Torcetrapib
CETP directly delivers HDL cholesteryl ester to the liver through a receptor-independent pathway that torcetrapib only partly blocks (Arterioscler Thromb Vasc Biol 2005)
Original title: Cholesteryl ester transfer protein directly mediates selective uptake of high density lipoprotein cholesteryl esters by the liver
Researchers tested whether CETP directly mediates selective uptake of HDL cholesteryl ester by hepatocytes, and how the CETP inhibitor torcetrapib affects this process. Using adenovirus-mediated CETP expression in primary mouse hepatocytes from wild-type, LDL receptor-knockout, or SR-BI-knockout mice, CETP enhanced selective accumulation of HDL-derived labeled cholesteryl ester independently of known lipoprotein receptors. Adding torcetrapib to the media did not impair cell-associated CETP's ability to enhance uptake, but reduced the ability of exogenously added CETP to increase selective uptake by up to 80%. In mice infected with CETP-expressing adenovirus and treated with daily torcetrapib or vehicle, hepatic CETP expression caused a 50% decrease in HDL cholesterol in vehicle-treated animals versus a 33% decrease in torcetrapib-treated animals, showing CETP mediates HDL cholesteryl ester uptake through both a torcetrapib-sensitive exogenous pathway and a torcetrapib-insensitive cell-associated pathway.
Original 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.
Methods And 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.