Peroxisome proliferator-activated receptor-beta signaling contributes to enhanced proliferation of hepatic stellate cells.
OBJECTIVE
The peroxisome proliferator-activated nuclear receptors (PPAR-alpha, PPAR-beta, and PPAR-gamma), which modulate the expression of genes involved in energy homeostasis, cell cycle, and immune function, may play a role in hepatic stellate cell activation. Previous studies focused on the decreased expression of PPAR-gamma in hepatic stellate cell activation but did not investigate the expression and role of the PPAR-alpha and -beta isotypes. The aim of this study was to evaluate the expression of the different PPARs during hepatic stellate cell activation in vitro and in situ and to analyze possible factors that might contribute to their expression. In a second part of the study, the effect of a PPAR-beta agonist on acute liver injury was evaluated.


METHODS
The effects of PPAR isotype-specific ligands on hepatic stellate cell transition were evaluated by bromodeoxyuridine incorporation, gel shifts, immunoprecipitation, and use of antisense PPAR-beta RNA-expressing adenoviruses. Tumor necrosis factor alpha-induced PPAR-beta phosphorylation and expression was evaluated by metabolic labeling and by using specific P38 inhibitors.


RESULTS
Hepatic stellate cells constitutively express high levels of PPAR-beta, which become further induced during culture activation and in vivo fibrogenesis. No significant expression of PPAR-alpha or -gamma was found. Stimulation of the P38 mitogen-activated protein kinase pathway modulated the expression of PPAR-beta. Transcriptional activation of PPAR-beta by L165041 enhanced hepatic stellate cell proliferation. Treatment of rats with a single bolus of CCl(4) in combination with L165041 further enhanced the expression of fibrotic markers.


CONCLUSIONS
PPAR-beta is an important signal-transducing factor contributing to hepatic stellate cell proliferation during acute and chronic liver inflammation.
Hellemans
Karine
K
Laboratory of Molecular Liver Cell Biology, Faculty of Medicine and Pharmacy, Free University of Brussels, Laarbeeklaan 103, 1090 Brussel-Jette, Belgium. khellem@minf.vub.ac.be
Michalik
Liliane
L
Dittie
Andrea
A
Knorr
Andreas
A
Rombouts
Krista
K
De Jong
Jan
J
Heirman
Carlo
C
Quartier
Erik
E
Schuit
Frans
F
Wahli
Walter
W
Geerts
Albert
A
D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D002251:Carbon Tetrachloride; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2; D004247:DNA / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005822:Genetic Vectors; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000502:physiology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D016375:Antisense Elements (Genetics); D002352:Carrier Proteins; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D004247:DNA; D002251:Carbon Tetrachloride; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases