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PMID: 21446920 Published · ppublish English Journal Article Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Methionine and protein metabolism in non-alcoholic steatohepatitis: evidence for lower rate of transmethylation of methionine.

Clinical science (London, England : 1979) ·Vol. 121 ·No. 4 ·2011-08-00 ·Pages 179-89

Kalhan SC, Edmison J, Marczewski S, Dasarathy S, Gruca LL, Bennett C, Duenas C, Lopez R

Abstract

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.

MeSH Terms
Adipokines/blood Adult Aged Calorimetry, Indirect/methods Case-Control Studies Cysteine/blood Fatty Liver/metabolism Female Glutathione/blood Homocysteine/blood Humans Inflammation Mediators/blood Insulin Resistance/physiology Liver/metabolism Male Methionine/metabolism Methylation Middle Aged Non-alcoholic Fatty Liver Disease Phenylalanine/metabolism Proteins/metabolism Urea/metabolism Young Adult
Chemicals
Adipokines Inflammation Mediators Proteins Homocysteine Phenylalanine Urea Methionine Glutathione Cysteine
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Kalhan Satish C
Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, USA. [email protected]
Edmison John
Marczewski Susan
Dasarathy Srinivasan
Gruca Lourdes L
Bennett Carole
Duenas Clarita
Lopez Rocio
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Article Info
Journal
Clinical science (London, England : 1979)
Abbr.
Clin Sci (Lond)
ISSN
1470-8736
DOI
10.1042/CS20110060
Email
[email protected]
Published
2011-08-00
Pages
179-89
Language
English
Region
England
NLM ID
7905731
PMCID
PMC3097472
Subset
IM
Grants
NCRR NIH HHS · UL1 RR024989 · United States
NIDDK NIH HHS · R01 DK079937-02 · United States
NIDDK NIH HHS · R01 DK079937-01A1 · United States
NIDDK NIH HHS · DK079937 · United States
NIDDK NIH HHS · R01 DK079937 · United States
NCRR NIH HHS · RR024989 · United States
NCRR NIH HHS · UL1 RR024989-05 · United States
External Links
PubMed source DOI: 10.1042/CS20110060 PMC Full Text View journal details
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