title: Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils.
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.
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA. Electronic address: tgkakm@gmail.com.
authors: Todd G
authors: TG
authors: Kirchgessner
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Paul
authors: P
authors: Sleph
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Jacek
authors: J
authors: Ostrowski
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: John
authors: J
authors: Lupisella
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Carol S
authors: CS
authors: Ryan
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Xiaoqin
authors: X
authors: Liu
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Gayani
authors: G
authors: Fernando
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Denise
authors: D
authors: Grimm
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Petia
authors: P
authors: Shipkova
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Rongan
authors: R
authors: Zhang
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Ricardo
authors: R
authors: Garcia
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Jun
authors: J
authors: Zhu
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Aiqing
authors: A
authors: He
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Harold
authors: H
authors: Malone
authors: Exelixis, Inc., South San Francisco, CA 94080, USA.
authors: Richard
authors: R
authors: Martin
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Kamelia
authors: K
authors: Behnia
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Zhaoqing
authors: Z
authors: Wang
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Yu Chen
authors: YC
authors: Barrett
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Robert J
authors: RJ
authors: Garmise
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Long
authors: L
authors: Yuan
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Jane
authors: J
authors: Zhang
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Mohit D
authors: MD
authors: Gandhi
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Philip
authors: P
authors: Wastall
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Tong
authors: T
authors: Li
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Shuyan
authors: S
authors: Du
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Lisa
authors: L
authors: Salvador
authors: Exelixis, Inc., South San Francisco, CA 94080, USA.
authors: Raju
authors: R
authors: Mohan
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Glenn H
authors: GH
authors: Cantor
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Ellen
authors: E
authors: Kick
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: John
authors: J
authors: Lee
authors: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Robert J A
authors: RJ
authors: Frost
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy; D007093:Imidazoles / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D007958:Leukocyte Count; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism*; D000071518:Liver X Receptors / Q000819:agonists*; D008252:Macaca fascicularis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D012157:Mononuclear Phagocyte System / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D008074:Lipoproteins; D000071518:Liver X Receptors; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol