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Journal of Lipid Research, Vol. 44, 280-295, February 2003
Copyright © 2003 by Lipid Research, Inc.

PPARß regulates vitamin A metabolism-related gene expression in hepatic stellate cells undergoing activation

Karine Hellemans^1,*, Krista Rombouts^*, Erik Quartier, Andrea S. Dittié^**, Andreas Knorr^**, Liliane Michalik, Vera Rogiers, Frans Schuit, Walter Wahli and Andrea Geerts^*

^* Laboratory of Molecular Liver Cell Biology, Vrije Universiteit Brussel, 1090 Brussels Belgium
Molecular Pharmacology Unit, Vrije Universiteit Brussel, 1090 Brussels Belgium
Diabetes Research Center, Department of Toxicology, Vrije Universiteit Brussel, 1090 Brussels Belgium
^** Bayer AG, Institute for Cardiovascular Research, Wuppertal, Germany
Institute for Animal Biology, University of Lausanne, Switzerland

¹ To whom correspondence should be addressed. e-mail: khellem{at}minf.vub.ac.be

Activation of cultured hepatic stellate cells correlated with an enhanced expression of proteins involved in uptake and storage of fatty acids (FA translocase CD36, Acyl-CoA synthetase 2) and retinol (cellular retinol binding protein type I, CRBP-I; lecithin:retinol acyltransferases, LRAT). The increased expression of CRBP-I and LRAT during hepatic stellate cells activation, both involved in retinol esterification, was in contrast with the simultaneous depletion of their typical lipid-vitamin A (vitA) reserves. Since hepatic stellate cells express high levels of peroxisome proliferator activated receptor ß (PPARß), which become further induced during transition into the activated phenotype, we investigated the potential role of PPARß in the regulation of these changes. Administration of L165041, a PPARß-specific agonist, further induced the expression of CD36, B-FABP, CRBP-I, and LRAT, whereas their expression was inhibited by antisense PPARß mRNA. PPARß-RXR dimers bound to CRBP-I promoter sequences.

Our observations suggest that PPARß regulates the expression of these genes, and thus could play an important role in vitA storage. In vivo, we observed a striking association between the enhanced expression of PPARß and CRBP-I in activated myofibroblast-like hepatic stellate cells and the manifestation of vitA autofluorescent droplets in the fibrotic septa after injury with CCl₄ or CCl₄ in combination with retinol.

Abbreviations: ACS, acyl-CoA synthetase; ARAT, acyl-CoA:retinol acyltransferase; FAT/CD36, FA translocase; CRABP, cellular retinoic acid binding protein; CRBP, cellular retinol binding protein; FABP, fatty acid binding protein; LCFA, long chain fatty acid; LRAT, lecithin:retinol acyltransferase; PPAR, peroxisome proliferator-activated receptor; PPRE, PPAR-responsive element; RAR, retinoic acid receptor; RARE, RAR-responsive element; RBP, retinol-binding protein; RE, retinyl ester; RXR, retinoid X receptor; vitA, vitamin A

Supplementary key words liver fibrosis • peroxisome proliferator-activated receptor ß • fatty acid binding protein • CD36 • ACS2 • cellular retinol binding protein • lecithin:retinol acyltransferases

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