Sulfur-containing amino acids attenuate the development of liver fibrosis in rats through down-regulation of stellate cell activation

We tested the pharmacological action of sulfur-containing amino acids on the development of liver fibrosis in rats and on the function of cultured stellate cells. Liver fibrosis was induced in rats by thioacetamide administration or by ligating the common bile duct. DNA synthesis of cultured stellate cells was evaluated by BrdU incorporation. The expression of proteins and phospho-proteins was determined by western blot analysis. mRNA expression was evaluated by RT-PCR. Oral administration of l-cysteine or l-methionine attenuated the deposition of collagen in liver tissues in the two fibrotic models, accompanying a reduction in the expression of smooth muscle α-actin and platelet-derived growth factor receptor β and mRNAs of collagens, transforming growth factor-βs and tissue inhibitors of matrix metalloproteinase. In cultured stellate cells, l-cysteine and l-methionine suppressed the DNA synthesis and the expression of growth factor receptors, smooth muscle α-actin and type I collagen. They hampered the phosphorylation of p44/42 MAPK and Akt under platelet-derived growth factor-BB stimulation. Stellate cells were found to express methionine adenosyltransferase 2A. l-Cysteine and l-methionine regulate the activation of stellate cells. Their oral supply aids the suppression of the progression of liver fibrosis.