Methionine and Protein Metabolism in Non Alcoholic Steatohepatitis: Evidence for Lower Rate of Transmethylation of Methionine

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 s-adenosylmethionine (SAM) the key methyl donor for phosphotidylcholine synthesis required for the export of VLDL triglycerides from the liver. We have examined the kinetics of methionine, its transmethylation and transsulfuration with estimates of whole body rate of protein turnover and urea synthesis in clinically stable biopsy confirmed subjects with non-alcoholic steatohepatitis (NASH). Subjects with NASH were more insulin resistant and had significantly higher plasma concentration of usCRP, TNF alpha and other inflammatory cytokines. There was no significant effect of insulin resistance and NASH on whole body rate of protein turnover (phenylalanine Ra) and on the rate of urea synthesis. The rates of methylation of homocysteine and transmethylation of methionine were significantly lower in NASH as compared with controls. There was no difference in the rate of transsulfuration of methionine between the two groups. Enteric mixed nutrient load resulted in a significant increase in all the measured parameters of methionine kinetics. Hetrozygosity for MTHFR (677C→T) did not impact 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 data are the first evidence for perturbed metabolism of methionine in NASH in humans and provide a rationale for the development of targeted intervention strategies.