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Timothy A. Garrow - One of the best experts on this subject based on the ideXlab platform.
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Hepatic Activity and Transcription of Betaine-Homocysteine Methyltransferase, Methionine Synthase, and Cystathionine Synthase in Periparturient Dairy Cows Are Altered to Different Extents by Supply of Methionine and Choline.
The Journal of nutrition, 2016Co-Authors: Z. Zhou, Timothy A. Garrow, Xianwen Dong, D. Luchini, Juan J. LoorAbstract:BACKGROUND Compared with choline, Met enhances milk yield and feed intake, and elicits a better immuno-metabolic status in periparturient cows. It is unknown whether hepatic activity and transcription of betaine-Homocysteine Methyltransferase (BHMT), 5-methyltetrahydrofolate-Homocysteine Methyltransferase (MTR), and cystathionine β-synthase (CBS) are responsive to Met and choline supply. OBJECTIVE This study sought to characterize hepatic BHMT, MTR, and CBS transcription and activity in response to Met and choline supplementation. METHODS Forty multiparous cows were used in a 2 × 2 factorial design from -21 d through 30 d around parturition to assess effects of dietary rumen-protected Met (0% or 0.08% dry matter basis) or rumen-protected choline (0 or 60 g · cow-1 · d-1). Liver tissue obtained on days -10, 7, 20, and 30 was used for analyses. RESULTS Met-supplemented cows had greater methionine adenosyltransferase 1A (MAT1A) (0.38 compared with 0.27; SEM = 0.05; P = 0.02) and phosphatidylethanolamine Methyltransferase (PEMT) (0.74 compared with 0.58; SEM = 0.08; P = 0.05) expression. Greater S-adenosylHomocysteine hydrolase (SAHH) (0.93 compared with 0.74; SEM = 0.05; P = 0.01) and CBS (1.16 compared with 1.02; SEM = 0.07; P = 0.04), as well as lower MTR activity (23.4 compared with 29.7 nmol product · h-1 · mg protein-1; SEM = 2.9; P = 0.04), also were detected in Met- but not choline-supplemented cows. Although BHMT and MTR expression and BHMT enzyme activity did not change (P > 0.05), MTR enzyme activity was lower in choline-supplemented cows (23.5 compared with 29.6 nmol product · h-1 · mg protein-1; SEM = 2.9; P = 0.05). CONCLUSIONS These findings indicate that greater synthesis of phosphatidylcholine and antioxidants contribute to the better performance and immuno-metabolic status in Met-supplemented cows. Failure to generate a comparable amount of endogenous Met from choline could be one reason that choline-fed cows fail to achieve comparable performance and health benefits during the periparturient period.
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Betaine Homocysteine Methyltransferase Is Active in the Mouse Blastocyst and Promotes Inner Cell Mass Development
The Journal of biological chemistry, 2012Co-Authors: Martin B. Lee, Timothy A. Garrow, Michael Lever, Baohua Zhang, Jacquetta M. Trasler, Megan Kooistra, Sandy Slow, Amanda L. Fortier, Jay M. BaltzAbstract:Methyltransferases are an important group of enzymes with diverse roles that include epigenetic gene regulation. The universal donor of methyl groups for Methyltransferases is S-adenosylmethionine (AdoMet), which in most cells is synthesized using methyl groups carried by a derivative of folic acid. Another mechanism for AdoMet synthesis uses betaine as the methyl donor via the enzyme betaine-Homocysteine Methyltransferase (BHMT, EC 2.1.1.5), but it has been considered to be significant only in liver. Here, we show that mouse preimplantation embryos contain endogenous betaine; Bhmt mRNA is first expressed at the morula stage; BHMT is abundant at the blastocyst stage but not other preimplantation stages, and BHMT activity is similarly detectable in blastocyst homogenates but not those of two-cell or morula stage embryos. Knockdown of BHMT protein levels and reduction of enzyme activity using Bhmt-specific antisense morpholinos or a selective BHMT inhibitor resulted in decreased development of embryos to the blastocyst stage in vitro and a reduction in inner cell mass cell number in blastocysts. The detrimental effects of BHMT knockdown were fully rescued by the immediate methyl-carrying product of BHMT, methionine. A physiological role for betaine and BHMT in blastocyst viability was further indicated by increased fetal resorption following embryo transfer of BHMT knockdown blastocysts versus control. Thus, mouse blastocysts are unusual in being able to generate AdoMet not only by the ubiquitous folate-dependent mechanism but also from betaine metabolized by BHMT, likely a significant pool of methyl groups in blastocysts.
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Molecular characterization and analysis of the porcine betaine Homocysteine Methyltransferase and betaine Homocysteine Methyltransferase-2 genes.
Gene, 2010Co-Authors: Radhika S. Ganu, Timothy A. Garrow, Monika Sodhi, Laurie A. Rund, Lawrence B. SchookAbstract:Abstract Betaine Homocysteine Methyltransferase (BHMT) and BHMT-2 enzymes methylate Homocysteine to form methionine using betaine and S-methylmethionine, respectively. These activities are observed only in the liver of adult rodents, but in adult humans and pigs these activities are detected in both the liver and kidney, indicating the pig is a more appropriate model for studying the biochemical and physiological roles of these enzymes in human biology. Porcine BHMT and BHMT-2 cDNAs were cloned and sequenced, and their 5′ and 3′ UTR were amplified using RLM-RACE. The BHMT transcript had significantly longer 5′ and 3′ UTRs than BHMT-2. The pig BHMT and BHMT-2 genes span approximately 26 and 16 kb, respectively, and both genes have 8 exons. The deduced amino acid sequences of BHMT and BHMT-2 contain 407 and 363 amino acids, respectively, and shared 78% amino acid identity. No promoter element (TATA or CAAT box) was observed for either BHMT or BHMT-2, although a CpG island surrounding the promoter and transcriptional start site was observed in both genes implying that methylation could regulate their expression. Using qPCR, it was determined that BHMT and BHMT-2 transcripts are very abundant in liver and kidney cortex, whereas the expression is significantly less in other tissues. These findings confirm that the expression pattern of BHMT and BHMT-2 genes in pigs is similar to humans, supporting the use of the pig as an animal model to study the genetics and regulation of BHMT and BHMT-2 expression.
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Betaine-Homocysteine S-Methyltransferase-2 is an S-methylmethionine-Homocysteine Methyltransferase.
Journal of Biological Chemistry, 2008Co-Authors: Sandra S. Szegedi, Carmen Castro, Markos Koutmos, Timothy A. GarrowAbstract:We demonstrate that purified recombinant human betaineHomocysteine Methyltransferase-2 (BHMT-2) is a zinc metalloenzyme that uses S-methylmethionine (SMM) as a methyl donor for the methylation of Homocysteine. Unlike the highly homologous betaine-Homocysteine Methyltransferase (BHMT), BHMT-2 cannot use betaine. The Km of BHMT-2 for SMM was determined to be 0.94 mm, and it has a turnover number similar to BHMT. Several compounds were tested as inhibitors of recombinant human BHMT and BHMT-2. The SMM-specific Methyltransferase activity of BHMT-2 is not inhibited by dimethylglycine and betaine, whereas the former is a potent inhibitor of BHMT. Methionine is a stronger inhibitor of BHMT-2 than BHMT, and S-adenosylmethionine does not inhibit BHMT but is a weak inhibitor of BHMT-2. BHMT can use SMM as a methyl donor with a kcat/Km that is 5-fold lower than the kcat/Km for betaine. However, SMM does not inhibit BHMT activity when it is presented to the enzyme at concentrations that are 10-fold greater than the subsaturating amounts of betaine used in the assay. Based on these data, it is our current hypothesis that in vivo most if not all of the SMM-dependent methylation of Homocysteine occurs via BHMT-2.
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Liver Choline Dehydrogenase and Kidney Betaine-Homocysteine Methyltransferase Expression Are Not Affected by Methionine or Choline Intake in Growing Rats
The Journal of nutrition, 2006Co-Authors: Sandy Slow, Timothy A. GarrowAbstract:Choline dehydrogenase (CHDH) and betaine-Homocysteine Methyltransferase (BHMT) are 2 enzymes involved in choline oxidation. BHMT is expressed at high levels in rat liver and its expression is regulated by dietary Met and choline. BHMT is also found in rat kidney, albeit in substantially lower amounts, but it is not known whether kidney BHMT expression is regulated by dietary Met or choline. Similarly, CHDH activity is highest in the liver and kidney, but the regulation of its expression by diet has not been thoroughly investigated. Sprague Dawley rats (∼50 g) were fed, for 9 d in 2 x 3 factorial design (n = 8), an L-amino acid-defined diet varying in L-Met (0.125, 0.3, or 0.8%) and choline (0 or 25 mmol/kg diet). Liver and kidney BHMT and CHDH were assessed using enzymatic, Western blot, and real-time PCR analyses. Liver samples were also fixed for histological analysis. Liver BHMT activity was 1.3-fold higher in rats fed the Met deficient diet containing choline, which was reflected in corresponding increases in mRNA content and immunodetectable protein. Independent of dietary choline, supplemental Met increased hepatic BHMT activity ∼30%. Kidney BHMT and liver CHDH expression were refractory to these diets. Some degree of fatty liver developed in all rats fed a choline-devoid diet, indicating that supplemental Met cannot completely compensate for the lack of dietary choline in growing rats. J. Nutr. 136: 2279-2283, 2006.
Neil Kaplowitz - One of the best experts on this subject based on the ideXlab platform.
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differences in betaine Homocysteine Methyltransferase expression endoplasmic reticulum stress response and liver injury between alcohol fed mice and rats
Hepatology, 2010Co-Authors: Masao Shinohara, Neil KaplowitzAbstract:Chronic ethanol infusion resulted in greater serum ALT elevation, lipid accumulation, necroinflammation, and focal hepatic cell death in mice than rats. Mice exhibited a remarkable hyperHomocysteinemia but no increase was seen in rats. Similarly, a high methionine low folate diet (HMLF) induced less steatosis, serum ALT increase, and hyperHomocysteinemia in rats than in mice. Western blot analysis of betaine Homocysteine Methyltransferase (BHMT) expression showed that rats fed either ethanol or HMLF had significantly increased BHMT expression which did not occur in mice. Nuclear NFκB p65 was increased in mouse in response to alcohol feeding. The human BHMT promoter was repressed by Homocysteine in mouse hepatocytes but not rat hepatocytes. BHMT induction was faster and greater in primary rat hepatocytes than mouse hepatocytes in response to exogenous Homocysteine exposure. Mice fed ethanol i.g. exhibited an increase in GRP78 and IRE1 which was not seen in the rat and SREBP-1 was increased to a greater extent in mice than rats. Thus, rats are more resistant to ethanol induced steatosis, ER stress and hyperHomocysteinemia and this correlates with induction of BHMT in rats. These findings support the hypothesis that a critical factor in the pathogenesis of alcoholic liver injury is the enhanced ability of rat or impaired ability of mouse to up-regulate BHMT which prevents hyperHomocysteinemia, ER stress and liver injury.
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Differences in betaine‐Homocysteine Methyltransferase expression, endoplasmic reticulum stress response, and liver injury between alcohol‐fed mice and rats
Hepatology (Baltimore Md.), 2010Co-Authors: Masao Shinohara, Neil KaplowitzAbstract:Chronic ethanol infusion resulted in greater serum ALT elevation, lipid accumulation, necroinflammation, and focal hepatic cell death in mice than rats. Mice exhibited a remarkable hyperHomocysteinemia but no increase was seen in rats. Similarly, a high methionine low folate diet (HMLF) induced less steatosis, serum ALT increase, and hyperHomocysteinemia in rats than in mice. Western blot analysis of betaine Homocysteine Methyltransferase (BHMT) expression showed that rats fed either ethanol or HMLF had significantly increased BHMT expression which did not occur in mice. Nuclear NFκB p65 was increased in mouse in response to alcohol feeding. The human BHMT promoter was repressed by Homocysteine in mouse hepatocytes but not rat hepatocytes. BHMT induction was faster and greater in primary rat hepatocytes than mouse hepatocytes in response to exogenous Homocysteine exposure. Mice fed ethanol i.g. exhibited an increase in GRP78 and IRE1 which was not seen in the rat and SREBP-1 was increased to a greater extent in mice than rats. Thus, rats are more resistant to ethanol induced steatosis, ER stress and hyperHomocysteinemia and this correlates with induction of BHMT in rats. These findings support the hypothesis that a critical factor in the pathogenesis of alcoholic liver injury is the enhanced ability of rat or impaired ability of mouse to up-regulate BHMT which prevents hyperHomocysteinemia, ER stress and liver injury.
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Effect of transgenic extrahepatic expression of betaine-Homocysteine Methyltransferase on alcohol or Homocysteine-induced fatty liver.
Alcoholism clinical and experimental research, 2008Co-Authors: Masao Shinohara, Christine Chan, Dennis E. Vance, Tin Aung Than, Murad Ookhtens, Neil KaplowitzAbstract:IN THE LIVER, the essential amino acid methionine is converted to Homocysteine after removal of its methyl group by the conversion of S-adenosylmethionine (SAM) to S-adenosylHomocysteine (SAH) (Finkelstein, 2006; Stead et al., 2006). SAM is a methyl donor for numerous methylation reactions that play major roles in biosynthesis, regulation, and detoxification. Homeostasis of SAM is maintained by glycine Methyltransferase (GNMT), which utilizes glycine as the methyl receptor to consume excess SAM and forms a nontoxic product. SAH is reversibly converted to Homocysteine catalyzed by SAH hydrolase. Two other methylation reactions also contribute significantly to Homocysteine production in the liver: the methylation of phosphatidylethanolamine (PE) forming phosphatidylcholine (PC) which is catalyzed by phosphatidylethanolamine Methyltransferase (PEMT) and the methylation of guanidinoacetic acid forming creatine which is catalyzed by guanidinoacetic acid Methyltransferase. Homocysteine can be metabolized through either transsulfuration or remethylation. Transsulfuration converts Homocysteine to cysteine for glutathione (GSH) production which is initiated by cystathionine β-synthase. Remethylation of Homocysteine back to methionine is catalyzed by cobalamin-dependent methionine synthase using 5-methylfolate as co-substrate supplied by 5, 10-methylenetetrahydrofolate reductase and by betaine-Homocysteine Methyltransferase (BHMT) using betaine (trimethylglycine) as a methyl donor. These reactions maintain homeostasis of methionine, Homocysteine, SAM, and GSH. Alcohol induced liver injury starts with fatty liver which is followed by steatohepatitis, fibrosis, and cirrhosis. Factors including oxidative stress, acetaldehyde toxicity, endotoxins, cytokines, impaired immune response, and nutritional deficiencies have been suggested to contribute to the injury. Recent evidence indicates that disturbance of methionine and Homocysteine homeostasis may contribute to the development of alcoholic liver disease (ALD) (Lu et al., 2002; Halsted et al., 2002; Ji and Kaplowitz, 2004). For example, chronic ethanol exposure has been shown to decrease hepatic concentrations of SAM and folate but increase concentrations of plasma Homocysteine and hepatic SAH in animal and human studies (Lieber et al., 1990; Barak et al., 1994; Cravo et al., 1996; Halsted et al., 1996; de la Vega et al., 2001; Ji and Kaplowitz, 2003; Barak et al., 2003). The changes are associated with different degrees of liver injury. Exogenous administration of SAM or betaine has been shown to prevent alcoholic liver injury in animal studies (Feo et al., 1986; Lieber et al., 1990; Ji and Kaplowitz, 2003; Song et al., 2003). The mechanisms by which SAM exerts its protection include attenuation of oxidative stress by restoring GSH concentrations, inhibition of inflammation by down-regulating tumor necrosis factor tumor necrosis factor-α and up-regulating interleukin-10 synthesis, prevention of apoptosis by reducing mitochondrial cytochrome c release and caspase-3 activation in hepatocytes, and induction of apoptosis of liver tumor cells by increasing DNA oxidation and strand breaks (Feo et al., 1986; Fernandez-Checa et al., 2002; Ishii et al., 2003; Song et al., 2003; Yang et al., 2004; Barve et al., 2006). How betaine ameliorates ALD is not fully understood. We have previously studied the direct role of BHMT/betaine in cell protection by over-expressing BHMT in HepG2 cells and found that BHMT expression inhibited Homocysteine-induced endoplasmic reticulum (ER) stress response, lipid accumulation, and cell death (Ji et al., 2007). Suppression of BHMT expression in primary mouse hepatocytes potentiated Homocysteine-induced, but not tunicamycin-induced, ER stress response and cell injury. In addition, in the presence of betaine, expression of BHMT correlated with increased apolipoprotein B (ApoB) expression and increased SAM to SAH ratio. The evidence suggests that BHMT/betaine has multiple beneficial effects in cultured hepatocytes. To know whether the protective effects also occur in vivo, we produced transgenic (Tg) mice expressing human BHMT and compared the Tg and wild type (WT) mice in their response to intragastric alcohol infusion or to oral feeding of a high methionine low folate diet (HMLF). These mice had a significant expression of the transgene only in extrahepatic tissues allowing us to assess its effect independent of a direct effect of transgene expression in the liver. We found that in conjunction with lowering Homocysteine and increasing ratios of SAM/SAH and PC/PE, the BHMT Tg mice were resistant to alcohol or diet-induced hyperHomocysteinemia (HHcy) and liver steatosis.
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mechanisms of protection by the betaine Homocysteine Methyltransferase betaine system in hepg2 cells and primary mouse hepatocytes
Hepatology, 2007Co-Authors: Masao Shinohara, John Kuhlenkamp, Christine Chan, Neil KaplowitzAbstract:Betaine-Homocysteine Methyltransferase (BHMT) is a cytosolic zinc metalloenzyme that is highly expressed in the liver and kidneys.1–6 BMHT catalyzes methyl transfer from betaine, a product of choline oxidation, to Homocysteine, yielding methionine and N,N-dimethylglycine. Homocysteine remethylation is also catalyzed by a cobalamin-dependent enzyme, methionine synthase (MS), with 5-methylfolate as a cosubstrate supplied by 5,10-methylenetetrahydrofolate reductase. Both BHMT and MS have a low Michaelis-Menten constant (Km) for Homocysteine. Elevated S-adenosylmethionine (SAM), resulting from a methionine excess, inhibits BHMT and the formation of 5-methyltetrahydrofolate catalyzed by 5,10-methylenetetrahydrofolate reductase.7 Hence, Homocysteine remethylation is predominant at low levels of Homocysteine and methionine. At high levels, SAM stimulates 2 high-Km enzymes, methionine adenosyltransferase-III and cystathionine β-synthase (CBS). The latter converts Homocysteine toward the transsulfuration pathway for the production of cysteine.8,9 Thus, BHMT is a component of the methionine cycle, and when folate-dependent methionine synthesis is impaired by either genetic or environmental factors (for example, a chronic alcohol treatment), the BHMT/betaine system plays a critical role in Homocysteine homeostasis.10 Impaired BHMT results in elevated Homocysteine levels and could contribute to the risk for vascular, hepatic, and neurological diseases.4,10–13 Betaine supplementation ameliorates the biochemical abnormalities and the clinical course in homocystinuria due to a deficiency of CBS or to several remethylation defects.14 We and others have previously observed that betaine supplementation protects against alcohol-induced fatty liver and endoplasmic reticulum (ER) stress and, at the same time, prevents alcohol-induced hyperHomocysteinemia.15–20 Other potential mechanisms of protection by betaine may contribute to the amelioration of an alcoholic fatty liver/injury, including increasing the SAM to S-adenosylHomocysteine (SAH) ratio and phosphatidylethanolamine Methyltransferase activity and acting as a molecular chaperone. In addition, the expression of apolipoprotein B (ApoB) is increased in McArdle RH-7777 expressing BHMTand in rat livers following the in vivo induction of BHMT,21–24 which could increase triglyceride mobilization/secretion to minimize fatty liver. In the liver, BHMT is responsible for 50% of the Homocysteine remethylation.3–5,25 A severe reduction of BHMT messenger RNA(mRNA) was found in 90% of patients with hepatitis C virus–induced cirrhosis and in about 50% of patients with chronic alcohol– induced cirrhosis.26 In order to investigate the direct role of the BHMT/betaine system in liver steatosis and injury, we generated BHMT transgenic cell models and silenced BHMT expression in primary mouse hepatocytes. We compared the response of the transgenic models and wild type to homo-cysteine challenge versus other inducers of ER stress and found that BHMT/betaine protected specifically against Homocysteine-induced ER stress and cell death in the hepatocytes and decreased hepatocellular lipids, which correlated with decreased sterol regulatory element binding protein 1 (SREBP-1) induction, increased ApoB expression, and restored SAM/SAH.
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Mechanisms of protection by the betaine-Homocysteine Methyltransferase/betaine system in HepG2 cells and primary mouse hepatocytes.
Hepatology (Baltimore Md.), 2007Co-Authors: Masao Shinohara, John Kuhlenkamp, Christine Chan, Neil KaplowitzAbstract:Betaine-Homocysteine Methyltransferase (BHMT) is a cytosolic zinc metalloenzyme that is highly expressed in the liver and kidneys.1–6 BMHT catalyzes methyl transfer from betaine, a product of choline oxidation, to Homocysteine, yielding methionine and N,N-dimethylglycine. Homocysteine remethylation is also catalyzed by a cobalamin-dependent enzyme, methionine synthase (MS), with 5-methylfolate as a cosubstrate supplied by 5,10-methylenetetrahydrofolate reductase. Both BHMT and MS have a low Michaelis-Menten constant (Km) for Homocysteine. Elevated S-adenosylmethionine (SAM), resulting from a methionine excess, inhibits BHMT and the formation of 5-methyltetrahydrofolate catalyzed by 5,10-methylenetetrahydrofolate reductase.7 Hence, Homocysteine remethylation is predominant at low levels of Homocysteine and methionine. At high levels, SAM stimulates 2 high-Km enzymes, methionine adenosyltransferase-III and cystathionine β-synthase (CBS). The latter converts Homocysteine toward the transsulfuration pathway for the production of cysteine.8,9 Thus, BHMT is a component of the methionine cycle, and when folate-dependent methionine synthesis is impaired by either genetic or environmental factors (for example, a chronic alcohol treatment), the BHMT/betaine system plays a critical role in Homocysteine homeostasis.10 Impaired BHMT results in elevated Homocysteine levels and could contribute to the risk for vascular, hepatic, and neurological diseases.4,10–13 Betaine supplementation ameliorates the biochemical abnormalities and the clinical course in homocystinuria due to a deficiency of CBS or to several remethylation defects.14 We and others have previously observed that betaine supplementation protects against alcohol-induced fatty liver and endoplasmic reticulum (ER) stress and, at the same time, prevents alcohol-induced hyperHomocysteinemia.15–20 Other potential mechanisms of protection by betaine may contribute to the amelioration of an alcoholic fatty liver/injury, including increasing the SAM to S-adenosylHomocysteine (SAH) ratio and phosphatidylethanolamine Methyltransferase activity and acting as a molecular chaperone. In addition, the expression of apolipoprotein B (ApoB) is increased in McArdle RH-7777 expressing BHMTand in rat livers following the in vivo induction of BHMT,21–24 which could increase triglyceride mobilization/secretion to minimize fatty liver. In the liver, BHMT is responsible for 50% of the Homocysteine remethylation.3–5,25 A severe reduction of BHMT messenger RNA(mRNA) was found in 90% of patients with hepatitis C virus–induced cirrhosis and in about 50% of patients with chronic alcohol– induced cirrhosis.26 In order to investigate the direct role of the BHMT/betaine system in liver steatosis and injury, we generated BHMT transgenic cell models and silenced BHMT expression in primary mouse hepatocytes. We compared the response of the transgenic models and wild type to homo-cysteine challenge versus other inducers of ER stress and found that BHMT/betaine protected specifically against Homocysteine-induced ER stress and cell death in the hepatocytes and decreased hepatocellular lipids, which correlated with decreased sterol regulatory element binding protein 1 (SREBP-1) induction, increased ApoB expression, and restored SAM/SAH.
Eric I. Park - One of the best experts on this subject based on the ideXlab platform.
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investigations of a common genetic variant in betaine Homocysteine Methyltransferase bhmt in coronary artery disease
Atherosclerosis, 2003Co-Authors: Ilan Weisberg, Timothy A. Garrow, Eric I. Park, Karla V. Ballman, Peter B. Berger, Martha E. Nunn, Daniel S. Suh, Andrew P. Breksa, Rima RozenAbstract:Abstract HyperHomocysteinemia, a risk factor for cardiovascular disease, can be caused by genetic mutations in enzymes of Homocysteine metabolism. Homocysteine remethylation to methionine is catalyzed by folate-dependent methionine synthase, or by betaine–Homocysteine Methyltransferase (BHMT), which utilizes betaine as the methyl donor. Since genetic variants in folate-dependent remethylation have been reported to increase risk for cardiovascular disease and other common disorders, we screened BHMT for sequence changes that might alter risk for coronary artery disease (CAD). A variant in exon 6—R239Q—was identified. The frequency of this change was examined in 504 individuals who had undergone coronary angiography and were stratified into controls (those with no or mild disease) and cases (those with significant [>50% reduction in luminal diameter stenosis] 1-, 2-, 3-vessel disease). Although this variant did not affect plasma Homocysteine, the QQ genotype was present in higher frequency in those with no or mild disease, compared with those with significant disease (11 vs. 6%), suggesting that it may decrease risk of CAD; a statistically-significant decrease was seen in the older subjects (13 vs. 7%). Multivariate analysis for the entire group revealed an odds ratio of 0.48 (95% CI: 0.21–1.06) for the QQ genotype; this association was similar in the younger (OR=0.36; 95% CI: 0.09–1.41) and older subjects (OR=0.42; 95% CI: 0.15–1.18). Our study suggests that the Q allele of the R239Q mutation may decrease the risk of CAD and that this variant warrants additional investigation of its relationship with the development of CAD as well as other Homocysteine-dependent disorders.
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Investigations of a common genetic variant in betaine–Homocysteine Methyltransferase (BHMT) in coronary artery disease
Atherosclerosis, 2003Co-Authors: Ilan S. Weisberg, Timothy A. Garrow, Eric I. Park, Karla V. Ballman, Peter B. Berger, Martha E. Nunn, Daniel S. Suh, Andrew P. Breksa, Rima RozenAbstract:Abstract HyperHomocysteinemia, a risk factor for cardiovascular disease, can be caused by genetic mutations in enzymes of Homocysteine metabolism. Homocysteine remethylation to methionine is catalyzed by folate-dependent methionine synthase, or by betaine–Homocysteine Methyltransferase (BHMT), which utilizes betaine as the methyl donor. Since genetic variants in folate-dependent remethylation have been reported to increase risk for cardiovascular disease and other common disorders, we screened BHMT for sequence changes that might alter risk for coronary artery disease (CAD). A variant in exon 6—R239Q—was identified. The frequency of this change was examined in 504 individuals who had undergone coronary angiography and were stratified into controls (those with no or mild disease) and cases (those with significant [>50% reduction in luminal diameter stenosis] 1-, 2-, 3-vessel disease). Although this variant did not affect plasma Homocysteine, the QQ genotype was present in higher frequency in those with no or mild disease, compared with those with significant disease (11 vs. 6%), suggesting that it may decrease risk of CAD; a statistically-significant decrease was seen in the older subjects (13 vs. 7%). Multivariate analysis for the entire group revealed an odds ratio of 0.48 (95% CI: 0.21–1.06) for the QQ genotype; this association was similar in the younger (OR=0.36; 95% CI: 0.09–1.41) and older subjects (OR=0.42; 95% CI: 0.15–1.18). Our study suggests that the Q allele of the R239Q mutation may decrease the risk of CAD and that this variant warrants additional investigation of its relationship with the development of CAD as well as other Homocysteine-dependent disorders.
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Interaction between dietary methionine and methyl donor intake on rat liver betaine-Homocysteine Methyltransferase gene expression and organization of the human gene.
The Journal of biological chemistry, 1999Co-Authors: Eric I. Park, Timothy A. GarrowAbstract:Abstract We previously showed that rat liver betaine-Homocysteine Methyltransferase (BHMT) mRNA content and activity increased 4-fold when rats were fed a methionine-deficient diet containing adequate choline, compared with rats fed the same diet with control levels of methionine (Park, E. I., Renduchintala, M. S., and Garrow, T. A. (1997) J. Nutr. Biochem.8, 541–545). A further 2-fold increase was observed in rats fed the methionine-deficient diet with supplemental betaine. The nutrition studies reported here were designed to determine whether other methyl donors would induce rat liver BHMT gene expression when added to a methionine-deficient diet and to define the relationship between the degree of methionine restriction and level of methyl donor intake on BHMT expression. Therefore, rats were fed amino acid-defined diets varying in methionine and methyl donor composition. The effect of diet on BHMT expression was evaluated using Northern, Western, and enzyme activity analyses. Similar to when betaine was added to a methionine-deficient diet, choline or sulfonium analogs of betaine induced BHMT expression. The diet-induced induction of hepatic BHMT activity was mediated by increases in the steady-state level of its mRNA and immunodetectable protein. Using methyl donor-free diets, we found that methionine restriction was required but alone not sufficient for the high induction of BHMT expression. Concomitant with methionine restriction, dietary methyl groups were required for high levels of BHMT induction, and a dose-dependent relationship was observed between methyl donor intake and BHMT induction. Furthermore, the severity of methionine restriction influenced the magnitude of BHMT induction. To study the molecular mechanisms that regulate the expression of BHMT, we have cloned the human BHMT gene. This gene spans about 20 kilobases of DNA and contains 8 exons and 7 introns. Using RNA isolated from human liver and hepatoma cells, a major transcriptional start site has been mapped using the 5′ rapid amplification of cDNA ends technique, and this start site is 26 nucleotides downstream from a putative TATA box.
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BETAINE-Homocysteine Methyltransferase EXPRESSION IN PORCINE AND HUMAN TISSUES AND CHROMOSOMAL LOCALIZATION OF THE HUMAN GENE
Archives of biochemistry and biophysics, 1997Co-Authors: Sara L.f. Sunden, Murty S. Renduchintala, Eric I. Park, Steven D. Miklasz, Timothy A. GarrowAbstract:Abstract We have prepared antibodies against porcine liver betaine–Homocysteine Methyltransferase (BHMT; EC 2.1.1.5) and recently cloned cDNAs encoding the porcine and human liver enzymes. Porcine tissues were evaluated for BHMT expression by measuring catalytic activity and Western analysis. Liver and kidney were the only organs tested that had immunodetectable levels of BHMT, and these organs expressed high levels of enzyme activity. BHMT was expressed in the kidney cortex and not the medulla. Porcine pancreas, brain, heart, lung, and spleen were devoid of BHMT activity and immunodetectable protein. Human tissues were tested for BHMT expression by Northern analysis. Human liver and kidney were the only organs tested that expressed BHMT mRNA. Human pancreas, brain, heart, skeletal muscle, spleen, and placenta were devoid of BHMT mRNA. The human BHMT gene has been mapped to chromosome 5q13.1-q15.
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Rapid Communication Diet-induced changes in hepatic betaine- Homocysteine Methyltransferase activity are mediated by changes in the steady- state level of its mRNA
1997Co-Authors: Eric I. Park, Murty S. Renduchintala, Timothy A. GarrowAbstract:Liver betaine-Homocysteine Methyltransferase (EC 2.1.1.5) activity fluctuates with changes in the dietary intake of sulfur amino acids, choline, and betaine. The purpose of this study was to determine whether dietary-induced changes in the activity of hepatic betaine-Homocysteine Methyltransferase are mediated by changes in the level of its mRNA. The hepatic activity and mRNA content of betaine-Homocysteine Methyltransferase were measured in rats fed one of five amino acid‐ defined diets: basal (1 g/kg methionine, 3 g/kg cystine, 1.25 g/kg choline bitartrate), control (basal plus 2 g/kg methionine), betaine supplemented (basal plus 3 g/kg betaine), cystine supplemented (basal plus 3 g/kg cystine), or betaine and cystine supplemented (basal plus 3 g/kg betaine plus 3 g/kg cystine). The basal diet was deficient solely in methionine, and the control diet was adequate in all nutrients. When compared with rats consuming the control diet, rats fed the methionine-deficient diet exhibited a 4-fold increase in the steady-state level of betaine-Homocysteine Methyltransferase mRNA ( p , 0.05). Betaine addition to the methionine-deficient diet elevated mRNA level even further, resulting in a nearly 10-fold higher mRNA levels compared with the methionine-adequate control diet ( p , 0.05). Dietary cystine had no effect on betaine-Homocysteine Methyltransferase mRNA levels. Liver betaine-Homocysteine Methyltransferase activity mirrored its mRNA levels. We conclude that dietary-induced changes of liver betaine-Homocysteine Methyltransferase activity are mediated by changes in the steady-state levels of its mRNA. (J. Nutr. Biochem. 8:541‐545, 1997) © Elsevier Science Inc. 1997
Masao Shinohara - One of the best experts on this subject based on the ideXlab platform.
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differences in betaine Homocysteine Methyltransferase expression endoplasmic reticulum stress response and liver injury between alcohol fed mice and rats
Hepatology, 2010Co-Authors: Masao Shinohara, Neil KaplowitzAbstract:Chronic ethanol infusion resulted in greater serum ALT elevation, lipid accumulation, necroinflammation, and focal hepatic cell death in mice than rats. Mice exhibited a remarkable hyperHomocysteinemia but no increase was seen in rats. Similarly, a high methionine low folate diet (HMLF) induced less steatosis, serum ALT increase, and hyperHomocysteinemia in rats than in mice. Western blot analysis of betaine Homocysteine Methyltransferase (BHMT) expression showed that rats fed either ethanol or HMLF had significantly increased BHMT expression which did not occur in mice. Nuclear NFκB p65 was increased in mouse in response to alcohol feeding. The human BHMT promoter was repressed by Homocysteine in mouse hepatocytes but not rat hepatocytes. BHMT induction was faster and greater in primary rat hepatocytes than mouse hepatocytes in response to exogenous Homocysteine exposure. Mice fed ethanol i.g. exhibited an increase in GRP78 and IRE1 which was not seen in the rat and SREBP-1 was increased to a greater extent in mice than rats. Thus, rats are more resistant to ethanol induced steatosis, ER stress and hyperHomocysteinemia and this correlates with induction of BHMT in rats. These findings support the hypothesis that a critical factor in the pathogenesis of alcoholic liver injury is the enhanced ability of rat or impaired ability of mouse to up-regulate BHMT which prevents hyperHomocysteinemia, ER stress and liver injury.
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Differences in betaine‐Homocysteine Methyltransferase expression, endoplasmic reticulum stress response, and liver injury between alcohol‐fed mice and rats
Hepatology (Baltimore Md.), 2010Co-Authors: Masao Shinohara, Neil KaplowitzAbstract:Chronic ethanol infusion resulted in greater serum ALT elevation, lipid accumulation, necroinflammation, and focal hepatic cell death in mice than rats. Mice exhibited a remarkable hyperHomocysteinemia but no increase was seen in rats. Similarly, a high methionine low folate diet (HMLF) induced less steatosis, serum ALT increase, and hyperHomocysteinemia in rats than in mice. Western blot analysis of betaine Homocysteine Methyltransferase (BHMT) expression showed that rats fed either ethanol or HMLF had significantly increased BHMT expression which did not occur in mice. Nuclear NFκB p65 was increased in mouse in response to alcohol feeding. The human BHMT promoter was repressed by Homocysteine in mouse hepatocytes but not rat hepatocytes. BHMT induction was faster and greater in primary rat hepatocytes than mouse hepatocytes in response to exogenous Homocysteine exposure. Mice fed ethanol i.g. exhibited an increase in GRP78 and IRE1 which was not seen in the rat and SREBP-1 was increased to a greater extent in mice than rats. Thus, rats are more resistant to ethanol induced steatosis, ER stress and hyperHomocysteinemia and this correlates with induction of BHMT in rats. These findings support the hypothesis that a critical factor in the pathogenesis of alcoholic liver injury is the enhanced ability of rat or impaired ability of mouse to up-regulate BHMT which prevents hyperHomocysteinemia, ER stress and liver injury.
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Effect of transgenic extrahepatic expression of betaine-Homocysteine Methyltransferase on alcohol or Homocysteine-induced fatty liver.
Alcoholism clinical and experimental research, 2008Co-Authors: Masao Shinohara, Christine Chan, Dennis E. Vance, Tin Aung Than, Murad Ookhtens, Neil KaplowitzAbstract:IN THE LIVER, the essential amino acid methionine is converted to Homocysteine after removal of its methyl group by the conversion of S-adenosylmethionine (SAM) to S-adenosylHomocysteine (SAH) (Finkelstein, 2006; Stead et al., 2006). SAM is a methyl donor for numerous methylation reactions that play major roles in biosynthesis, regulation, and detoxification. Homeostasis of SAM is maintained by glycine Methyltransferase (GNMT), which utilizes glycine as the methyl receptor to consume excess SAM and forms a nontoxic product. SAH is reversibly converted to Homocysteine catalyzed by SAH hydrolase. Two other methylation reactions also contribute significantly to Homocysteine production in the liver: the methylation of phosphatidylethanolamine (PE) forming phosphatidylcholine (PC) which is catalyzed by phosphatidylethanolamine Methyltransferase (PEMT) and the methylation of guanidinoacetic acid forming creatine which is catalyzed by guanidinoacetic acid Methyltransferase. Homocysteine can be metabolized through either transsulfuration or remethylation. Transsulfuration converts Homocysteine to cysteine for glutathione (GSH) production which is initiated by cystathionine β-synthase. Remethylation of Homocysteine back to methionine is catalyzed by cobalamin-dependent methionine synthase using 5-methylfolate as co-substrate supplied by 5, 10-methylenetetrahydrofolate reductase and by betaine-Homocysteine Methyltransferase (BHMT) using betaine (trimethylglycine) as a methyl donor. These reactions maintain homeostasis of methionine, Homocysteine, SAM, and GSH. Alcohol induced liver injury starts with fatty liver which is followed by steatohepatitis, fibrosis, and cirrhosis. Factors including oxidative stress, acetaldehyde toxicity, endotoxins, cytokines, impaired immune response, and nutritional deficiencies have been suggested to contribute to the injury. Recent evidence indicates that disturbance of methionine and Homocysteine homeostasis may contribute to the development of alcoholic liver disease (ALD) (Lu et al., 2002; Halsted et al., 2002; Ji and Kaplowitz, 2004). For example, chronic ethanol exposure has been shown to decrease hepatic concentrations of SAM and folate but increase concentrations of plasma Homocysteine and hepatic SAH in animal and human studies (Lieber et al., 1990; Barak et al., 1994; Cravo et al., 1996; Halsted et al., 1996; de la Vega et al., 2001; Ji and Kaplowitz, 2003; Barak et al., 2003). The changes are associated with different degrees of liver injury. Exogenous administration of SAM or betaine has been shown to prevent alcoholic liver injury in animal studies (Feo et al., 1986; Lieber et al., 1990; Ji and Kaplowitz, 2003; Song et al., 2003). The mechanisms by which SAM exerts its protection include attenuation of oxidative stress by restoring GSH concentrations, inhibition of inflammation by down-regulating tumor necrosis factor tumor necrosis factor-α and up-regulating interleukin-10 synthesis, prevention of apoptosis by reducing mitochondrial cytochrome c release and caspase-3 activation in hepatocytes, and induction of apoptosis of liver tumor cells by increasing DNA oxidation and strand breaks (Feo et al., 1986; Fernandez-Checa et al., 2002; Ishii et al., 2003; Song et al., 2003; Yang et al., 2004; Barve et al., 2006). How betaine ameliorates ALD is not fully understood. We have previously studied the direct role of BHMT/betaine in cell protection by over-expressing BHMT in HepG2 cells and found that BHMT expression inhibited Homocysteine-induced endoplasmic reticulum (ER) stress response, lipid accumulation, and cell death (Ji et al., 2007). Suppression of BHMT expression in primary mouse hepatocytes potentiated Homocysteine-induced, but not tunicamycin-induced, ER stress response and cell injury. In addition, in the presence of betaine, expression of BHMT correlated with increased apolipoprotein B (ApoB) expression and increased SAM to SAH ratio. The evidence suggests that BHMT/betaine has multiple beneficial effects in cultured hepatocytes. To know whether the protective effects also occur in vivo, we produced transgenic (Tg) mice expressing human BHMT and compared the Tg and wild type (WT) mice in their response to intragastric alcohol infusion or to oral feeding of a high methionine low folate diet (HMLF). These mice had a significant expression of the transgene only in extrahepatic tissues allowing us to assess its effect independent of a direct effect of transgene expression in the liver. We found that in conjunction with lowering Homocysteine and increasing ratios of SAM/SAH and PC/PE, the BHMT Tg mice were resistant to alcohol or diet-induced hyperHomocysteinemia (HHcy) and liver steatosis.
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mechanisms of protection by the betaine Homocysteine Methyltransferase betaine system in hepg2 cells and primary mouse hepatocytes
Hepatology, 2007Co-Authors: Masao Shinohara, John Kuhlenkamp, Christine Chan, Neil KaplowitzAbstract:Betaine-Homocysteine Methyltransferase (BHMT) is a cytosolic zinc metalloenzyme that is highly expressed in the liver and kidneys.1–6 BMHT catalyzes methyl transfer from betaine, a product of choline oxidation, to Homocysteine, yielding methionine and N,N-dimethylglycine. Homocysteine remethylation is also catalyzed by a cobalamin-dependent enzyme, methionine synthase (MS), with 5-methylfolate as a cosubstrate supplied by 5,10-methylenetetrahydrofolate reductase. Both BHMT and MS have a low Michaelis-Menten constant (Km) for Homocysteine. Elevated S-adenosylmethionine (SAM), resulting from a methionine excess, inhibits BHMT and the formation of 5-methyltetrahydrofolate catalyzed by 5,10-methylenetetrahydrofolate reductase.7 Hence, Homocysteine remethylation is predominant at low levels of Homocysteine and methionine. At high levels, SAM stimulates 2 high-Km enzymes, methionine adenosyltransferase-III and cystathionine β-synthase (CBS). The latter converts Homocysteine toward the transsulfuration pathway for the production of cysteine.8,9 Thus, BHMT is a component of the methionine cycle, and when folate-dependent methionine synthesis is impaired by either genetic or environmental factors (for example, a chronic alcohol treatment), the BHMT/betaine system plays a critical role in Homocysteine homeostasis.10 Impaired BHMT results in elevated Homocysteine levels and could contribute to the risk for vascular, hepatic, and neurological diseases.4,10–13 Betaine supplementation ameliorates the biochemical abnormalities and the clinical course in homocystinuria due to a deficiency of CBS or to several remethylation defects.14 We and others have previously observed that betaine supplementation protects against alcohol-induced fatty liver and endoplasmic reticulum (ER) stress and, at the same time, prevents alcohol-induced hyperHomocysteinemia.15–20 Other potential mechanisms of protection by betaine may contribute to the amelioration of an alcoholic fatty liver/injury, including increasing the SAM to S-adenosylHomocysteine (SAH) ratio and phosphatidylethanolamine Methyltransferase activity and acting as a molecular chaperone. In addition, the expression of apolipoprotein B (ApoB) is increased in McArdle RH-7777 expressing BHMTand in rat livers following the in vivo induction of BHMT,21–24 which could increase triglyceride mobilization/secretion to minimize fatty liver. In the liver, BHMT is responsible for 50% of the Homocysteine remethylation.3–5,25 A severe reduction of BHMT messenger RNA(mRNA) was found in 90% of patients with hepatitis C virus–induced cirrhosis and in about 50% of patients with chronic alcohol– induced cirrhosis.26 In order to investigate the direct role of the BHMT/betaine system in liver steatosis and injury, we generated BHMT transgenic cell models and silenced BHMT expression in primary mouse hepatocytes. We compared the response of the transgenic models and wild type to homo-cysteine challenge versus other inducers of ER stress and found that BHMT/betaine protected specifically against Homocysteine-induced ER stress and cell death in the hepatocytes and decreased hepatocellular lipids, which correlated with decreased sterol regulatory element binding protein 1 (SREBP-1) induction, increased ApoB expression, and restored SAM/SAH.
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Mechanisms of protection by the betaine-Homocysteine Methyltransferase/betaine system in HepG2 cells and primary mouse hepatocytes.
Hepatology (Baltimore Md.), 2007Co-Authors: Masao Shinohara, John Kuhlenkamp, Christine Chan, Neil KaplowitzAbstract:Betaine-Homocysteine Methyltransferase (BHMT) is a cytosolic zinc metalloenzyme that is highly expressed in the liver and kidneys.1–6 BMHT catalyzes methyl transfer from betaine, a product of choline oxidation, to Homocysteine, yielding methionine and N,N-dimethylglycine. Homocysteine remethylation is also catalyzed by a cobalamin-dependent enzyme, methionine synthase (MS), with 5-methylfolate as a cosubstrate supplied by 5,10-methylenetetrahydrofolate reductase. Both BHMT and MS have a low Michaelis-Menten constant (Km) for Homocysteine. Elevated S-adenosylmethionine (SAM), resulting from a methionine excess, inhibits BHMT and the formation of 5-methyltetrahydrofolate catalyzed by 5,10-methylenetetrahydrofolate reductase.7 Hence, Homocysteine remethylation is predominant at low levels of Homocysteine and methionine. At high levels, SAM stimulates 2 high-Km enzymes, methionine adenosyltransferase-III and cystathionine β-synthase (CBS). The latter converts Homocysteine toward the transsulfuration pathway for the production of cysteine.8,9 Thus, BHMT is a component of the methionine cycle, and when folate-dependent methionine synthesis is impaired by either genetic or environmental factors (for example, a chronic alcohol treatment), the BHMT/betaine system plays a critical role in Homocysteine homeostasis.10 Impaired BHMT results in elevated Homocysteine levels and could contribute to the risk for vascular, hepatic, and neurological diseases.4,10–13 Betaine supplementation ameliorates the biochemical abnormalities and the clinical course in homocystinuria due to a deficiency of CBS or to several remethylation defects.14 We and others have previously observed that betaine supplementation protects against alcohol-induced fatty liver and endoplasmic reticulum (ER) stress and, at the same time, prevents alcohol-induced hyperHomocysteinemia.15–20 Other potential mechanisms of protection by betaine may contribute to the amelioration of an alcoholic fatty liver/injury, including increasing the SAM to S-adenosylHomocysteine (SAH) ratio and phosphatidylethanolamine Methyltransferase activity and acting as a molecular chaperone. In addition, the expression of apolipoprotein B (ApoB) is increased in McArdle RH-7777 expressing BHMTand in rat livers following the in vivo induction of BHMT,21–24 which could increase triglyceride mobilization/secretion to minimize fatty liver. In the liver, BHMT is responsible for 50% of the Homocysteine remethylation.3–5,25 A severe reduction of BHMT messenger RNA(mRNA) was found in 90% of patients with hepatitis C virus–induced cirrhosis and in about 50% of patients with chronic alcohol– induced cirrhosis.26 In order to investigate the direct role of the BHMT/betaine system in liver steatosis and injury, we generated BHMT transgenic cell models and silenced BHMT expression in primary mouse hepatocytes. We compared the response of the transgenic models and wild type to homo-cysteine challenge versus other inducers of ER stress and found that BHMT/betaine protected specifically against Homocysteine-induced ER stress and cell death in the hepatocytes and decreased hepatocellular lipids, which correlated with decreased sterol regulatory element binding protein 1 (SREBP-1) induction, increased ApoB expression, and restored SAM/SAH.
Rima Rozen - One of the best experts on this subject based on the ideXlab platform.
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investigations of a common genetic variant in betaine Homocysteine Methyltransferase bhmt in coronary artery disease
Atherosclerosis, 2003Co-Authors: Ilan Weisberg, Timothy A. Garrow, Eric I. Park, Karla V. Ballman, Peter B. Berger, Martha E. Nunn, Daniel S. Suh, Andrew P. Breksa, Rima RozenAbstract:Abstract HyperHomocysteinemia, a risk factor for cardiovascular disease, can be caused by genetic mutations in enzymes of Homocysteine metabolism. Homocysteine remethylation to methionine is catalyzed by folate-dependent methionine synthase, or by betaine–Homocysteine Methyltransferase (BHMT), which utilizes betaine as the methyl donor. Since genetic variants in folate-dependent remethylation have been reported to increase risk for cardiovascular disease and other common disorders, we screened BHMT for sequence changes that might alter risk for coronary artery disease (CAD). A variant in exon 6—R239Q—was identified. The frequency of this change was examined in 504 individuals who had undergone coronary angiography and were stratified into controls (those with no or mild disease) and cases (those with significant [>50% reduction in luminal diameter stenosis] 1-, 2-, 3-vessel disease). Although this variant did not affect plasma Homocysteine, the QQ genotype was present in higher frequency in those with no or mild disease, compared with those with significant disease (11 vs. 6%), suggesting that it may decrease risk of CAD; a statistically-significant decrease was seen in the older subjects (13 vs. 7%). Multivariate analysis for the entire group revealed an odds ratio of 0.48 (95% CI: 0.21–1.06) for the QQ genotype; this association was similar in the younger (OR=0.36; 95% CI: 0.09–1.41) and older subjects (OR=0.42; 95% CI: 0.15–1.18). Our study suggests that the Q allele of the R239Q mutation may decrease the risk of CAD and that this variant warrants additional investigation of its relationship with the development of CAD as well as other Homocysteine-dependent disorders.
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Common variant in betaine-Homocysteine Methyltransferase (BHMT) and risk for spina bifida.
American Journal of Medical Genetics Part A, 2003Co-Authors: Isabelle Morin, Timothy A. Garrow, Robert W. Platt, Ilan S. Weisberg, Nelly Sabbaghian, Rima RozenAbstract:Neural tube defects (NTD) are common malformations resulting from incomplete closure of the neural tube in the first month after conception. Since genetic deficiencies in folate-dependent Homocysteine metabolism have been identified in NTD families, we investigated a common variant in betaine-Homocysteine Methyltransferase (BHMT), 742GA (R239Q), as a genetic modifier of NTD risk. Genotypes, nutrient levels, and plasma total Homocysteine (tHcy) were assessed in 54 patients with spina bifida, 57 mothers of patients, 93 control children, and 86 mothers of controls. The QQ genotype (present in 17% and 7% of the control and case mothers, respectively, and in 12% and 6% of the control and case children, respectively) was associated with a decreased risk of NTD (odds ratios of 0.52 (95% CI 0.13–2.05) for children and 0.37 (95% CI 0.11–1.22) for mothers). The small sample size limited the statistical power of the analyses, but these decreases, although not statistically significant, are compatible with a protective effect. We did not observe statistically-significant genotype-dependent differences in plasma Homocysteine, although women with the QQ genotype did have lower Homocysteine; in children, the mean Homocysteine level was higher in the QQ group. This inconsistency could be explained by the fact that age is a strong determinant of Homocysteine in children and the QQ group was on average older than the other genotype groups. Our study suggests that the Q allele of the R239Q mutation may decrease risk of the condition. This warrants further investigation of its relationship with the development of NTD. © 2003 Wiley-Liss, Inc.
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Investigations of a common genetic variant in betaine–Homocysteine Methyltransferase (BHMT) in coronary artery disease
Atherosclerosis, 2003Co-Authors: Ilan S. Weisberg, Timothy A. Garrow, Eric I. Park, Karla V. Ballman, Peter B. Berger, Martha E. Nunn, Daniel S. Suh, Andrew P. Breksa, Rima RozenAbstract:Abstract HyperHomocysteinemia, a risk factor for cardiovascular disease, can be caused by genetic mutations in enzymes of Homocysteine metabolism. Homocysteine remethylation to methionine is catalyzed by folate-dependent methionine synthase, or by betaine–Homocysteine Methyltransferase (BHMT), which utilizes betaine as the methyl donor. Since genetic variants in folate-dependent remethylation have been reported to increase risk for cardiovascular disease and other common disorders, we screened BHMT for sequence changes that might alter risk for coronary artery disease (CAD). A variant in exon 6—R239Q—was identified. The frequency of this change was examined in 504 individuals who had undergone coronary angiography and were stratified into controls (those with no or mild disease) and cases (those with significant [>50% reduction in luminal diameter stenosis] 1-, 2-, 3-vessel disease). Although this variant did not affect plasma Homocysteine, the QQ genotype was present in higher frequency in those with no or mild disease, compared with those with significant disease (11 vs. 6%), suggesting that it may decrease risk of CAD; a statistically-significant decrease was seen in the older subjects (13 vs. 7%). Multivariate analysis for the entire group revealed an odds ratio of 0.48 (95% CI: 0.21–1.06) for the QQ genotype; this association was similar in the younger (OR=0.36; 95% CI: 0.09–1.41) and older subjects (OR=0.42; 95% CI: 0.15–1.18). Our study suggests that the Q allele of the R239Q mutation may decrease the risk of CAD and that this variant warrants additional investigation of its relationship with the development of CAD as well as other Homocysteine-dependent disorders.