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

Natalia Nieto, Arthur I. Cederbaum

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)30963-30974
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number35
DOIs
StatePublished - 2 Sep 2005

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