Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats.
OBJECTIVE
Peroxisome proliferator activated receptor gamma (PPARgamma) agonists have been shown to prevent hepatic fibrosis in rodents. We evaluated the therapeutic antifibrotic potential of the PPARgamma agonist pioglitazone on established hepatic fibrosis.


METHODS
Repeated injections of carbon tetrachloride (CCl4), a choline deficient diet, or bile duct ligation (BDL) were used to induce hepatic fibrosis in rats. Pioglitazone treatment was introduced at various time points. Therapeutic efficacy was assessed by comparison of the severity of hepatic fibrosis in pioglitazone treated versus untreated fibrotic controls.


RESULTS
When introduced after two weeks of CCl4, pioglitazone reduced hepatic fibrosis, OH proline content, hepatic mRNA expression of collagen type I, and profibrotic genes, as well as the number of activated alpha smooth muscle actin positive hepatic stellate cells, compared with rats receiving CCl4 only, with no significant change in necroinflammation. When pioglitazone treatment was initiated after five weeks of CCl4, no antifibrotic effect was observed. Similarly, pioglitazone was associated with a reduced severity of fibrosis induced by a choline deficient diet when introduced early, while delayed treatment with pioglitazone remained ineffective. In contrast, pioglitazone failed to interrupt progression of fibrosis due to BDL, irrespective of the timing of its administration.


CONCLUSIONS
In rats, the therapeutic antifibrotic efficacy of pioglitazone is limited and dependent on the type of injury, duration of disease, and/or the severity of fibrosis at the time of initiation of treatment.
Laboratoire de Gastroenterologie, Gastroenterology Unit, Université Catholique de Louvain, GAEN 53/79, Avenue Mounier, 53, B-1200 Brussels, Belgium. isabelle.leclercq@gaen.ucl.ac.be
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Leclercq
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Sempoux
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Stärkel
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Horsmans
D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D002251:Carbon Tetrachloride; D002794:Choline / Q000008:administration & dosage; D024042:Collagen Type I / Q000235:genetics; D018450:Disease Progression; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D024042:Collagen Type I; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D045162:Thiazolidinediones; D002251:Carbon Tetrachloride; D002794:Choline; D000077205:Pioglitazone