Retinoic acid modulates rat Ito cell proliferation, collagen, and transforming growth factor beta production

Recent studies suggest that vitamin A plays an inhibitory role with respect to "activation " of the hepatic Ito cell, a likely effector of hepatic fibrogenesis. Ito cell "activation " during fibrogenesis is characterized by a decrease in intracellular vi-tamin A and an increase in cellular proliferation and collagen production. To explore the hypothesis that retinoids have the capacity to diminish Ito cell activation, cultured Ito cells were exposed to retinoic acid and its effects assessed on three key features: cell proliferation, collagen protein production and mRNA abundance, and transforming growth factor j9 protein production. Retinoic acid was 100-1,OOOX more potent than retinol with respect to inhibition of Ito cell proliferation. Inter-stitial collagen and transforming growth factor f production were also reduced by 10-6 M retinoic acid. The relative abun-dance of type I collagen mRNA however, was not significantly altered. By contrast, retinoic acid administration to rats caused a marked reduction in the abundance of type I collagen mRNA in both total hepatic and purified Ito cell RNA. The relative abundance of rat hepatic fibronectin or apolipoprotein E mRNA was not significantly altered. These studies demon-strate that retinoic acid can differentially modulate several key features of hepatic fibrogenesis in vitro and in vivo. (J. Clin