Hepatic metabolism of methionine is the source of cysteine, the precursor of glutathione, the major intracellular antioxidant in the body. Methionine also is the immediate precursor of SAM (S-adenosylmethionine) the key methyl donor for phosphatidylcholine synthesis required for the export of VLDL (very-low-density lipoprotein) triacylglycerols (triglycerides) from the liver. We have examined the kinetics of methionine, its transmethylation and trans-sulfuration with estimates of whole body rate of protein turnover and urea synthesis in clinically stable biopsy-confirmed subjects with NASH (non-alcoholic steatohepatitis). Subjects with NASH were more insulin-resistant and had significantly higher plasma concentrations of usCRP (ultrasensitive C-reactive protein), TNFα (tumour necrosis factor α) and other inflammatory cytokines. There was no significant effect of insulin resistance and NASH on whole body rate of protein turnover [phenylalanine Ra (rate of appearance)] and on the rate of urea synthesis. The rates of methylation of homocysteine and transmethylation of methionine were significantly lower in NASH compared with controls. There was no difference in the rate of trans-sulfuration of methionine between the two groups. Enteric mixed nutrient load resulted in a significant increase in all the measured parameters of methionine kinetics. Heterozygosity for MTHFR (5,10-methylene-tetrahydrofolate reductase) (677C→T) did not have an impact on methionine metabolism. We speculate that, as a result of oxidant stress possibly due to high fatty acid oxidation, the activity of methionine adenosyltransferase is attenuated resulting in a lower rate of transmethylation of methionine and of SAM synthesis. These results are the first evidence for perturbed metabolism of methionine in NASH in humans and provide a rationale for the development of targeted intervention strategies.
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Research Article|
May 04 2011
Methionine and protein metabolism in non-alcoholic steatohepatitis: evidence for lower rate of transmethylation of methionine
Satish C. Kalhan;
*Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
Correspondence: Dr Satish C. Kalhan (email [email protected]).
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John Edmison;
John Edmison
†Department of Gastroenterology, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Susan Marczewski;
Susan Marczewski
*Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Srinivasan Dasarathy;
Srinivasan Dasarathy
†Department of Gastroenterology, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Lourdes L. Gruca;
Lourdes L. Gruca
*Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Carole Bennett;
Carole Bennett
*Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Clarita Duenas;
Clarita Duenas
*Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Rocio Lopez
Rocio Lopez
‡Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Publisher: Portland Press Ltd
Received:
January 29 2011
Revision Received:
March 15 2011
Accepted:
March 30 2011
Accepted Manuscript online:
March 30 2011
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2011 Biochemical Society
2011
Clin Sci (Lond) (2011) 121 (4): 179–189.
Article history
Received:
January 29 2011
Revision Received:
March 15 2011
Accepted:
March 30 2011
Accepted Manuscript online:
March 30 2011
Citation
Satish C. Kalhan, John Edmison, Susan Marczewski, Srinivasan Dasarathy, Lourdes L. Gruca, Carole Bennett, Clarita Duenas, Rocio Lopez; Methionine and protein metabolism in non-alcoholic steatohepatitis: evidence for lower rate of transmethylation of methionine. Clin Sci (Lond) 1 August 2011; 121 (4): 179–189. doi: https://doi.org/10.1042/CS20110060
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