PPARbeta regulates vitamin A metabolism-related gene expression in hepatic stellate cells undergoing activation.
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 beta (PPARbeta), which become further induced during transition into the activated phenotype, we investigated the potential role of PPARbeta in the regulation of these changes. Administration of L165041, a PPARbeta-specific agonist, further induced the expression of CD36, B-FABP, CRBP-I, and LRAT, whereas their expression was inhibited by antisense PPARbeta mRNA. PPARbeta-RXR dimers bound to CRBP-I promoter sequences. Our observations suggest that PPARbeta 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 PPARbeta 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.
Hellemans
Karine
K
Laboratory of Molecular Liver Cell Biology, Vrije Universiteit Brussel, 1090 Brussels, Belgium. khellem@minf.vub.ac.be
Rombouts
Krista
K
Quartier
Erik
E
Dittié
Andrea S
AS
Knorr
Andreas
A
Michalik
Liliane
L
Rogiers
Vera
V
Schuit
Frans
F
Wahli
Walter
W
Geerts
Andrea
A
D000085:Acetates / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000378:metabolism / Q000633:toxicity; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000074026:Fatty Acid Binding Protein 3; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010636:Phenols / Q000494:pharmacology; D010641:Phenotype; D010642:Phenoxyacetates; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D047488:Retinoid X Receptors; D012177:Retinol-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054840:Retinol-Binding Proteins, Cellular; D016415:Sequence Alignment; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D014801:Vitamin A / Q000378:metabolism*
C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D000085:Acetates; D018955:CD36 Antigens; D002352:Carrier Proteins; C493408:FABP3 protein, human; C107608:FABP7 protein, human; C490174:Fabp7 protein, rat; D000074026:Fatty Acid Binding Protein 3; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010636:Phenols; D010642:Phenoxyacetates; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014801:Vitamin A; D002251:Carbon Tetrachloride; D007862:Phosphatidylcholine-Sterol O-Acyltransferase