Adenovirus mediated overexpression of human phospholipid transfer protein alters plasma HDL levels in mice1

Abstract

To study the function of plasma phospholipid transfer protein (PLTP) in vivo, a liver directed adenoviral gene transfer system was used to overexpress human PLTP in mice. For the experiments, two strains of mice, wild type (C57/Bl) and mice transgenic for the human apoA-I gene (HuApoA-ITg), were utilized. Five days after injection of the recombinant PLTP adenovirus, wild type mice showed a 4-fold increase in serum PLTP activity in (12.2 ± 1.3 μmol/ml/per h to 48.1 ± 8.6 μmol/ml per h (+394%), P < 0.001). The PLTP overexpression induced significant 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 mmol/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 serum. These lipid changes were due to a dramatic reduction of high density lipoprotein (HDL). The HuApoA-ITg mice displayed higher basal HDL level and PLTP activity. Adenovirus mediated PLTP overexpression in these mice resulted in a similar decrease of the lipid levels as that seen in the C57/Bl mice. However, the lipoprotein profile revealed a redistribution 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 plays a central role in HDL metabolism.—Ehnholm, S., K. Willems van Dijk, B. van't Hof, A. van der Zee, V. M. Olkkonen, M. Jauhiainen, M. Hofker, L. Havekes, and C. Ehnholm. Adenovirus-mediated overexpression of human phospholipid transfer protein alters plasma HDL levels in mice. J. Lipid Res. 1998. 39: 1248–1253.

Keywords

• recombinant adenovirus
• phospholipid transfer protein
• HDL metabolism
• HDL conversion
• apolipoprotein A-I
• lipid metabolism