S-adenosylmethionine blocks collagen I production by preventing transforming growth factor-β induction of the COL1A2 promoter

To study the antifibrogenic mechanisms of S-adenosylmethionine (AdoMet), transgenic mice harboring the -17 kb to +54 bp of the collagen α2 (I) promoter (COL1A2) cloned upstream from the β-gal reporter gene were injected with carbon tetrachloride (CCl₄) to induce fibrosis and coadministered either AdoMet or saline. Control groups received AdoMet or mineral oil. AdoMet lowered the pathology in CCl₄-treated mice as shown by transaminase levels, hematoxylin and eosin, Masson's trichrome staining, and collagen I expression. β-Galactosidase activity indicated activation of the COL1A2 promoter in stellate cells from CCl₄-treated mice and repression of such activation by AdoMet. Lipid peroxidation, transforming growth factor-β (TGFβ) expression, and decreases in glutathione levels were prevented by AdoMet. Incubation of primary stellate cells with AdoMet down-regulated basal and TGFβ-induced collagen I and α-smooth muscle actin proteins. AdoMet metabolites down-regulated collagen I protein and mRNA levels. AdoMet repressed basal and TGFβ-induced reporter activity in stellate cells transfected with COL1A2 promoter deletion constructs. AdoMet blocked TGFβ induction of the -378 bp region of the COL1A2 promoter and prevented the phosphorylation of extracellular signal-regulated kinase 1/2 and the binding of Sp1 to the TGFβ-responsive element. These observations unveil a novel mechanism by which AdoMet could ameliorate liver fibrosis.