Hepatic molecular effects of rosiglitazone in human non-alcoholic steatohepatitis suggest long-term pro-inflammatory damage

Abstract

Aim: Glitazones are agonists of peroxisome proliferator-activated receptor-γ (PPAR-γ) and have been proposed for the treatment of non-alcoholic steatohepatitis (NASH). However, efficacy results are conflicting and hepatic molecular changes induced by glitazones are mostly unknown. The aim of this study was to analyze the hepatic inflammatory and fibrogenic molecular effects of rosiglitazone in NASH patients.

Methods: Hepatic expression of PPAR-γ and several inflammatory/immune and fibrogenic genes were studied before and after a 12-month treatment with rosiglitazone or placebo in 25 patients with NASH from the Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial.

Results: Treatment with rosiglitazone induced hepatic PPAR-γ expression but increased the expression of several pro-inflammatory genes such as SOCS3 and TLR4. There was a significant reduction in mRNA and protein levels of α-smooth muscle actin, compatible with previously documented antifibrotic actions of rosiglitazone on stellate cells. However, there was no change in type 1 collagen and transforming growth factor-β expression thus suggesting an offset of the antifibrogenic actions by long-term pro-inflammatory changes.

Conclusion: In NASH patients, hepatic PPAR-γ induction by rosiglitazone was associated with increased hepatic expression of pro-inflammatory genes which may explain the lack of long-term histological benefit shown in human studies with this drug. It is unclear whether these results are a class effect of PPAR-γ agonists or a specific effect of rosiglitazone.

Keywords: fibrosis; inflammation; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; peroxisome proliferator-activated receptor-gamma; rosiglitazone.