAT4 revealed that only human and rat SNAT2 have betaine uptake activity. The Michaelis constants (K_m) of betaine uptake by human and rat SNAT2 were estimated to be 5.3 mM and 4.6 mM, respectively. Betaine exclusively inhibited the uptake activity of SNAT2 among the rat system A subtypes. We found that rat SNAT1, SNAT2 and SNAT4 were expressed at the mRNA level under isotonic conditions, while expression of SNAT2 and SNAT4 was induced by hypertonicity in TR-TBT 18d-1 cells. Western blot analyses revealed that SNAT2 expression on plasma membrane of TR-TBT 18d-1 cells was more potently induced by hypertonicity than that in total cell lysate. Immunocytochemistry confirmed the induction of SNAT2 expression in TR-TBT 18d-1 cells exposed to hypertonic conditions and indicated that SNAT2 was localized on the plasma membrane in these cells. Our results indicate that SNAT2 transports betaine, and that tonicity-sensitive SNAT2 expression may be involved in regulation of betaine concentration in placental trophoblasts.     

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.     

A method for the determination of betaine in tissues using high performance liquid chromatography

Betaine is a major metabolite of choline in liver and kidney and may be an important product of choline metabolism in other tissues. The available methods for assay of betaine, however, are time consuming and relatively insensitive. We describe a modification of published methods that provides a sensitive and specific assay for betaine by derivatization and HPLC separation with UV quantitation. Betaine and other water-soluble choline metabolites are extracted from biological samples and separated by HPLC based on mobility of 14C-labeled internal standards. The betaine fraction is collected and derivatized with 4'-bromo-phenacyl triflate. The betaine-triflate derivative is quantitated by UV absorbance and the result is corrected for possible losses due to incomplete extraction recovery and incomplete derivatization by simultaneous measurement of radioactivity from the derivatized 14C-betaine internal standard. Betaine concentrations determined with this procedure are reported for several adult and fetal rat tissues.     

The oxidation of choline by liver slices and mitochondria during liver development in the rat

Betaine is the major oxidation product of [Me-¹⁴C] choline produced by rat liver slices. Liver slices from adult rats rapidly oxidize [Me-¹⁴C] choline to betaine and the bulk of the betaine produced is recovered in the incubation medium. Considerably more choline is oxidized to betaine than is phosphorylated to phosphorylcholine. The rate of phosphorylation of choline appears to be independent of the rate of choline oxidation. Liver slices from fetal and young rats oxidize choline to betaine at a lower rate than adult liver slices.The ability of mitochondria to oxidize [Me-¹⁴C] choline to betaine aldehyde and betaine is considerably lower in fetal liver than in adult liver. The major product with both fetal and adult mitochondria is betaine aldehyde. Choline oxidation by mitochondria begins to increase 1 day prior to birth and increases progressively to adult levels by 18 days. The developmental pattern for choline oxidation is similar to the pattern for succinic dehydrogenase activity.     

Fatty acid concentration of plasma,muscle, adipose and liver from beef heifers fed an encapsulated n-3 polyunsaturated fatty acid supplement

Increasing the content of polyunsaturated fat in the human diet is a priority for reducing cardiovascular disease and cancer risks. Beef has the potential to contribute to the polyunsaturated fat content in the human diet; however, ruminants cannot synthesise many long-chain fatty acids de novo; they require dietary supplementation. The objectives of the current study were to evaluate (i) the effect of a partially rumen protected n-3 long-chain polyunsaturated fatty acid (LC-PUFA) dietary supplement on the fatty acid composition of muscle (Longissimus dorsi), adipose and liver tissues of beef heifers and (ii) the usefulness of blood plasma as a predictor of tissue concentrations of specific fatty acids. Charolais crossbred heifers (n = 20) were assigned to one of two isolipid dietary treatments namely palmitic acid (control) or an n-3 LC-PUFA supplement for a 91-day period. Blood plasma and adipose tissue samples were taken to determine the temporal effect of these diets on fatty acid composition (days 0, 10, 35 and 91), while liver and muscle samples were taken following slaughter. Dietary lipid source did not influence animal growth rate or body condition score. At day 91, the percentage differences between control and n-3 LC-PUFA heifers in concentrations of eicosapentaenoic acid were +61, +176 and +133 % in liver, muscle and adipose, respectively. For docosahexaenoic acid, at the same time point, the percentage differences were +57, +73 and +138 % for liver, muscle and adipose, respectively. Medium-to-strong positive correlation coefficients were evident for liver and plasma fatty acids, in particular, there were positive relationships with concentrations of total saturated fatty acid (SFA), total n-6 PUFA and total n-3 PUFA. This trend also extended to both the ratio of PUFA to SFA (slope (β₁) = 0.56 ± 0.167, intercept (β₀) = 0.56, R² = 0.61, P < 0.05) and the ratio of n-6 to n-3 PUFA (β₁ = 0.15 ± 0.054, β₀ = 0.24, R² = 0.52, P < 0.05). A strong correlation was also detected in the ratio of n-6 to n-3 in plasma and muscle tissue of heifers fed the n-3 LC-PUFA diet (β₁ = 0.53 ± 0.089, β₀ = −0.31, R² = 0.83, P < 0.001). The results of this study show that the n-3 LC-PUFA can be readily increased through targeted supplementation and that plasma concentrations of n-3 LC-PUFA are useful predictors of their concentrations in a number of economically important tissues.     

Metabolomic analyses of plasma and liver of mice fed with immature Citrus tumida peel

ABSTRACT

In this study, we investigated the effects of dietary supplementation of Citrus tumida hort. ex Tanaka on food intake, body and fat tissue weights, and metabolic profiles of plasma and liver in mice. Supplementation with 5% (w/w) of peels of immature C. tumida (PIC) for 4 weeks significantly suppressed body weight gain and decreased adipose tissue weight in epididymal, perirenal, and subcutaneous fats. Metabolome analyses showed that 2-hydroxyvaleric acid levels were reduced in the blood plasma of mice fed with PIC. PIC supplementation significantly elevated dipeptide (Thr-Asp, Ser-Glu, and Ala-Ala), glucuronic acid, and S-methylglutathione levels, and significantly reduced betaine aldehyde levels in the liver. In conclusion, PIC supplementation affects the metabolism of fatty acids, pectin, glutathione, and choline, showing potential beneficial effects for metabolic syndrome and obesity. PIC may be developed as a functional food and used in the treatment of these diseases.     

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.     

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.