Dalcetrapib
The rodent-specific scavenger receptor MARCO drives the off-target lipid uptake seen with dalcetrapib in mouse macrophages (Toxicol In Vitro 2010)
Original title: MARCO, a macrophage scavenger receptor highly expressed in rodents, mediates dalcetrapib-induced uptake of lipids by rat and mouse macrophages
Dalcetrapib was observed in preclinical models to cause increased lipid uptake into the lamina propria of the small intestine and into mesenteric lymph node macrophages, an off-target effect whose receptor was investigated here. Using triglyceride assays and fluorescent labeling in primary macrophages and the cell lines CHO, J774A.1 mouse macrophages, and THP-1 human macrophages, researchers excluded the lectin-like oxidized LDL receptor and scavenger receptor type AI as candidates based on their lack of association with uptake of dalcetrapib-treated lipids. In mouse J774A.1 cells, LPS-stimulated uptake of dalcetrapib-treated chylomicrons was instead associated with expression of the macrophage receptor with collagenous domain, MARCO, which was expressed at very low levels in human macrophages and not inducible by LPS, potentially explaining why this dalcetrapib-related effect varies between species.
Original abstract
Dalcetrapib (RO4607381/JTT-705), an agent that targets cholesteryl ester transfer protein, is in development for prevention of cardiovascular events. In vitro studies were performed to identify receptors that mediate an off-target effect of dalcetrapib observed in preclinical models: increased lipid uptake into the lamina propria of the small intestine and into mesenteric lymph node macrophages. Uptake of oxidized low-density lipoprotein (LDL) cholesterol or dalcetrapib-treated chylomicrons was quantitated by triglyceride assay or fluorescent labeling in primary macrophages and the cell lines CHO, J774A.1 (mouse macrophages) and THP-1 (human macrophages). Quantitative reverse-transcriptase polymerase chain reaction and immunoblotting measured candidate receptor expression. Lectin-like oxidized LDL receptor (LOX-1) and scavenger receptor type AI (SR-AI) were excluded as candidate receptors based on lack of association between their expression and uptake of dalcetrapib-treated lipids. In J774A.1 cells, uptake of dalcetrapib-treated chylomicrons was increased by LPS and associated with expression of MAcrophage Receptor with COllagenous domain (MARCO). MARCO was expressed at very low levels in human macrophages and was not inducible by LPS. The MARCO receptor may account for the variable species susceptibility towards dalcetrapib-mediated chylomicron uptake by macrophages.
dalcetrapibinfectionmechanismssafety
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.