ADENOVIRUS-MEDIATED OVEREXPRESSION OF HUMAN PHOSPHOLIPID TRANSFER PROTEIN ALTERS PLASMA HDL LEVELS IN MICE

To study the function of plasma phospholipid transfer protein (PLTP) i n vivo, a liver directed adenoviral gene transfer system was used to o verexpress human PLTP in mice. For the experiments, two strains of mic e, wild type (C57/B1) and mice transgenic for the human apoA-I gene (H uApoA-ITg), were utilized. Five days after injection of the recombinan t PLTP adenovirus, wild type mice showed a 4-fold increase in serum PL TP activity in (12.2 +/- 1.3 mu mol/ ml/per h to 48.1 +/- 8.6 mu mol/m l per h (+394%), P < 0.001), The PLTP overexpression induced significa nt reduction of serum cholesterol (2.46 +/- 0.08 to 0.69 +/- 0.42 mmol /l (-72%), P < 0.001), phospholipids (3.10 +/- 0.06 to 0.90 +/- 0.24 m mol/l (-71%), P < 0.01), and triglycerides (0.2 +/- 0.07 to 0.08 +/- 0 .03 mmol/l (-69%), (P < 0.001), ApoA-I was hardly detectable in the se rum. These lipid changes were due to a dramatic reduction of high dens ity lipoprotein (HDL), The HuApoA-ITg mice displayed higher basal HDL level and PLTP activity. Adenovirus mediated PLTP overexpression in th ese mice resulted in a similar decrease of the lipid levels as that se en in the C57/B1 mice. However, the lipoprotein profile revealed a red istribution of HDL, with the appearance of larger buoyant HDL species. The results demonstrate that plasma phospholipid transfer protein in vivo causes high density lipoprotein (HDL) conversion and thereby play s a central role in HDL metabolism.