A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans

Abstract

This article is available online at http://www.jlr.org reverse cholesterol transport in vivo in humans. J. Lipid Res. 2017. 58: 752-762. Supplementary key words lipoproteins • high density lipoproteinAlthough an association between plasma concentrations of HDL cholesterol (HDL-C) levels and CVD has been found in epidemiological studies, the causal basis of this association has been recently questioned by the negative results observed in human genetics studies and clinical trials (1, 2). However, substantial interest remains in the concept that measures of HDL function may be more closely tied mechanistically to atherosclerosis (3). One of the biological functions of HDL is its ability to promote cellular cholesterol efflux and the return of that cholesterol to the liver for excretion in the feces in a process known as reverse cholesterol transport (RCT) (4). By using an in vivo assay in mice that we developed to measure the rate of RCT from macrophages to liver and feces, a large number of studies from multiple laboratories have demonstrated that the rate of in vivo macrophage RCT is a much better predictor of the impact of a genetic or pharmacologic perturbation on atherosclerosis than is the simple measure of HDL-C itself (5). Furthermore, using an ex vivo method developed to assess the cholesterol efflux capacity of HDL from a specific individual, we showed that this was strongly Abstract Reverse cholesterol transport (RCT) is thought to be an atheroprotective function of HDL, and macrophagespecific RCT in mice is inversely associated with atherosclerosis. We developed a novel method using

HDL and Reverse Cholesterol Transport

“…More recently, Cuchel et al adapted the conventional RCT method to allow for quantification of RCT in humans. This method involves intravenous delivery of 3 H-cholesterol nanoparticles, followed by blood and sample collection to quantify tracer counts in plasma, non-HDL and HDL fractions, as well as fecal fractions 127 . This is an exciting advance in the field, providing a feasible approach to quantify RCT in vivo in humans.…”

HDL cholesterol efflux capacity is inversely associated with subclinical cardiovascular risk markers in young adults: The cardiovascular risk in Young Finns study

“…The in vivo RCT was developed by Dan Rader and colleges and involves injecting macrophages loaded with radiolabeled cholesterol into the peritoneal cavity, and measuring the appearance of the radiolabel into the plasma, liver, and feces of experimental models over time. Recently the macrophage-specific RCT method was adopted for quantification of RCT in humans 47 . The further development of the in vivo assay would be useful in ongoing research assessing the role of key proteins regulating RCT in humans, and in evaluating the potential of novel therapeutic approaches targeting cholesterol efflux and RCT 47 .…”

Utilizing state‐of‐the‐art “omics” technology and bioinformatics to identify new biological mechanisms and biomarkers for coronary artery disease

“…Elucidation of the patient‐specific factors governing HDL structure and function and its cholesterol transport sequelae may yet evolve into an important prognostication tool in cardiovascular risk assessment. Recent technological advances have allowed accurate in vivo radiolabelled macrophage cholesterol tracing to further characterize HDL and the RCT pathway …”