Hyperglucagonemia in Rats Results in Decreased Plasma Homocysteine and Increased Flux through the Transsulfuration Pathway in Liver

Jacobs, René L.; Stead, Lori M.; Brosnan, Margaret E.; Brosnan, John T.

doi:10.1074/jbc.m107553200

Cited by 63 publications

(51 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, in the absence of flux studies it is difficult to determine homocysteine catabolism because CBS is regulated allosterically by other factors such as AdoMet, a known allosteric stimulator of CBS activity (33). In support of the increase in CBS abundance that we reported, we also found that the hepatic concentration of AdoMet was elevated in agreement with previous studies using hyperglucogonemic rats (20). Elevations in hepatic AdoMet levels may be the result of increased expression of methionine adenosyltransferase, as it is up-regulated by glucocorticoids (34).…”

Section: Discussionsupporting

confidence: 80%

“…As has been reported (19,20), we also found that a diabetic state was characterized by a reduction in circulating homocysteine levels. This change in homocysteine homeostasis appears to reflect an increase in the activity of BHMT and the abundance of CBS, even though the activity of MS was reduced.…”

Section: Discussionsupporting

confidence: 68%

“…Here, we have extended these findings by demonstrating that a diabetic condition, mediated by treatment with STZ, also has a profound impact on the activity of hepatic GNMT. Previous rat studies using alloxaninduced diabetes reported similar increases (85%) in GNMT activity (6), whereas treatment with glucagon were less pronounced (23%) (20); however, the mechanistic basis for this increase in GNMT activity has not been thoroughly explored. A novel aspect of our studies demonstrates that for both diabetes and RA, the abundance of GNMT protein was markedly elevated, indicating that GNMT was regulated by transcriptional and/or translational mechanisms or possibly at the level of degradation of the protein.…”

Section: Discussionmentioning

confidence: 86%

See 2 more Smart Citations

Modulation of Methyl Group Metabolism by Streptozotocin-induced Diabetes and All-trans-retinoic Acid

Nieman

Rowling

Garrow

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The hepatic enzyme glycine N-methyltransferase (GNMT) plays a major role in the control of methyl group and homocysteine metabolism. Because disruption of these vital pathways is associated with numerous pathologies, understanding GNMT control is important for evaluating methyl group regulation. Recently, gluconeogenic conditions have been shown to modulate homocysteine metabolism and treatment with glucocorticoids and/or all-trans-retinoic acid (RA)-induced active GNMT protein, thereby leading to methyl group loss. This study was conducted to determine the effect of diabetes, alone and in combination with RA, on GNMT regulation. Diabetes and RA increased GNMT activity 87 and 148%, respectively. Moreover, the induction of GNMT activity by diabetes and RA was reflected in its abundance. Cell culture studies demonstrated that pretreatment with insulin prevented GNMT induction by both RA and dexamethasone. There was a significant decline in homocysteine concentrations in diabetic rats, owing in part to a 38% increase in the abundance of the transsulfuration enzyme cystathionine ␤-synthase; treatment of diabetic rats with RA prevented cystathionine ␤-synthase induction. A diabetic state also increased the activity of the folate-independent homocysteine remethylation enzyme betaine-homocysteine S-methyltransferase, whereas the activity of the folatedependent enzyme methionine synthase was diminished 52%. In contrast, RA treatment attenuated the streptozotocin-mediated increase in betaine-homocysteine Smethyltransferase, whereas methionine synthase activity remained diminished. These results indicate that both a diabetic condition and RA treatment have marked effects on the metabolism of methyl groups and homocysteine, a finding that may have significant implications for diabetics and their potential sensitivity to retinoids.

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

Modulation of Methyl Group Metabolism by Streptozotocin-induced Diabetes and All-trans-retinoic Acid

Nieman

Rowling

Garrow

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This shift is also reflected in other 270 gluconeogenic states, such as diabetes. We and others have demonstrated that a diabetic state or 271 administration of synthetic glucocorticoid compounds has a major impact on methyl group and 272 homocysteine metabolism [23][24][25][26][49][50][51][52]. A consistent finding from these reports is a reduction 273 in circulating homocysteine concentrations owing to an increase in folate-independent 274 remethylation (i.e., BHMT) and catabolism of homocysteine through the transsulfuration 275 pathway.…”

mentioning

confidence: 88%

Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model

Neuman¹,

Albright²,

Schalinske³

2013

Nutrition Research

View full text Add to dashboard Cite

Hyperhomocysteinemia is a condition that results from altered methyl group metabolism and is associated with numerous pathological conditions. A number of nutritional and hormonal factors have been shown to influence circulating homocysteine concentrations; however, the impact of exercise on homocysteine and methyl group balance is not well understood. Our hypothesis was that exercise represents an effective means to prevent hyperhomocysteinemia in a folate-independent manner. The purpose of this study was to determine the influence of exercise on homocysteine metabolism in a dietary folate-restricted mouse model characterized by moderate hyperhomocysteinemia. Female outbred mice (12 weeks old) were assigned to either a sedentary or free-access wheel exercise group. Following a 4-week acclimation period, half of the mice in each group were provided a folate-restricted diet for 7-weeks prior to euthanasia and tissue collection. As expected, folate-restricted sedentary mice exhibited a 2-fold increase in plasma total homocysteine concentrations; however, exercise completely prevented the increase in circulating homocysteine concentrations. Moreover, exercise reduced plasma homocysteine concentrations 36% within the group fed only the control diet. The prevention of hyperhomocysteinemia by exercise appears, at least in part, to be the result of increased folate-independent homocysteine remethylation owing to a 2-fold increase in renal betaine homocysteine S-methyltransferase. To our knowledge, this is the first report demonstrating the prevention of hyperhomocysteinemia by exercise in a dietary folate-restriction model. Future research will be directed at determining if exercise can have a positive impact on other nutritional, hormonal, and genetic models of hyperhomocysteinemia relevant to humans. Hyperhomocysteinemia is a condition that results from altered methyl group metabolism and is 30 associated with numerous pathological conditions. A number of nutritional and hormonal factors 31 have been shown to influence circulating homocysteine concentrations; however, the impact of 32 exercise on homocysteine and methyl group balance is not well understood. Our hypothesis was 33 that exercise represents an effective means to prevent hyperhomocysteinemia in a folate-34 independent manner. The purpose of this study was to determine the influence of exercise on 35 homocysteine metabolism in a dietary folate-restricted mouse model characterized by moderate 36 hyperhomocysteinemia. Female outbred mice (12 wk old) were assigned to either a sedentary or 37 free-access wheel exercise group. Following a 4-wk acclimation period, half of the mice in each 38 group were provided a folate-restricted diet for 7-wk prior to euthanasia and tissue collection. As 39 expected, folate-restricted sedentary mice exhibited a 2-fold increase in plasma total 40 homocysteine concentrations; however, exercise completely prevented the increase in circulating 41 homocysteine concentrations. Moreover, exercise reduced plasma homocysteine c...

show abstract

“…Recently, we (33) have shown that a diabetic state leads to the disruption of hepatic methyl group metabolism, characterized by elevations in GNMT activity and abundance, as well as an increase in the folate-independent remethylation of homocysteine by BHMT. Similarly, administration of specific counterregulatory hormones (e.g., dexamethasone, glucagon) has also been shown (23,45) to alter methyl group and homocysteine metabolism both in vivo and in vitro. Because the folate-dependent onecarbon pool supplies methyl groups for the remethylation of homocysteine and SAM-dependent transmethylation reactions and serves as a regulatory mechanism for the control of GNMT activity via allosteric inhibition by 5-CH 3 -THF, the aim of these studies was to examine how dietary folate status may impact the previously reported findings.…”

mentioning

confidence: 99%

Folate status modulates the induction of hepatic glycineN-methyltransferase and homocysteine metabolism in diabetic rats

Nieman¹,

Hartz²,

Szegedi³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

status modulates the induction of hepatic glycine N-methyltransferase and homocysteine metabolism in diabetic rats. Am J Physiol Endocrinol Metab 291: E1235-E1242, 2006. First published July 11, 2006 doi:10.1152/ajpendo.00237.2006.-A diabetic state induces the activity and abundance of glycine N-methyltransferase (GNMT), a key protein in the regulation of folate, methyl group, and homocysteine metabolism. Because the folate-dependent one-carbon pool is a source of methyl groups and 5-methyltetrahydrofolate allosterically inhibits GNMT, the aim of this study was to determine whether folate status has an impact on the interaction between diabetes and methyl group metabolism. Rats were fed a diet containing deficient (0 ppm), adequate (2 ppm), or supplemental (8 ppm) folate for 30 days, after which diabetes was initiated in one-half of the rats by streptozotocin treatment. The activities of GNMT, phosphatidylethanolamine Nmethyltransferase (PEMT), and betaine-homocysteine S-methyltransferase (BHMT) were increased about twofold in diabetic rat liver; folate deficiency resulted in the greatest elevation in GNMT activity. The abundance of GNMT protein and mRNA, as well as BHMT mRNA, was also elevated in diabetic rats. The marked hyperhomocysteinemia in folate-deficient rats was attenuated by streptozotocin, likely due in part to increased BHMT expression. These results indicate that a diabetic state profoundly modulates methyl group, choline, and homocysteine metabolism, and folate status may play a role in the extent of these alterations. Moreover, the upregulation of BHMT and PEMT may indicate an increased choline requirement in the diabetic rat.choline; phosphatidylethanolamine; betaine-homocysteine S-methyltransferase THE FOLATE-DEPENDENT ONE-CARBON POOL and methyl group metabolism are interrelated pathways that are critically important in optimal health, as perturbation of these metabolic processes is associated with a number of pathologies, including cardiovascular disease, cancer development, and birth defects ( Fig. 1) (26,43,46). The primary methyl group donor, S-adenosylmethionine (SAM), requires a constant supply of methyl groups from the diet and/or the one-carbon pool for numerous transmethylation reactions, such as the synthesis of phosphatidylcholine (PC) by the action of the liver-specific enzyme phosphatidylethanolamine N-methyltransferase (PEMT) (31). Therefore, it is essential to regulate the supply and utilization of methyl groups to optimize SAM-dependent transmethylation reactions, a function that is accomplished by the enzymatic activity of a key regulatory protein, glycine N-methyltransferase (GNMT). GNMT is an abundant protein in the liver, comprising ϳ1-3% of all hepatic cytosolic protein, and has also been identified in renal and pancreatic tissue (36, 61). GNMT optimizes the SAM/S-adenosylhomocysteine (SAH) ratio by catalyzing the conversion of SAM and glycine to SAH and sarcosine, respectively (5, 17). Because SAH is a potent inhibitor of methyltransferase activity (28), optimizing the SA...

show abstract

Hyperglucagonemia in Rats Results in Decreased Plasma Homocysteine and Increased Flux through the Transsulfuration Pathway in Liver

Cited by 63 publications

References 43 publications

Modulation of Methyl Group Metabolism by Streptozotocin-induced Diabetes and All-trans-retinoic Acid

Modulation of Methyl Group Metabolism by Streptozotocin-induced Diabetes and All-trans-retinoic Acid

Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model

Folate status modulates the induction of hepatic glycineN-methyltransferase and homocysteine metabolism in diabetic rats

Contact Info

Product

Resources

About