© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Clearance of Cationized LDL Cholesterol From a Muscle Depot Is Not Enhanced in Human Apolipoprotein A-IV Transgenic Mice
From the Lipid Research Laboratory (Y.S., Y.D., G.H.), Division of Medicine, Hadassah University Hospital, Jerusalem, Israel; the Department of Experimental Medicine and Cancer Research (O.S., M.B.-N.), Hebrew University-Hadassah Medical School, Jerusalem, Israel; the Cardiovascular Department (N.D.), Centre de Recherches de Vitry-Alforville, Vitry sur Seine, France; and the Lipid Research Institute (G.H.), Sheba Hospital, Tel-Hashomer, Israel.
Correspondence to Y. Stein, MD, Lipid Research Laboratory, Division of Medicine, Hadassah University Hospital, Ein Karem, POB 12220, Jerusalem 91120, Israel. E-mail ystein{at}hadassah.org.il
Abstract—Human apolipoprotein
A-IV (apoA-IV) transgenic mice fed an atherogenic diet were shown
previously to develop less atherosclerosis than control
mice. The question arose whether the antiatherogenic effect of
human apoA-IV is due to enhancement of reverse
cholesterol transport despite no increase in plasma
high-density lipoprotein (HDL) cholesterol. We studied male
and female mice overexpressing human apoA-IV and their wild-type (WT)
controls, all of which were fed a chow diet. Plasma total and HDL
cholesterol and total phospholipids were not increased in
the transgenic mice, and regression analysis showed no
correlation between plasma levels of cholesterol or
phospholipids and plasma human apoA-IV. To study reverse
cholesterol transport in vivo, the disappearance of
cholesterol from a depot of
[3H]cholesterol-labeled cationized
low-density lipoprotein injected into the rectus femoris muscle was
compared in high expressers of human apoA-IV and WT controls. The loss
of radioactivity and the diminution of the exogenous
cholesterol mass were determined on days 8 and 12 after
injection. No enhanced loss of radioactivity or cholesterol
mass was seen in the transgenic mice even at levels of 2500 mg/dL of
human apoA-IV. In some instances, there was even slower loss of
exogenous cholesterol (radioactivity and mass) in the
transgenic mice. Although [3H]cholesterol
efflux from cultured human skin fibroblasts and mouse peritoneal
macrophages was only 
30% higher in the presence of sera
from high expressers of human apoA-IV, addition of phosphatidylcholine
liposomes enhanced the efflux in both groups to the same extent.
Another paradoxical finding was that the cholesterol
esterification rate in plasma was 34% to 36% lower in human apoA-IV
mice than in WT controls. In conclusion, even though apoA-IV was found
previously to be atheroprotective under
hypercholesterolemic conditions, high plasma levels of
human apoA-IV did not enhance cholesterol mobilization in
vivo in normocholesterolemic mice.
Key Words: reverse cholesterol transport • apolipoprotein A-IV • high-density lipoprotein • lecithin-cholesterol acyltransferase • phospholipids
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