Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro.
OBJECTIVE
The ligand-dependent transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in hepatic stellate cells (HSC), and its transcriptional activity is reduced during cell transdifferentiation in culture. PPARgamma transcriptional activation decreases platelet-derived growth factor-induced proliferation and inhibits alpha-smooth muscle actin expression in cultured HSC. The aim of our study was to evaluate whether oral administration of synthetic PPARgamma ligands, thiazolidinediones (TZD), might affect collagen deposition in animal models of liver fibrosis.


METHODS
The effect of 2 TZD (pioglitazone or rosiglitazone) was tested on liver fibrosis induced in rats by either toxin administration (dimethylnitrosamine or carbon tetrachloride) or bile duct ligation. In vivo PPARgamma activation was evaluated by gel shift assay using nuclear extracts from HSC isolated from control and treated rats.


RESULTS
Oral administration of TZD reduced extracellular matrix deposition and HSC activation in both toxic and cholestatic models of liver fibrosis. PPARgamma-specific DNA binding was significantly impaired in nuclear extracts of HSC isolated from fibrotic rats compared with HSC from control rats. TZD administration restored PPARgamma DNA binding in HSC nuclei. In vitro, TZD-induced PPARgamma activation inhibited collagen and fibronectin synthesis induced by transforming growth factor (TGF)-beta1 in human HSC, as measured by enzyme-linked immunosorbent assay and Northen blotting. TZD also reduced the TGF-beta1-induced activity of a 3.5-kilobase procollagen type I promoter transfected in human HSC.


CONCLUSIONS
These findings indicate that PPARgamma activation in HSC retards fibrosis in vivo and suggest the use of TZD for the treatment of liver fibrosis.
Galli
Andrea
A
Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy.
Crabb
David W
DW
Ceni
Elisabetta
E
Salzano
Renata
R
Mello
Tommaso
T
Svegliati-Baroni
Gianluca
G
Ridolfi
Francesco
F
Trozzi
Luciano
L
Surrenti
Calogero
C
Casini
Alessandro
A
D000818:Animals; D001559:Benzhydryl Compounds; D001652:Bile Ducts; D002251:Carbon Tetrachloride; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004128:Dimethylnitrosamine; D004852:Epoxy Compounds / Q000494:pharmacology; D005353:Fibronectins / Q000096:biosynthesis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008026:Ligation; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D010636:Phenols / Q000494:pharmacology; D000077205:Pioglitazone; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D002251:Carbon Tetrachloride; D003094:Collagen; D004247:DNA; D004128:Dimethylnitrosamine; D004852:Epoxy Compounds; D005353:Fibronectins; D007004:Hypoglycemic Agents; D010636:Phenols; D000077205:Pioglitazone; D018160:Receptors, Cytoplasmic and Nuclear; D000077154:Rosiglitazone; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C020344:glycidyl ethers; C006780:bisphenol A; D000098826:Bisphenol A Compounds