Abstract
The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRβ-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
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Clinical Trial, Phase I
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Randomized Controlled Trial
MeSH terms
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ATP Binding Cassette Transporter 1 / genetics
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ATP Binding Cassette Transporter 1 / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily G, Member 1 / metabolism
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Adipose Tissue / metabolism
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Adolescent
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Adult
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Animals
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Cell Movement* / drug effects
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Cholesterol / blood
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Cholesterol / metabolism
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Healthy Volunteers
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
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Hypercholesterolemia / blood
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Hypercholesterolemia / drug therapy
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Imidazoles / adverse effects*
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Imidazoles / pharmacology*
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Imidazoles / therapeutic use
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Leukocyte Count
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Lipid Metabolism*
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Lipoproteins / blood
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Lipoproteins / metabolism*
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Liver X Receptors / agonists*
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Macaca fascicularis
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Macrophages / metabolism
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Male
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Mice, Inbred C57BL
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Mononuclear Phagocyte System / metabolism
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Neutrophils / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Triglycerides / blood
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Young Adult
Substances
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ABCA1 protein, human
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ABCG1 protein, human
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ATP Binding Cassette Transporter 1
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ATP Binding Cassette Transporter, Subfamily G, Member 1
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Imidazoles
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Lipoproteins
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Liver X Receptors
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RNA, Messenger
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Triglycerides
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Cholesterol