MARCO, a macrophage scavenger receptor highly expressed in rodents, mediates dalcetrapib-induced uptake of lipids by rat and mouse macrophages.
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.
Perez
Anne
A
F Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Wright
Matthew B
MB
Maugeais
Cyrille
C
Braendli-Baiocco
Annamaria
A
Okamoto
Hiroshi
H
Takahashi
Akemi
A
Singer
Thomas
T
Mueller
Lutz
L
Niesor
Eric J
EJ
D000577:Amides; D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D015243:Cholesterol, VLDL / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism; D018899:CpG Islands; D004952:Esters; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D050356:Lipid Metabolism / Q000187:drug effects*; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000502:physiology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D018417:Th1 Cells / Q000187:drug effects
D000577:Amides; D000924:Anticholesteremic Agents; D015243:Cholesterol, VLDL; D002914:Chylomicrons; D004952:Esters; C092228:Marco protein, mouse; D011971:Receptors, Immunologic; D013438:Sulfhydryl Compounds; D018664:Interleukin-12; D015847:Interleukin-4; C411602:dalcetrapib; D012313:RNA; D016173:Macrophage Colony-Stimulating Factor; D000594:Amino Acid Oxidoreductases; C482019:Loxl1 protein, mouse