A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans.
Reverse cholesterol transport (RCT) is thought to be an atheroprotective function of HDL, and macrophage-specific RCT in mice is inversely associated with atherosclerosis. We developed a novel method using3H-cholesterol nanoparticles to selectively trace macrophage-specific RCT in vivo in humans. Use of3H-cholesterol nanoparticles was initially tested in mice to assess the distribution of tracer and response to interventions known to increase RCT. Thirty healthy subjects received3H-cholesterol nanoparticles intravenously, followed by blood and stool sample collection. Tracer counts were assessed in plasma, nonHDL, HDL, and fecal fractions. Data were analyzed by using multicompartmental modeling. Administration of3H-cholesterol nanoparticles preferentially labeled macrophages of the reticuloendothelial system in mice, and counts were increased in mice treated with a liver X receptor agonist or reconstituted HDL, as compared with controls. In humans, tracer disappeared from plasma rapidly after injection of nanoparticles, followed by reappearance in HDL and nonHDL fractions. Counts present as free cholesterol increased rapidly and linearly in the first 240 min after nadir; counts in cholesteryl ester increased steadily over time. Estimates of fractional transfer rates of key RCT steps were obtained. These results support the use of3H-cholesterol nanoparticles as a feasible approach for the measurement of macrophage RCT in vivo in humans.
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address: mcuchel@mail.med.upenn.edu.
Marina
M
Cuchel
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
Anna C
AC
Raper
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
Donna M
DM
Conlon
Department of Radiology, University of Pennsylvania, Philadelphia, PA.
Daniel A
DA
Pryma
Department of Radiology, University of Pennsylvania, Philadelphia, PA.
Richard H
RH
Freifelder
Department of Radiology, University of Pennsylvania, Philadelphia, PA.
Rahul
R
Poria
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
Debra
D
Cromley
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
Xiaoyu
X
Li
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
Richard L
RL
Dunbar
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA.
Benjamin
B
French
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
Liming
L
Qu
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
William
W
Farver
Bristol-Myers Squibb R&D, Princeton, NJ.
Ching-Chiang
CC
Su
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
Sissel
S
Lund-Katz
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
Amanda
A
Baer
AstraZeneca R&D, Molndal, Sweden.
Giacomo
G
Ruotolo
AstraZeneca R&D, Molndal, Sweden.
Peter
P
Akerblad
Bristol-Myers Squibb R&D, Princeton, NJ.
Carol S
CS
Ryan
Bristol-Myers Squibb R&D, Princeton, NJ.
Lan
L
Xiao
Bristol-Myers Squibb R&D, Princeton, NJ.
Todd G
TG
Kirchgessner
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
John S
JS
Millar
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
Jeffrey T
JT
Billheimer
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
Daniel J
DJ
Rader
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D050197:Atherosclerosis / Q000097:blood* / Q000473:pathology; D001692:Biological Transport / Q000235:genetics; D002784:Cholesterol / Q000097:blood* / Q000737:chemistry / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood* / Q000737:chemistry / Q000302:isolation & purification; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000302:isolation & purification / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors / Q000819:agonists / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry
D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D002784:Cholesterol
high density lipoprotein; lipoproteins