Rat hepatic stellate cells acquire retinoid responsiveness after activation in vitro by post-transcriptional regulation of retinoic acid receptor alpha gene expression

Activation of hepatic stellate cells (HSCs) is a key process in liver fibrogenesis and retinoid loss is a remarkable feature of activated HSCs. However, roles of retinoids in liver fibrogenesis are obscure. We show that mRNA levels of RAR alpha, beta and gamma were decreased during rat HSC activation in vitro. However, protein levels of RAR alpha and beta were increased during HSC activation. A retinoic acid response element-containing luciferase assay indicated that HSCs became responsive to retinoids only after activation in vitro and that this response was mediated by, at least in part, RAR alpha subtype. Immunocytochemical analysis showed that RAR alpha proteins were mainly distributed in cytosol as many spots. All-trans retinoic acid treatment strongly lowered the cytosolic RAR alpha protein levels. These results indicate that rat HSCs become retinoid responsive after activation in vitro, through post-transcriptional up-regulation of RAR alpha gene expression. (C) 2007 Elsevier Inc. All rights reserved.