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Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils
- Source :
- Cell Metabolism. 24:223-233
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
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.
- 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
Subjects
Details
- ISSN :
- 15504131
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Cell Metabolism
- Accession number :
- edsair.doi.dedup.....3ab02b44e38f42df280821d0a942bc40
- Full Text :
- https://doi.org/10.1016/j.cmet.2016.07.016