Vitamin A deficiency associated with enhanced proliferation of bile duct epithelial cells in the rat

Background: Vitamin A and its derivative retinoic acid regulate various aspects of cell behavior as growth, differentiation, and proliferation. Retinoic acid derivatives have been suggested to play a role in processes such as hepatic regeneration and fibrosis. Objectives: To evaluate the influence of vitamin A on rat liver epithelial cell proliferation. Methods: We performed common bile duct ligation in rats that had been subjected to differing vitamin A diets and compared their livers to control rats. Proliferation, apoptosis, and retinoic acid receptors were evaluated by histology and immunohistochemistry in bile duct cells and hepatocytes. Results: Vitamin A deficiency was found to be associated with enhanced proliferation of bile duct epithelial cells following CBD ligation. The proliferation was manifested by increased numbers of ducts, by aberrant extended ductal morphology, and by elevated numbers of nuclei expressing the proliferation marker Ki67. The amount of vitamin A in the rat diet did not affect detectably ductal cell apoptosis. We observed up-regulated expression of the retinoid X receptoralpha in the biliary epithelium of vitamin A-deficient rats that had undergone CBD ligation, but not in vitamin A-sufficient rats. Conclusions: We speculate that the mechanism underlying the ductal proliferation response involves differential expression of RXR-alpha. Our observations suggest that deficiency of vitamin A may exacerbate cholestasis, due to excessive intrahepatic bile duct proliferation.