Amino acids, L-Cysteine and L-Methionine, Attenuate Activation of Rat Stellate Cells in Primary Culture

Abstract

Regulation of hepatic stellate cell activation is currently one of the focuses of clinical investigation in order to establish a useful therapeutic strategy for liver fibrosis. Because oxidative stress caused at the inflammatory site and reactive oxygen species derived from damaged hepatocytes has been thought to pull the trigger for the cell activation, it is reasonable to speculate that antioxidative substances are promising to attenuate the activation process. In fact, alpha-tocopherol and natural flavonoids have potential to inhibit collagen gene expression and DNA synthesis of stellate cells, respectively. Our laboratory demonstrated that N-acetyl-L-cysteine (NAC) inhibits DNA synthesis of rat stellate cells in response to serum and PDGF-BB [1]. NAC was found to downregulate the expression of PDGF receptor beta PDGFR beta), thereby hampering PDGF-BB-dependent phosphorylation of MAP kinase and Akt [2,3]. In addition, Kim et al. [4] reported that NAC induces cell cycle arrest at G1 phase through inducing p21. Suppression of dimethylnitrosamine-induced liver fibrosis by NAC was also reported. Taken together, these results suggested that reducing compounds with -SH suppliers would be promising candidates attenuating the activation of stellate cells in culture and also in vivo. NAC is an analogue of amino acid L-cysteine that has -SH base. L-Cysteine has been reported to suppress oxidative stress caused by smoking, alcohol intake and noxious metals. L-Methionine is a precursor of L-cysteine and plays important roles in the methylation of genes. Also, DL isoform of methionine has been used for the treatment of liver disease. However, pharmacological action of amino acids has been largely unknown. Thus, we tested in this study the effect of amino acids on rat hepatic stellate cells.