Pioglitazone increases the fractional catabolic and production rates of high-density lipoproteins apo AI in the New Zealand White Rabbit

Abstract

Pioglitazone is an agonist of the peroxisome proliferator-activated receptor γ (PPARγ) that raises HDL-cholesterol plasma in humans. Whether pioglitazone-mediated modifications in HDL-apolipoprotein AI (apo AI) turnover in vivo contribute to this effect has not been completely elucidated. Therefore, we performed kinetic studies of HDL-apo AI radiolabeled with 125I in male New Zealand White rabbits after 6 weeks of 0.6 ( n = 8), 1.75 ( n = 8), and 2.6 mg/kg/day ( n = 7) pioglitazone and vehicle ( n = 12) treatment. Fractional catabolic rate (FCR) of HDL-apo AI was significantly higher in 1.75 and 2.6 mg/kg pioglitazone-treated animals, as compared with control rabbits (0.057 ± 0.014 and 0.049 ± 0.01 versus 0.025 ± 0.005 pools/h, respectively); these changes were associated to a similar increase in apo AI production rates (PR) (1.24 ± 0.62 and 1.14 ± 0.40 versus 0.53 ± 0.17 mg/kg/h, p < 0.01). Consequently, apo AI plasma levels in pioglitazone-treated animals were similar to those of controls. The apo AI-FRC and -PR correlated with the relative proportion of the HDL3c subclass, as determined by polyacrylamide gradient electrophoresis. Our data demonstrate that pioglitazone markedly modifies apo AI kinetics and enhances the proportion of small HDL3c particles, despite the unchanged apo AI concentration. Whether or not the pioglitazone-induced structural changes of HDL contribute to the anti-atherosclerotic effects of the drug remains to be determined.