Methionine-MAT2A-SAM axis controls lipid levels by regulating ACSL4

The four major metabolic pathways in cells, including amino acid, glucose, nucleotide and lipid metabolism, constitute the fundamental framework of cellular metabolic networks. However, the intricate reciprocal regulatory mechanisms between amino acid metabolism and lipid metabolism remain poorly understood. In the present study, an essential amino acid-deficient culture medium was established and applied to cell cultures. Subsequent analysis using flow cytometry demonstrated that methionine deprivation significantly reduced cellular lipid accumulation and impaired the fatty acid uptake capacity. Mechanistic investigations using western blotting revealed that the methionine-methionine adenosyltransferase 2A (MAT2A)-S-adenosylmethionine (SAM) metabolic axis regulates the protein expression of ACSL4, a critical enzyme governing fatty acid uptake. Notably, the results indicated that the protein expression of MAT2A may be tightly regulated by SAM through a feedback mechanism, ensuring homeostasis of the methionine-MAT2A-SAM metabolic axis. In summary, the findings of the present study demonstrate that the methionine-MAT2A-SAM axis modulates lipid metabolism by regulating ACSL4 expression and function.