Acetaldehyde inhibits PPARgamma via H2O2-mediated c-Abl activation in human hepatic stellate cells.
OBJECTIVE
Accumulating evidence indicates that acetaldehyde (AcCHO) is one of the main mediators of fibrogenesis in alcoholic liver disease. AcCHO stimulates synthesis of fibrillar collagens in hepatic stellate cells, but the molecular events directly involved in the activation of collagen genes are debatable.


METHODS
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that is expressed in stellate cells, and its activation by specific ligands inhibits collagen synthesis. In this study, we evaluated the effects of AcCHO on PPARgamma transcriptional activity and its correlation with the AcCHO-induced collagen synthesis in hepatic stellate cells.


RESULTS
AcCHO treatment inhibited ligand-dependent and -independent PPARgamma transcriptional activity, and this effect was correlated with an increased phosphorylation of a mitogen-activated protein kinase site at serine 84 of the human PPARgamma. Transfection of the PPARgammaSer84Ala mutant completely prevented the effect of AcCHO on PPARgamma activity and in parallel abrogated the induction of collagen gene expression by AcCHO. The effect of AcCHO on PPARgamma activity and phosphorylation was blocked by extracellular signal-regulated kinase (ERK) 1/2 and protein kinase C (PKC)delta inhibitors as well as by catalase, suggesting that hydrogen peroxide is involved in the molecular cascade responsible for PPARgamma phosphorylation via activation of the PKCdelta/ERK pathway. Furthermore, inhibition of c-Abl completely abrogated the effect of AcCHO on either PPARgamma function or collagen synthesis; in addition, expression of the PPARgammaSer84Ala mutant prevented the profibrogenic signals mediated by c-Abl activation.


CONCLUSIONS
Our results showed that the induction of collagen expression by AcCHO in stellate cells is dependent on PPARgamma phosphorylation induced by a hydrogen peroxide-mediated activation of the profibrogenic c-Abl signaling pathway.
Ceni
Elisabetta
E
Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Viale Morgagni 85, 50134 Florence, Italy.
Crabb
David W
DW
Foschi
Marco
M
Mello
Tommaso
T
Tarocchi
Mirko
M
Patussi
Valentino
V
Moraldi
Luca
L
Moretti
Renato
R
Milani
Stefano
S
Surrenti
Calogero
C
Galli
Andrea
A
D000079:Acetaldehyde / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000493:pharmacokinetics; D003094:Collagen / Q000378:metabolism; D000431:Ethanol / Q000493:pharmacokinetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008297:Male; D016297:Mutagenesis, Site-Directed; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects
D002492:Central Nervous System Depressants; D047495:PPAR gamma; D034741:RNA, Small Interfering; D000431:Ethanol; D003094:Collagen; D006861:Hydrogen Peroxide; D016315:Proto-Oncogene Proteins c-abl; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D000079:Acetaldehyde