Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils
Open accessAbstract
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.
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LXR agonists reduce lipid droplet accumulation through enhanced cholesterol efflux and exhibit anti-inflammatory properties, but their concurrent promotion of lipogenesis also leads to adverse effects such as hepatic steatosis and hyperlipidemia.
“For example, liver X receptor (LXR) agonists reduce LD accumulation through enhanced cholesterol efflux and exhibit anti-inflammatory properties, but their concurrent promotion of lipogenesis also leads to adverse effects such as hepatic steatosis and hyperlipidemia.82,83”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [82]
Cites
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Liver X receptors in lipid signalling and membrane homeostasis
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- Authors
- Kirchgessner, T. G., Sleph, P., Ostrowski, J., Lupisella, J., Ryan, C. S., Liu, X., Fernando, G., Grimm, D., Shipkova, P., Zhang, R., Garcia, R., Zhu, J., He, A., Malone, H., Martin, R., Behnia, K., Wang, Z., Barrett, Y. C., Garmise, R. J., Yuan, L., Zhang, J., Gandhi, M. D., Wastall, P., Li, T., Du, S., Salvador, L., Mohan, R., Cantor, G. H., Kick, E., Lee, J., & Frost, R. J. A.
- Affiliations
- Bristol-Myers Squibb (United States) (US)
- Exelixis (United States) (US)
- Corresponding author
- Kirchgessner, Todd G.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 24
- Issue
- 2
- Pages
- 223-233
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2497098123
- Cited by
- 172
- References
- 2
- Citations by year
- 2026: 18 · 2025: 29 · 2024: 14 · 2023: 13 · 2022: 14 · 2021: 18 · 2020: 21 · 2019: 19 · 2018: 13 · 2017: 10 · 2016: 3
- FWCI
- 16.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- LXR agonists, LXRβ, reverse cholesterol transport, lipid metabolism, lipoprotein metabolism, neutrophils, hypercholesterolemia, LDL cholesterol, triglycerides, cholesteryl ester transfer protein, apolipoproteins, hepatic lipogenesis, coronary artery disease
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 1, Liver X Receptors, Adipose Tissue, Adolescent, Adult, Animals, Cell Movement, Cholesterol, Humans, Hypercholesterolemia, Imidazoles, Leukocyte Count, Lipoproteins, Macaca fascicularis, Macrophages, Male, Mice, Inbred C57BL, Neutrophils, Mononuclear Phagocyte System, RNA, Messenger, Triglycerides, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipid Metabolism, Rats, Young Adult, ATP Binding Cassette Transporter 1, Healthy Volunteers
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