Effect of troglitazone on plasma lipid metabolism and lipoprotein lipase

Abstract

Aims To clarify how troglitazone, an insulin-sensitizing agent, affects lipid metabolism and postheparin plasma lipoprotein lipase (LPL). Methods Fifteen patients (3 male, 12 female) (the average age 62±7 years; the mean body mass index (BMI) 25±3 kg/m 2 ) were recruited for this study. The serum lipids and postheparin plasma lipoprotein lipase (LPL) mass before and 4 weeks after oral administration of troglitazone (200 mg day −1 ) were measured. A mouse preadipocyte cell line, 3T3-L1, was incubated with troglitazone and LPL enzyme protein mass in the culture media was measured by an enzyme linked immunosorbent assay. A reverse transcription polymerase chain reaction (RT-PCR) using primers specific for the carboxyl terminal 135 amino acid of mouse LPL cDNA was used to evaluate the effect of troglitazone on expression of LPL and Northern blot analysis carried out to determine expression of LPL. ResultsThe average levels before treatment of fasting serum total cholesterol, triglycerides, high density lipoprotein cholesterol, plasma glucose and glycohaemoglobin A1c were 5.6±0.9, 1.8±1.0, 1.5±0.5, 8.1±1.7 mmol l −1 and 7.8±1.6%respectively. Four weeks after treatment, those levels were 5.4±0.9, 1.2±0.3 ( P= 0.004), 1.6±0.5 ( P=0.02) mmol l −1 , 7.7±2.3 mmol l −1 and 7.3±0.6% ( P= 0.01), respectively. The postheparin plasma LPL mass increased from 226±39 to 257±68 ng ml −1 ( P=0.03) during that period. The LPL mass in the media of 3T3 L1 cells cultured in the presence of 10, 20 or 30 mm of this compound increased in a dose dependent manner. RT-PCR revealed that the area of the bands of the RT-PCR products on 1.5% agarose gel analyzed with NIH image from the cell extracts cultured in the presence of 10 mm troglitazone was significantly larger ( P= 0.0069) than that in the absence of this compound. Northern blot analysis revealed that in the cultured 3T3-L1 cells, the expression of LPL was enhanced in the presence of 10 mm troglitazone. Conclusions Troglitazone improves plasma triglyceride-rich lipoproteins metabolism by enhancing the expression of LPL in adipocytes.

Serum lipoprotein lipase mass: Clinical significance of its measurement

“…The men group showed a higher serum TG and lower HDL-C levels along with lower plasma LPL mass than did women. Troglitazone, an insulin sensitizer and now out of market in Japan, was reported to cause an increase in pre-heparin LPL mass [32], which is consistent with our study showing this agents increased LPL mass in PHP [33].…”

The Proline 12 Alanine Substitution in the Peroxisome Proliferator–Activated Receptor-γ2 Gene Is Associated With Lower Lipoprotein Lipase Activity in Vivo

“…Stepwise multiple regression analysis confirmed that the association of the Pro12Ala polymorphism with LPL activity was independent of potential confounding factors such as age, BMI, insulin levels, hypertension, and pack-years (data not shown). Our data of the association of a PPAR-␥2 polymorphism that is characterized by lower transcriptional activity with lower LPL activity in vivo supports the recent observation that treatment with troglitazone, a PPAR-␥ agonist, increases LPL concentration in postheparin plasma (12). …”

Pre-heparin Lipoprotein Lipase Mass

“…This observation has been in line with the previous reports on the effects of this compound on LPL activity in PHP (26,27). Troglitazone, an insulin sensitizer, has also been reported to cause an increase in pre-heparin LPL mass (29), which is consistent with our study showing this agent increased LPL mass in PHP (30). In contrast, atorvastatin did not produce an increase in pre-heparin LPL mass in hyperlipidemic subjects, despite causing a substantial reduction in serum TG level (31), which may be related to the fact that the main mechanisms for the reduction in serum TG by this agent are the inhibition of the production and secretion of VLDL from the liver.…”