Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport.
BACKGROUND
Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high-density lipoproteins to apolipoprotein (apo) B-containing lipoproteins and in humans plays an important role in lipoprotein metabolism. However, the role that CETP plays in mediation of reverse cholesterol transport (RCT) remains unclear. We used a validated in vivo assay of macrophage RCT to test the effect of CETP expression in mice (which naturally lack CETP) on macrophage RCT, including in mice that lack the low-density lipoprotein receptor or the scavenger receptor class B, type I.


RESULTS
A vector based on adeno-associated virus serotype 8 (AAV8) with a liver-specific thyroglobulin promoter was used to stably express human CETP in livers of mice and was compared with an AAV8-lacZ control vector. The RCT assay was performed 4 weeks after vector injection and involved the intraperitoneal injection of acetylated low-density lipoprotein cholesterol-loaded and 3H-cholesterol-labeled J774 macrophages in mice with plasma sampling at several time points, liver and bile sampling at 48 hours, and continuous fecal collection to measure 3H-sterol as an integrated readout of macrophage RCT. In apobec-1-null mice, CETP expression reduced plasma high-density lipoprotein cholesterol levels but significantly increased fecal 3H-sterol excretion. In low-density lipoprotein receptor/apobec-1 double-null mice, CETP expression reduced high-density lipoprotein cholesterol levels and had no effect on fecal 3H-sterol excretion. Finally, in scavenger receptor class B, type I-null mice, CETP expression reduced high-density lipoprotein cholesterol levels and significantly increased fecal 3H-sterol excretion.


CONCLUSIONS
The present results demonstrate that CETP expression promotes macrophage RCT in mice, that this effect is dependent on the low-density lipoprotein receptor, and that CETP expression restores to normal the impaired RCT in mice deficient in scavenger receptor class B, type I.
Tanigawa
Hiroyuki
H
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, USA.
Billheimer
Jeffrey T
JT
Tohyama
Jun-ichiro
J
Zhang
YuZhen
Y
Rothblat
George
G
Rader
Daniel J
DJ
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout
D053480:Cholesterol Ester Transfer Proteins; D002784:Cholesterol