ABSTRACT
Background: Insulin resistance is linked to dyslipidemia, characterized by a decrease in high density lipo-proteins and an increase in low density lipoproteins. Thiazolidinediones (TZDs) are insulin-sensitizing agents used to improve glycemic control in patients with type 2 diabetes. Recently, the safety of certain TZD regimens has been questioned because of associated adverse effects on the plasma lipid profile. We examined the effect of a TZD, Ciglitazone, on apolipoprotein synthesis and secretion in human liver HepG2 cells. Methods and Results: The effect of Ciglitazone treatment on apolipoprotein synthesis was addressed at the level of transcription, translation and secretion. RT-PCR showed that Ciglitazone increased the transcription of apoE and apoAI but reduced the levels of apoCI and apoB mRNA. Western blot analysis showed an increase in apoAI and apoE secreted in the cell culture media, whereas the amounts of apoB100 and apoCI were reduced. To confirm that Ciglitazone regulates apolipoprotein translation, its effect on de novo protein synthesis was evaluated by metabolic labeling with [35S]-methionine/cysteine, and a similar pattern of regulation was observed. The change in apolipoprotein levels was not secondary to cholesterol biosynthesis or clearance, since Ciglita-zone did not regulate the transcription of HMGCoA reductase, or the LDL receptor. However, mRNA levels for both PPAR-γ and LXRα were induced, suggesting a role for either or both receptors in modulating the hepatic apolipoprotein profile. The involvement of these nuclear receptor transcription factors was confirmed since direct activation of these receptors by endogenous PPAR-γ ligand, 15d-prostaglandin J2, or LXRα ligand, 22(R)hydroxycholesterol, similarly upregulated apoAI and apoE, but down-regulated apoB100 protein synthesis. Conclusion: Our results suggest that Ciglita-zone treatment results in an atheroprotective lipoprotein profile in liver cells. Thus, while the adipose and muscle tissues may be primary targets in TZD-mediated glucose homeostasis, liver PPAR-γ contributes significantly to the regulation of plasma lipoprotein profile.