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.
Hilding
Agneta
A
Department of Molecular Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden.
Hall
Kerstin
K
Skogsberg
Josefin
J
Ehrenborg
Ewa
E
Lewitt
Moira S
MS
D006528:Carcinoma, Hepatocellular; D002839:Chromans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D007700:Kinetics; D008113:Liver Neoplasms; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
D002839:Chromans; D007004:Hypoglycemic Agents; D018970:Insulin-Like Growth Factor Binding Protein 1; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D000077288:Troglitazone