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Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils

Authors :
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
Xiaoqin Liu
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.

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