Troglitazone, an antidiabetic agent, inhibits cholesterol biosynthesis through a mechanism independent of peroxisome proliferator-activated receptor-gamma.

Abstract

Troglitazone is an antidiabetic agent of the thiazolidinedione family. It is generally believed that thiazolidinediones exert their insulin-sensitizing activity through activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the steroid nuclear receptor superfamily. In the present study, we examined the effect of troglitazone on cholesterol biosynthesis in cultured Chinese hamster ovary (CHO) cells. Troglitazone inhibited biosynthesis of cholesterol, but not that of total sterols, in a dose-dependent manner, with a half-maximal concentration (IC50) value of 8 micromol/l. At 20 micromol/l, troglitazone inhibited cholesterol biosynthesis by more than 80%, resulting in the accumulation of lanosterol and several other sterol products. This inhibitory effect observed in CHO cells was also reproduced in HepG2, L6, and 3T3-L1 cells, suggesting that there is a common pathway for this troglitazone action. One hour after removal of troglitazone from the culture medium, disappearance of the accumulated sterols was accompanied by restored cholesterol synthesis, indicating that those accumulated sterols are precursors of cholesterol. PPAR-gamma reporter assays showed that PPAR-gamma activation by troglitazone was completely blocked by actinomycin D and cycloheximide. In contrast, the inhibition of cholesterol synthesis by troglitazone remained unchanged in the presence of the above compounds, suggesting that this inhibition is mechanistically distinct from the transcriptional regulation by PPAR-gamma. Like troglitazone, two other thiazolidinediones, ciglitazone and englitazone, exhibited similar inhibitory effect on cholesterol synthesis; however, other known PPAR-gamma ligands such as BRL49653, pioglitazone, and 15-deoxy-delta(12,14)-prostaglandin J2 showed only weak or no inhibition. The dissociation of PPAR-gamma binding ability from the potency for inhibition of cholesterol synthesis further supports the conclusion that inhibition of cholesterol biosynthesis by troglitazone is unlikely to be mediated by PPAR-gamma.