title: Cholesteryl ester transfer protein directly mediates selective uptake of high density lipoprotein cholesteryl esters by the liver.
abstract: 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.
authors.affiliation: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Andre
authors.initials: A
authors.lastname: Gauthier
authors.forename: Paulina
authors.initials: P
authors.lastname: Lau
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zha
authors.forename: Ross
authors.initials: R
authors.lastname: Milne
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
mesh_terms: 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
chemical_list: 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