Limits...
Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease.

Pacana T, Cazanave S, Verdianelli A, Patel V, Min HK, Mirshahi F, Quinlivan E, Sanyal AJ - PLoS ONE (2015)

Bottom Line: SAH hydrolase protein levels decreased significantly (p <0.01).The protein levels of protein arginine methytransferase 1 (PRMT1) increased significantly, but its products, monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), decreased significantly.Although gene expression of the DNA methyltransferase Dnmt3a decreased, the global DNA methylation was unaltered.

View Article: PubMed Central - PubMed

Affiliation: Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, United States of America.

ABSTRACT
Methionine metabolism plays a central role in methylation reactions, production of glutathione and methylarginines, and modulating homocysteine levels. The mechanisms by which these are affected in NAFLD are not fully understood. The aim is to perform a metabolomic, molecular and epigenetic analyses of hepatic methionine metabolism in diet-induced NAFLD. Female 129S1/SvlmJ;C57Bl/6J mice were fed a chow (n = 6) or high-fat high-cholesterol (HFHC) diet (n = 8) for 52 weeks. Metabolomic study, enzymatic expression and DNA methylation analyses were performed. HFHC diet led to weight gain, marked steatosis and extensive fibrosis. In the methionine cycle, hepatic methionine was depleted (30%, p< 0.01) while s-adenosylmethionine (SAM)/methionine ratio (p< 0.05), s-adenosylhomocysteine (SAH) (35%, p< 0.01) and homocysteine (25%, p< 0.01) were increased significantly. SAH hydrolase protein levels decreased significantly (p <0.01). Serine, a substrate for both homocysteine remethylation and transsulfuration, was depleted (45%, p< 0.01). In the transsulfuration pathway, cystathionine and cysteine trended upward while glutathione decreased significantly (p< 0.05). In the transmethylation pathway, levels of glycine N-methyltransferase (GNMT), the most abundant methyltransferase in the liver, decreased. The phosphatidylcholine (PC)/ phosphatidylethanolamine (PE) ratio increased significantly (p< 0.01), indicative of increased phosphatidylethanolamine methyltransferase (PEMT) activity. The protein levels of protein arginine methytransferase 1 (PRMT1) increased significantly, but its products, monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), decreased significantly. Circulating ADMA increased and approached significance (p< 0.06). Protein expression of methionine adenosyltransferase 1A, cystathionine β-synthase, γ-glutamylcysteine synthetase, betaine-homocysteine methyltransferase, and methionine synthase remained unchanged. Although gene expression of the DNA methyltransferase Dnmt3a decreased, the global DNA methylation was unaltered. Among individual genes, only HMG-CoA reductase (Hmgcr) was hypermethylated, and no methylation changes were observed in fatty acid synthase (Fasn), nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (Nfκb1), c-Jun, B-cell lymphoma 2 (Bcl-2) and Caspase 3. NAFLD was associated with hepatic methionine deficiency and homocysteine elevation, resulting mainly from impaired homocysteine remethylation, and aberrancy in methyltransferase reactions. Despite increased PRMT1 expression, hepatic ADMA was depleted while circulating ADMA was increased, suggesting increased export to circulation.

No MeSH data available.


Related in: MedlinePlus

Summary of changes in the methionine cycle, transsulfuration pathway and methyltransferase reactions in advance NAFLD.HFHC diet for 52 weeks resulted in methionine depletion, excess homocysteine and aberrancy in transmethylation pathway. The decrease in the substrate serine impairs homocysteine remethylation and limits the ability to replete glutathione in the transsulfuration pathway. Legend: cystathionine β-synthase (CBS); dimethylglycine (DMG); γ-glutamylcysteine synthetase (GCS); glutathione (GSH); 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR); methionine adenosyltransferase (MAT); phosphatidylcholine (PC); phosphatidylethanolamine (PE); protein arginine methytransferas 1 (PRMT1); s-adenosylmethionine (SAM); s-adenosylhomocysteine (SAH); s-adenosylhomocysteine hydrolase (SAHH).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4556375&req=5

pone.0136822.g005: Summary of changes in the methionine cycle, transsulfuration pathway and methyltransferase reactions in advance NAFLD.HFHC diet for 52 weeks resulted in methionine depletion, excess homocysteine and aberrancy in transmethylation pathway. The decrease in the substrate serine impairs homocysteine remethylation and limits the ability to replete glutathione in the transsulfuration pathway. Legend: cystathionine β-synthase (CBS); dimethylglycine (DMG); γ-glutamylcysteine synthetase (GCS); glutathione (GSH); 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR); methionine adenosyltransferase (MAT); phosphatidylcholine (PC); phosphatidylethanolamine (PE); protein arginine methytransferas 1 (PRMT1); s-adenosylmethionine (SAM); s-adenosylhomocysteine (SAH); s-adenosylhomocysteine hydrolase (SAHH).

Mentions: The current study demonstrates that with long-term (52 week) feeding of a HFHC diet and development of advance NAFLD with fibrosis, there is a depletion of methionine along with an increase in its downstream products SAM, SAH and homocysteine (Fig 5). The decrease in methionine, an essential amino acid, may reflect a dietary deficiency or increase in its utilization. In the mouse model studied, the methionine concentration in the HFHC diet was higher than in chow diet (7 mg/kg vs 3 mg/kg) and it is therefore unlikely that the observed decrease reflected a dietary deficiency. It is therefore inferred that the metabolic stress imposed by a HFHC diet increases demand for methionine-derived metabolites and accounts for a decrease in hepatic methionine concentration.


Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease.

Pacana T, Cazanave S, Verdianelli A, Patel V, Min HK, Mirshahi F, Quinlivan E, Sanyal AJ - PLoS ONE (2015)

Summary of changes in the methionine cycle, transsulfuration pathway and methyltransferase reactions in advance NAFLD.HFHC diet for 52 weeks resulted in methionine depletion, excess homocysteine and aberrancy in transmethylation pathway. The decrease in the substrate serine impairs homocysteine remethylation and limits the ability to replete glutathione in the transsulfuration pathway. Legend: cystathionine β-synthase (CBS); dimethylglycine (DMG); γ-glutamylcysteine synthetase (GCS); glutathione (GSH); 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR); methionine adenosyltransferase (MAT); phosphatidylcholine (PC); phosphatidylethanolamine (PE); protein arginine methytransferas 1 (PRMT1); s-adenosylmethionine (SAM); s-adenosylhomocysteine (SAH); s-adenosylhomocysteine hydrolase (SAHH).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556375&req=5

pone.0136822.g005: Summary of changes in the methionine cycle, transsulfuration pathway and methyltransferase reactions in advance NAFLD.HFHC diet for 52 weeks resulted in methionine depletion, excess homocysteine and aberrancy in transmethylation pathway. The decrease in the substrate serine impairs homocysteine remethylation and limits the ability to replete glutathione in the transsulfuration pathway. Legend: cystathionine β-synthase (CBS); dimethylglycine (DMG); γ-glutamylcysteine synthetase (GCS); glutathione (GSH); 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR); methionine adenosyltransferase (MAT); phosphatidylcholine (PC); phosphatidylethanolamine (PE); protein arginine methytransferas 1 (PRMT1); s-adenosylmethionine (SAM); s-adenosylhomocysteine (SAH); s-adenosylhomocysteine hydrolase (SAHH).
Mentions: The current study demonstrates that with long-term (52 week) feeding of a HFHC diet and development of advance NAFLD with fibrosis, there is a depletion of methionine along with an increase in its downstream products SAM, SAH and homocysteine (Fig 5). The decrease in methionine, an essential amino acid, may reflect a dietary deficiency or increase in its utilization. In the mouse model studied, the methionine concentration in the HFHC diet was higher than in chow diet (7 mg/kg vs 3 mg/kg) and it is therefore unlikely that the observed decrease reflected a dietary deficiency. It is therefore inferred that the metabolic stress imposed by a HFHC diet increases demand for methionine-derived metabolites and accounts for a decrease in hepatic methionine concentration.

Bottom Line: SAH hydrolase protein levels decreased significantly (p <0.01).The protein levels of protein arginine methytransferase 1 (PRMT1) increased significantly, but its products, monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), decreased significantly.Although gene expression of the DNA methyltransferase Dnmt3a decreased, the global DNA methylation was unaltered.

View Article: PubMed Central - PubMed

Affiliation: Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, United States of America.

ABSTRACT
Methionine metabolism plays a central role in methylation reactions, production of glutathione and methylarginines, and modulating homocysteine levels. The mechanisms by which these are affected in NAFLD are not fully understood. The aim is to perform a metabolomic, molecular and epigenetic analyses of hepatic methionine metabolism in diet-induced NAFLD. Female 129S1/SvlmJ;C57Bl/6J mice were fed a chow (n = 6) or high-fat high-cholesterol (HFHC) diet (n = 8) for 52 weeks. Metabolomic study, enzymatic expression and DNA methylation analyses were performed. HFHC diet led to weight gain, marked steatosis and extensive fibrosis. In the methionine cycle, hepatic methionine was depleted (30%, p< 0.01) while s-adenosylmethionine (SAM)/methionine ratio (p< 0.05), s-adenosylhomocysteine (SAH) (35%, p< 0.01) and homocysteine (25%, p< 0.01) were increased significantly. SAH hydrolase protein levels decreased significantly (p <0.01). Serine, a substrate for both homocysteine remethylation and transsulfuration, was depleted (45%, p< 0.01). In the transsulfuration pathway, cystathionine and cysteine trended upward while glutathione decreased significantly (p< 0.05). In the transmethylation pathway, levels of glycine N-methyltransferase (GNMT), the most abundant methyltransferase in the liver, decreased. The phosphatidylcholine (PC)/ phosphatidylethanolamine (PE) ratio increased significantly (p< 0.01), indicative of increased phosphatidylethanolamine methyltransferase (PEMT) activity. The protein levels of protein arginine methytransferase 1 (PRMT1) increased significantly, but its products, monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), decreased significantly. Circulating ADMA increased and approached significance (p< 0.06). Protein expression of methionine adenosyltransferase 1A, cystathionine β-synthase, γ-glutamylcysteine synthetase, betaine-homocysteine methyltransferase, and methionine synthase remained unchanged. Although gene expression of the DNA methyltransferase Dnmt3a decreased, the global DNA methylation was unaltered. Among individual genes, only HMG-CoA reductase (Hmgcr) was hypermethylated, and no methylation changes were observed in fatty acid synthase (Fasn), nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (Nfκb1), c-Jun, B-cell lymphoma 2 (Bcl-2) and Caspase 3. NAFLD was associated with hepatic methionine deficiency and homocysteine elevation, resulting mainly from impaired homocysteine remethylation, and aberrancy in methyltransferase reactions. Despite increased PRMT1 expression, hepatic ADMA was depleted while circulating ADMA was increased, suggesting increased export to circulation.

No MeSH data available.


Related in: MedlinePlus