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All-trans and 9-cis retinoic acid alter rat hepatic stellate cell phenotype differentially
  1. K Hellemansa,
  2. I Grinkoa,
  3. K Romboutsa,
  4. D Schuppanb,
  5. A Geertsa
  1. aLaboratory for Cell Biology and Histology, Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Belgium, bDepartment of Gastroenterology, Klinikum Stegliz, Free University of Berlin, Germany
  1. Dr K Hellemans, Laboratory for Cell Biology and Histology, Faculty of Medicine and Pharmacy, Free University of Brussels, Laarbeeklaan 103, 1090 Brussel-Jette, Belgium.

Abstract

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.

AIMS 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.

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 stellate cells or in animals subjected to fibrogenic stimuli.

  • hepatic stellate cells
  • retinoic acid
  • extracellular matrix proteins
  • proliferation
  • Abbreviations used in this paper

    9RA
    9-cisretinoic acid
    ATRA
    all-trans retinoic acid
    BrdU
    5-bromo-2′-deoxyuridine
    ECM
    extracellular matrix
    GFAP
    glial fibrillary acidic protein
    MMP
    matrix metalloproteinase
    RA
    retinoic acid
    RAR
    retinoic acid receptor
    RXR
    retinoid X receptor
    SMA
    smooth muscle antibody
    TGF
    tumour growth factor
    TIMP
    tissue inhibitor of metalloproteinase
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  • Abbreviations used in this paper

    9RA
    9-cisretinoic acid
    ATRA
    all-trans retinoic acid
    BrdU
    5-bromo-2′-deoxyuridine
    ECM
    extracellular matrix
    GFAP
    glial fibrillary acidic protein
    MMP
    matrix metalloproteinase
    RA
    retinoic acid
    RAR
    retinoic acid receptor
    RXR
    retinoid X receptor
    SMA
    smooth muscle antibody
    TGF
    tumour growth factor
    TIMP
    tissue inhibitor of metalloproteinase
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