title: Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids.
abstract: Activation of hepatic stellate cells (HSC) is a central event in the pathogenesis of liver fibrosis during chronic liver injury. We examined the expression of retinoic acid (RAR) and retinoid X receptors (RXR) during HSC activation and evaluated the influence of natural and synthetic retinoic acids (RA) on the phenotype of culture-activated HSC. The expression of the major RAR/RXR subtypes and isoforms was analyzed by Northern hybridization. Presence of functional receptor proteins was established by gel shift analysis. Retinoic acids, RAR, and RXR selective agonists and an RAR antagonist were used to evaluate the effects of retinoid signalling on matrix synthesis by Northern blotting and immunoprecipitation, and on cell proliferation by BrdU incorporation. The 9-cisRA and synthetic RXR agonists reduced HSC proliferation and synthesis of collagen I and fibronectin. All-trans RA and RAR agonists both reduced the synthesis of collagen I, collagen III, and fibronectin, but showed a different effect on cell proliferation. Synthetic RAR agonists did not affect HSC proliferation, indicating that ATRA inhibits cell growth independent of its interaction with RARs. In contrast, RAR specific antagonists enhance HSC proliferation and demonstrate that RARs control proliferation in a negative way. In conclusion, natural RAs and synthetic RAR or RXR specific ligands exert differential effects on activated HSC. Our observations may explain prior divergent results obtained following retinoid administration to cultured stellate cells or to animals subjected to fibrogenic stimuli.
authors.affiliation: Lab. Molecular Liver Cell Biology, Free University Brussels, Brussels, Belgium. karine.hellemans@pandora.be
authors.forename: Karine
authors.initials: K
authors.lastname: Hellemans
authors.forename: Peggy
authors.initials: P
authors.lastname: Verbuyst
authors.forename: Erik
authors.initials: E
authors.lastname: Quartier
authors.forename: Frans
authors.initials: F
authors.lastname: Schuit
authors.forename: Krista
authors.initials: K
authors.lastname: Rombouts
authors.forename: Ross A S
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Albert
authors.initials: A
authors.lastname: Geerts
mesh_terms: D000077556:Alitretinoin; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D001565:Benzoates / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D019281:Dimerization; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000737:chemistry / Q000235:genetics*; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000737:chemistry / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C430898:AGN 194204; D000970:Antineoplastic Agents; D001565:Benzoates; D016326:Extracellular Matrix Proteins; D005231:Fatty Acids, Unsaturated; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid