Troglitazone stimulates IGF-binding protein-1 by a PPAR gamma-independent mechanism

IGFBP-1 modulates IGF availability for glucose homeostasis and it may also play a paracrine role in hepatocyte survival. IGFBP-1 is inhibited transcriptionally by insulin and is also regulated by a number of pathways that influence hepatic insulin sensitivity. The effect of the thiazolidinedione troglitazone on IGFBP-1 production was studied in HepG2 human hepatoma cells, which were found to express PPAR alpha, PPAR gamma, and PXR. Troglitazone stimulated IGFBP-1 mRNA expression 2-fold within 3h of exposure (P<0.001) and stimulated secretion up to 3-fold over a narrow dose range within 24h (P<0.001). This effect was mimicked by the PXR ligands clotrimazole and phenobarbital, but not by Wy14,643 or rosiglitazone, which are ligands for PPAR alpha and -gamma, respectively. We conclude that the effect of troglitazone on IGFBP-1 production by HepG2 cells is independent of PPAR and may involve PXR.