All-trans and 9-cis retinoic acid alter rat hepatic stellate cell phenotype differentially.
BACKGROUND
Hepatic stellate cells exert specific functions in the liver: storage of large amounts of retinyl esters, synthesis and breakdown of hepatic extracellular matrix, secretion of a variety of cytokines, and control of the diameter of the sinusoids.


OBJECTIVE
To examine the influence of all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9RA) on extracellular matrix production and proliferation of activated hepatic stellate cells.


METHODS
Cells were isolated using collagenase/pronase, purified by centrifugation in nycodenz, and cultured for two weeks. At this time point the cells exhibited the activated phenotype. Cells were exposed to various concentrations of ATRA and 9RA. The expression of procollagens I, III, and IV, of fibronectin and of laminin were analysed by immunoprecipitation and northern hybridisation.


RESULTS
ATRA exerted a significant inhibitory effect on the synthesis of procollagens type I, III, and IV, fibronectin, and laminin, but did not influence stellate cell proliferation, whereas 9RA showed a clear but late effect on proliferation. 9RA increased procollagen I mRNA 1.9-fold, but did not affect the expression of other matrix proteins.


CONCLUSIONS
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 stellate cells or in animals subjected to fibrogenic stimuli.
Hellemans
K
K
Laboratory for Cell Biology and Histology, Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Belgium.
Grinko
I
I
Rombouts
K
K
Schuppan
D
D
Geerts
A
A
D000818:Animals; D015152:Blotting, Northern; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D016130:Immunophenotyping; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008297:Male; D015531:Radioimmunoprecipitation Assay; D051381:Rats; D017208:Rats, Wistar; D014212:Tretinoin / Q000494:pharmacology*
D016326:Extracellular Matrix Proteins; D014212:Tretinoin