Methionine Metabolism in Liver Health and Disease

Methionine metabolism constitutes a central axis of hepatic one-carbon biochemistry, linking the folate cycle to the transsulfuration pathway. Dietary methionine is converted by methionine adenosyltransferases into S-adenosylmethionine (SAMe), the primary methyl donor for nucleic acids, proteins and phospholipids. Following methyl transfer, SAMe yields S-adenosylhomocysteine and homocysteine, which may be remethylated back to methionine or directed towards cysteine and glutathione synthesis. Fine-tuning of this cycle determines methylation potential, redox homeostasis and polyamine production. Dysregulation at any enzymatic node can precipitate hepatic steatosis, inflammation, fibrosis or hepatocellular carcinoma, as seen in conditions such as non-alcoholic fatty liver disease and chronic liver injury. Emerging evidence highlights the dual roles of methionine flux in energy balance, antioxidant defence and cell signalling, underscoring its therapeutic importance in liver disorders.

Research from Nature Portfolio

Targeting methionine adenosyltransferase 1a (MAT1A) with antisense oligonucleotides in obese mice has revealed a novel liver–brown adipose tissue axis. Suppression of MAT1A elevates NRF2-driven secretion of fibroblast growth factor 21, promoting energy expenditure, thermogenesis and reduced hepatic lipid accumulation, thereby reversing insulin resistance and steatosis. A complementary study of serine hydroxymethyltransferase 2 (SHMT2) deficiency in hepatocytes has defined stage-specific effects: loss of SHMT2 diminishes one-carbon units and predisposes to fatty liver, yet under a high-fat, high-fructose and high-cholesterol diet it attenuates inflammatory and fibrotic progression. Together, these works illuminate how modulating methyl donor enzymes reshapes systemic metabolism and liver pathology.

Methionine Metabolism in Liver Health and Disease publication trend

The graph below shows the total number of articles in methionine metabolism in liver health and disease across all publications each year (not limited to Nature Index journals).

Technical terms

S-adenosylmethionine (SAMe): The principal methyl donor generated from methionine by methionine adenosyltransferases.

Methionine adenosyltransferase (MAT): Enzyme family converting methionine into SAMe; MAT1A predominates in healthy adult liver.

One-carbon metabolism: Network of interlinked reactions that transfer single carbon units for methylation, nucleotide synthesis and redox balance.

Transsulfuration pathway: Sequence of reactions converting homocysteine into cysteine and glutathione, critical for antioxidant defence.

Betaine-homocysteine S-methyltransferase (BHMT): Liver enzyme that remethylates homocysteine to methionine using betaine as methyl donor.

References

1. Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis. Nature Communications (2022).
2. SHMT2 reduces fatty liver but is necessary for liver inflammation and fibrosis in mice. Communications Biology (2024).
3. Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication. Signal Transduction and Targeted Therapy (2020).
4. Deletion of Betaine-Homocysteine S-Methyltransferase in Mice Perturbs Choline and 1-Carbon Metabolism, Resulting in Fatty Liver and Hepatocellular Carcinomas*. Journal of Biological Chemistry (2011).
5. Intake of S-Methylmethionine Alters Glucose Metabolism and Hepatic Gene Expression in C57BL/6J High-Fat-Fed Mice. Foods (2024).