All-trans and 9-cis retinoic acid alter rat hepatic stellate cell phenotype differentially

Background-Hepatic stellate cells exert specific functions in the liver: st orage of large amounts of retinyl esters, synthesis and breakdown of hepati c extracellular matrix, secretion of a variety of cytokines, and control of the diameter of the sinusoids. Aims-To examine the influence of alltrans r etinoic acid (ATRA) and 9-cis retinoic acid (9RA) on extracellular matrix p roduction and proliferation of activated hepatic stellate cells. Methods-Cells were isolated using collagenase/pronase, purified by centrifu gation in nycodenz, and cultured for two weeks. At this time point the cell s exhibited the activated phenotype. Cells were exposed to various concentr ations of ATRA and 9RA. The expression of procollagens I, III, and IV of fi bronectin and of laminin were analysed by immunoprecipitation and northern hybridisation. Results-ATRA exerted a significant inhibitory effect on the synthesis of pr ocollagens type I, III, and IV: fibronectin, and laminin, but did not influ ence stellate cell proliferation, whereas 9RA showed a clear but late effec t on proliferation. 9RA increased procollagen, I mRNA 1.9-fold, but did not affect the expression of other matrix proteins. Conclusion-Results showed that ATRA and 9RA exert different, often contrary effects on activated stellate cells. These observations may explain prior divergent results obtained following retinoid administration to cultured st ellate cells or in animals subjected to fibrogenic stimuli.