Adenovirus mediated overexpression of human phospholipid transfer protein alters plasma HDL levels in mice.
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/B1) 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 micromol/ml per h to 48.1+/-8.6 micromol/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/B1 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
S
Department of Biochemistry, National Public Health Institute, Helsinki, Finland.
van Dijk
K W
KW
van 't Hof
B
B
van der Zee
A
A
Olkkonen
V M
VM
Jauhiainen
M
M
Hofker
M
M
Havekes
L
L
Ehnholm
C
C
D000256:Adenoviridae; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids / Q000097:blood; D011994:Recombinant Proteins / Q000096:biosynthesis; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D002352:Carrier Proteins; D002788:Cholesterol Esters; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D011994:Recombinant Proteins; D014280:Triglycerides; D002784:Cholesterol