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Troglitazone induces expression of PPARgamma in liver
G F Davies1, R L Khandelwal, W J Roesler
1Department of Biochemistry, University of Saskatchewan, Saskatoon, Canada.
Abstract:
Troglitazone is an insulin sensitizer which affects a number of target tissues. It is believed to exert these effects primarily by binding to and activating the y-isoform of peroxisome proliferator-activated receptor (PPARgamma), which in turn regulates the expression of specific genes. However, in a number of target organs, such as liver, the levels of PPARgamma are low and other isoforms predominate. In the present study, we examined whether troglitazone induces the expression of PPARgamma, thereby sensitizing cells for the action of this drug. Treatment of isolated rat hepatocytes with troglitazone induced both the mRNA and protein levels of PPARgamma in a dose-dependent fashion, with maximal levels of induction being three- to fourfold. This induction was also observed using the 15-deoxy-delta12,14-prostaglandin J2, a known natural ligand for PPARgamma, whereas ligands specific for PPARalpha were without effect. The induction of PPARgamma expression by troglitazone was also observed in livers from rats fed a diet containing troglitazone. Troglitazone had no effect on the expression of the alpha- or beta-isoforms of PPAR, the more predominant liver isoforms. These results indicate that troglitazone produces a reprogramming of PPAR isoform content in liver, which may in part underlie the mechanism whereby troglitazone sensitizes the liver to the action of insulin and/or ameliorates hyperglycemia.
Insights
Troglitazone increases peroxisome proliferator-activated receptor gamma (PPARγ) in liver cells. This induction may explain how troglitazone sensitizes the liver to insulin and improves hyperglycemia.
Area of Science:
- Pharmacology
- Molecular Biology
- Hepatology
Background:
- Troglitazone is an insulin sensitizer acting via peroxisome proliferator-activated receptor gamma (PPARγ).
- PPARγ levels are often low in target organs like the liver, where other PPAR isoforms predominate.
- The mechanism by which troglitazone sensitizes liver to insulin requires further elucidation.
Purpose of the Study:
- To investigate whether troglitazone induces PPARγ expression in liver cells.
- To determine if troglitazone alters the expression of other PPAR isoforms (α and β).
- To explore the potential role of PPARγ induction in troglitazone's mechanism of action.
Main Methods:
- Treatment of isolated rat hepatocytes with troglitazone and 15-deoxy-delta12,14-prostaglandin J2.
- Analysis of PPARγ mRNA and protein levels via dose-dependent assays.
- Administration of troglitazone-containing diet to rats and subsequent liver analysis.
- Assessment of PPARα and PPARβ expression levels.
Main Results:
- Troglitazone significantly increased PPARγ mRNA and protein levels in rat hepatocytes (3-4 fold induction).
- 15-deoxy-delta12,14-prostaglandin J2, a PPARγ ligand, also induced PPARγ expression, while PPARα ligands had no effect.
- Troglitazone administration to rats increased hepatic PPARγ expression.
- Troglitazone did not affect the expression of PPARα or PPARβ isoforms in the liver.
Conclusions:
- Troglitazone induces PPARγ expression in liver cells and in vivo.
- This induction represents a reprogramming of hepatic PPAR isoform content.
- PPARγ induction by troglitazone may contribute to its insulin-sensitizing effects and hyperglycemia amelioration in the liver.
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