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

Pioglitazone is an agonist of the peroxisorne proliferator-activated receptor gamma (PPAR gamma) that raises HDL-cholesterol plasma in humans. Whether pioglitazone-mediated modifications in HDL-apolipoprotein AI (apo At) turnover in vivo contribute to this effect has not been completely elucidated. Therefore, we performed kinetic studies of HDL-apo AI radiolabeled with I-125 in male New Zealand White rabbits after 6 weeks of 0.6 (n = 8), 1.75 (it = 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 m/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 Al 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 Al 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 gadient electrophoresis. Our data demonstrate that pioglitazone markedly modifies apo Al kinetics and enhances the proportion of small HDL3c particles, despite the unchanged apo Al concentration. Whether or not the pioglitazone-induced structural changes of HDL contribute to the anti-atherosclerotic effects of the drug remains to be determined. (c) 2005 Elsevier Ireland Ltd. All rights reserved.