1. Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils
- Author
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Lisa Salvador, Richard Martin, Raju Mohan, Philip Wastall, Zhaoqing Wang, John A. Lupisella, Kamelia Behnia, Paul G. Sleph, Todd G. Kirchgessner, Petia Shipkova, Gayani Fernando, Jane Zhang, Carol S. Ryan, Rongan Zhang, Shuyan Du, Tong Li, Harold Malone, Ellen K. Kick, Glenn H. Cantor, Jun Zhu, Yu Chen Barrett, Jacek Ostrowski, Long Yuan, Denise Grimm, Aiqing He, John S. Lee, Robert J.A. Frost, Mohit D. Gandhi, Ricardo Garcia, Robert J. Garmise, and Xiaoqin Liu
- Subjects
Male ,0301 basic medicine ,Apolipoprotein E ,Apolipoprotein B ,Neutrophils ,Physiology ,Leukocyte Count ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,Mononuclear Phagocyte System ,ATP Binding Cassette Transporter, Subfamily G, Member 1 ,Liver X Receptors ,biology ,Reverse cholesterol transport ,Imidazoles ,Healthy Volunteers ,3. Good health ,Cholesterol ,Adipose Tissue ,lipids (amino acids, peptides, and proteins) ,ATP Binding Cassette Transporter 1 ,Adult ,Agonist ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Lipoproteins ,Hypercholesterolemia ,Young Adult ,03 medical and health sciences ,Therapeutic index ,Internal medicine ,medicine ,Animals ,Humans ,RNA, Messenger ,Liver X receptor ,Molecular Biology ,Triglycerides ,Macrophages ,Lipid metabolism ,Cell Biology ,Lipid Metabolism ,Rats ,Mice, Inbred C57BL ,Macaca fascicularis ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,030217 neurology & neurosurgery - 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.
- Published
- 2016
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