ACETALDEHYDE ACTIVATES THE PROMOTER OF THE MOUSE ALPHA(2)(I) COLLAGENGENE

The mechanism whereby ethanol ingestion results in hepatic fibrosis re mains unknown. Acetaldehyde has been shown to increase alpha(1)(I) col lagen gene transcription in human fibroblasts and in rat myofibroblast like cells (Ito cells) in culture. In this study, the effect of acetal dehyde was determined on the activation of the alpha(2)(I) collagen pr omoter. A plasmid containing the mouse alpha(2)(I) collagen promoter r egion (-2000 to 54), fused to the coding sequence of the reporter gene chloramphenicol acetyl transferase and similar plasmid constructs con taining deletions in the collagen promoter, were transfected into NIH 3T3 fibroblasts in culture. Acetaldehyde (200 mu mol/L) and transformi ng growth factor-beta 1 (5 ng/ml) activated the wild type promoter. Th e combination of acetaldehyde and transforming growth factor-beta 1 di d not result in a greater effect than either alone. Acetaldehyde inhib ited, whereas transforming growth factor-beta 1 did not activate, the promoter, with a -352 to -104 deletion. By contrast, acetaldehyde had no effect, whereas transforming growth factor-beta 1 resulted in a sma ll decrease in the activity of the promoter, with a -501 to -352 delet ion. This study shows that acetaldehyde and transforming growth factor -beta 1 independently activate the mouse alpha(2)(I) collagen promoter and that this activation is mediated by the same proximal region of t he promoter.