PPARg ligand Pioglitazone does not prevent hepatic fibrosis in mice

last updated: 2015-05-10
ProjectN/A :: publications list
TitlePPARg ligand Pioglitazone does not prevent hepatic fibrosis in mice
Publication TypeComunications - Poster
Year of Publication2006
Authorsda Silva Morais A., Abarca-Quinones J., Stärkel P., Horsmans Y., and Leclercq I. A.

Background and Aims: Hepatic fibrosis results from activation of quiescent HSC into extracellular matrix producing, proliferative and contractile myofibroblast-like cells. Peroxisome proliferator-activated receptor gamma (PPAR-y) has been suggested to play a key role in the control of HSC activation. Indeed, in rats, PPAR-y expression is depleted in activated HSC and PPAR-y ligands inhibit the activation of HSC as well as prevent hepatic fibrosis in vivo. Also, forced expression of PPAR-y into activated HSC restores the quiescent phenotype. Here we evaluate the impact of PPAR-y agonist Pioglitazone (PGZ) on hepatic fibrogenesis in mice both in vitro and in vivo. Methods: Primary HSCs from Balb/C mice were cultured, with or without PGZ, on plastic dishes. Collagen Ial mRNA, R-smooth-muscle actin (aSMA) and desmin protein expression were measured to assess activation. PPAR-y mRNA and protein expression as well as the expression of the PPAR-y regulated genes CD36 and aP2 were evaluated to determine the biological effect of PGZ treatment. In in vivo experiments, mice were divided in 3 groups treated for 4 weeks with vehicle, CC14 (IR 400 L 3 • or CC14+PGZ as a 0.01% PGZ-supplemented diet (wt/wt). Results: In vitro, mRNA expression of PPAR-~ was stable in HSC cultured up to day 9. However, PPAR-? protein was only found in quiescent and early activated HSC (up to 5 days) there after, protein expression decreased dramatically. Exposure of HSC to PGZ from day 3 (at a time when PPAR-y is expressed) to day 7 maintained the expression of PPAR-y ?and stimulated the expression of PPAR-y-regulated gene CD36, but did not alter induction of collagen Ial mRNA or aSMA. In vivo, PGZ treatment induced adiponectin, CD36 and aP2 mRNA in adipose tissue and increased serum adiponectin concentrations, but PGZ treatment did not decrease the severity of hepatic fibrosis induced by CC14. Conclusion: Our data demonstrate that, although having anti-fibrotic properties in rats, PPAR-? stimulation by PGZ does not prevent activation of HSC in vitro, nor hepatic fibrogenesis in vivo in mice. Direct antifibrotic effect of such substances remains to be demonstrated in humans.

Conference Name41th Annual Meeting of the European Association for the Study of the Liver (EASL)
Date Published2006-04-23
Conference LocationVienna, Austria
KeywordsLiver fibrosis, Pioglitazone, PPAR
Peer reviewedno

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