PPARγ agonists prevent TGFβ1/Smad3-signaling in human hepatic stellate cells

PPARγ agonists inhibit liver fibrosis, but the mechanisms involved are uncertain. We hypothesized that PPARγ agonists inhibit transforming growth factor (TGF)β1-activation of TGFβ receptor (TGFβR)-1 signaling in quiescent stellate cells, thereby abrogating Smad3-dependent induction of extracellular matrix (ECM) genes, such as PAI-1 and collagen-1αI. To test this, human HSC were cultured to induce a quiescent phenotype, characterized by lipid accumulation and PPARγ expression and transcriptional activity. These adipocytic HSC were then treated with TGFβ1 ± a TGFβR-1 kinase inhibitor (SB431542) or a PPARγ agonist (GW7845). TGFβ1 caused dose- and time-dependent increases in Smad3 phosphorylation, followed by induction of collagen and PAI-1 expression. Like the TGFβR-1 kinase inhibitor, the PPARγ agonist caused dose-dependent inhibition of all of these responses without effecting HSC proliferation or viability. Thus, the anti-fibrotic actions of PPARγ agonists reflect their ability to inhibit TGFβ1-TGFβR1 signaling that initiates ECM gene expression in quiescent HSC.