Cholesteryl ester transfer protein directly mediates selective uptake of high density lipoprotein cholesteryl esters by the liver.
OBJECTIVE
To determine whether cholesteryl ester transfer protein (CETP) directly mediates selective uptake of high-density lipoprotein (HDL)-cholesteryl ester (CE) by hepatocytes and to quantify the effects of the CETP inhibitor, torcetrapib, on this process.


RESULTS
Using adenovirus-mediated CETP (ad-CETP) expression in primary mouse hepatocytes from either wild-type, low-density lipoprotein (LDL) receptor-/- or SR-BI-/- mice, we demonstrate that CETP enhances the selective accumulation of HDL-derived 3H-CE independently of known lipoprotein receptors. Addition of torcetrapib to the media did not impair the ability of cell-associated CETP to enhance CE uptake but reduced the ability of exogenously added CETP to increase selective uptake by up to 80%. When mice were infected with ad-CETP or ad-Luciferase and treated with daily intravenous injections of torcetrapib or vehicle, hepatic CETP expression resulted in a 50% decrease in HDL cholesterol in vehicle-treated animals versus a 33% decrease in HDL cholesterol in mice treated with torcetrapib.


CONCLUSIONS
CETP mediates selective uptake of HDL-CE by hepatocytes by both torcetrapib-sensitive (exogenous CETP) and torcetrapib-insensitive (cell-associated CETP) mechanisms. Hepatic expression of CETP in vivo results in a marked decrease in cholesterol in particles in the HDL density range, consistent with a physiological role for hepatocyte CETP in selective uptake.
Gauthier
Andre
A
Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada.
Lau
Paulina
P
Zha
Xiaohui
X
Milne
Ross
R
McPherson
Ruth
R
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018955:CD36 Antigens / Q000235:genetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011804:Quinolines / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics
D018955:CD36 Antigens; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D011804:Quinolines; D011973:Receptors, LDL; C483909:torcetrapib