PPAR gamma agonists inhibit liver fibrosis, but the mechanisms involved are uncertain. We hypothesized that PPAR gamma agonists inhibit transforming growth factor (TGF)beta 1-activation of TGF beta receptor (TGF beta R)-1 signaling in quiescent stellate cells, thereby abrogating Smad3-dependent induction of extracellular matrix (ECM) genes, such as PAI-1 and collagen-1 alpha I. To test this, human HSC were cultured to induce a quiescent phenotype, characterized by lipid accumulation and PPAR gamma expression and transcriptional activity. These adipocytic HSC were then treated with TGF beta 1 +/- a TGF beta R-1 kinase inhibitor (SB431542) or a PPAR gamma agonist (GW7845). TGF beta 1 caused dose- and time-dependent increases in Smad3 phosphorylation, followed by induction of collagen and PAI-1 expression. Like the TGF beta R-1 kinase inhibitor, the PPAR gamma agonist caused dose-dependent inhibition of all of these responses without effecting HSC proliferation or viability. Thus, the anti-fibrotic actions of PPAR gamma agonists reflect their ability to inhibit TGF beta 1-TGF beta R1 signaling that initiates ECM gene expression in quiescent HSC. (c) 2006 Elsevier Inc. All rights reserved.