Effect of retinoic acid on the enhancing effect of acetaldehyde on mouse type I collagen expression

Acetaldehyde alone and retinoic acid alone have been shown to increase and decrease, respectively, collagen production by stellate cells in culture. In this study the effects of retinoic acid on α₁(I) and α₂(I) collagen expression and its influence on the enhancing effects of acetaldehyde were determined. Retinoic acid decreased the activation of the α₂(I) collagen promoter and decreased the message of α₂(I) collagen in cultured stellate cells, but had no effect on either the activation of the α₁(I) collagen promoter or on the α₁(I) collagen message. This depressant effect of retinoic acid was also evident in the transfected α₂(I) collagen promoter mutated at the retinoic acid response element (RARE). The activation of the α₂(I) collagen promoter by acetaldehyde was not decreased significantly by retinoic acid, but was suppressed by the retinoic acid receptor (RAR) selective retinoid SRI-6751-84. Retinoic acid, however, decreased the acetaldehyde-induced enhancement of the α₁(I) and α₂(I) collagen messages. Acetaldehyde also resulted in a decrease in RAR β message and RARβ protein. This study shows that retinoic acid depresses α₂(I) collagen gene expression but that this effect is less pronounced when the expression of this collagen is enhanced by acetaldehyde, which also decreases RARβ message and protein. Furthermore, the action of retinoic acid in inhibiting α₂(I) collagen gene expression occurs at sites other than the RARE site.