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.Results The 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.

Cleavage of Protein Kinase D After Acute Hypoinsulinemia Prevents Excessive Lipoprotein Lipase–Mediated Cardiac Triglyceride Accumulation

“…Contrary to systemic overexpression, tissue-specific overexpression of LPL in skeletal muscle and heart is associated with lipid oversupply, insulin resistance, and severe myopathy, characterized by muscle fiber degeneration, extensive proliferation of mitochondria and peroxisomes, excessive dilatation, and impaired left ventricular systolic function ( 18 , 38 , 40 , 44 , 45 ). Interestingly, drugs such as pioglitazone that are known to decrease caspase-3 ( 46 ) have been reported to reduce circulating triglycerides ( 47 , 48 ) by increasing LPL in humans ( 49 ) and to increase the myocardial content of lipids in rats fed a high-fat diet ( 50 ). Whether this effect can explain the risk of heart failure when thiazolidenediones are used in patients with type 2 diabetes has yet to be determined ( 51 , 52 ).…”

Flavonoids as dietary regulators of nuclear receptor activity

“…TZDs were found to decrease insulin resistance, modify adipocyte differentiation and induce lipoprotein lipase (LPL) through PPARg activation. [45][46][47][48] However, the clinical use of early TZDs was discontinued due to hepatotoxicity. 49 A second generation of TZDs, including rosiglitazone and pioglitazone, lacked this side effect and was effectively used in the treatment of type II diabetes for over a decade.…”

Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

“…The stimulatory effect of PPAR agonists on plasma TG clearance is achieved by upregulating LPL expression and activity in adipose tissue [ 52 , 100 , 106 , 109 , 110 ], which is associated with an increase in postheparin plasma LPL mass/total activity [ 101 , 102 ]. As a consequence, LPL-mediated lipolysis and the fractional clearance rate of VLDL-TG are elevated [ 108 ].…”