Peroxisome proliferated-activated receptor gamma ligand, Pioglitazone, does not prevent hepatic fibrosis in mice.

Da Silva Morais, Alain [UCL] Abarca-Quinones, Jorge [UCL] Horsmans, Yves [UCL] Starkel, Peter [UCL] Leclercq, Isabelle [UCL]

During hepatic fibrogenesis, quiescent hepatic stellate cells (HSCs) undergo phenotypic transformation into activated matrix-producing cells. This process is recapitulated in primary HSCs cultured on plastic. Based on studies in rats, peroxisome proliferator-activated receptor gamma (PPARgamma) has been suggested to play a key role in the control of HSC activation. Indeed, in rats, PPARgamma expression is depleted in activated HSCs. PPARgamma ligands inhibit HSC activation and prevent hepatic fibrosis in vivo. Here we evaluated the impact of PPARgamma agonists on hepatic fibrogenesis in mice both in vitro and in vivo. Primary HSCs from Balb/C mice were cultured with PPARgamma ligands Pioglitazone (PGZ) or 15-deoxy-Delta12,14 prostaglandin J2 (15d-PGJ2). PPARgamma mRNA expression was stable during culture-activation of HSCs. However, PPARgamma protein was only found in quiescent HSCs but not in fully activated cells. Exposure of HSCs to PPARgamma agonists maintained the expression of PPARgamma, and transactivated this transcription factor as demonstrated by gelshift assay and by induction of CD36, a PPARgamma-regulated gene. However, PPARgamma ligands did not alter the induction of Collagen-I mRNA or alpha-smooth muscle actin (alpha-SMA) in cultured HSCs. To test the effect of PPARgamma agonist PGZ in vivo, hepatic fibrosis was evaluated in Balb/C or C57BL6/J mice treated with CCl4 (three times a week for 4 weeks; or corn oil for controls), and fed a normal or a PGZ-supplemented diet (0.01% wt/wt). PGZ treatment was associated with increased serum adiponectin concentrations but did not decrease the severity of hepatic fibrosis induced by CCl4. Our data demonstrate that, although having anti-fibrotic properties in rats, PPARgamma agonists do not prevent activation of HSCs in vitro, nor hepatic fibrogenesis in vivo in mice.