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

• Published in: Cell metabolism Vol. 24; no. 2; pp. 223 - 233
• Main Authors: Kirchgessner, Todd G., Sleph, Paul, Ostrowski, Jacek, Lupisella, John, Ryan, Carol S., Liu, Xiaoqin, Fernando, Gayani, Grimm, Denise, Shipkova, Petia, Zhang, Rongan, Garcia, Ricardo, Zhu, Jun, He, Aiqing, Malone, Harold, Martin, Richard, Behnia, Kamelia, Wang, Zhaoqing, Barrett, Yu Chen, Garmise, Robert J., Yuan, Long, Zhang, Jane, Gandhi, Mohit D., Wastall, Philip, Li, Tong, Du, Shuyan, Salvador, Lisa, Mohan, Raju, Cantor, Glenn H., Kick, Ellen, Lee, John, Frost, Robert J.A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.08.2016
• Subjects: Adipose Tissue - metabolism; Adolescent; Adult; Animals; ATP Binding Cassette Transporter 1 - genetics; ATP Binding Cassette Transporter 1 - metabolism; ATP Binding Cassette Transporter, Sub-Family G, Member 1 - genetics; ATP Binding Cassette Transporter, Sub-Family G, Member 1 - metabolism; Cell Movement - drug effects; Cholesterol - blood; Cholesterol - metabolism; Healthy Volunteers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypercholesterolemia - blood; Hypercholesterolemia - drug therapy; Imidazoles - adverse effects; Imidazoles - pharmacology; Imidazoles - therapeutic use; Leukocyte Count; Lipid Metabolism; Lipoproteins - blood; Lipoproteins - metabolism; Liver X Receptors - agonists; Macaca fascicularis; Macrophages - metabolism; Male; Mice, Inbred C57BL; Mononuclear Phagocyte System - metabolism; Neutrophils - metabolism; Rats; RNA, Messenger - genetics; RNA, Messenger - metabolism; Triglycerides - blood; Young Adult
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2016.07.016

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. [Display omitted] •An LXRβ-selective agonist caused positive and adverse effects in MAD clinical studies•RCT pathways were stimulated clinically and in animal models•Elevated plasma and liver lipids and neutropenia in healthy and statin-treated subjects•Pre-clinical studies predicted therapeutic, but not adverse, effects Kirchgessner et al. describe the effects of an LXR agonist in mice, cynomolgus monkeys, and humans. Although the LXRβ-selective agonist increased reverse cholesterol transport pathways in clinical trials, adverse effects not predicted from the pre-clinical models, such as elevated LDL cholesterol and triglycerides and decreased neutrophils, occurred.