Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages
Open accessAbstract
The nuclear oxysterol receptors LXRalpha (NR1H3) and LXRbeta (NR1H2) coordinately regulate the expression of genes involved in the transport and catabolism of cholesterol. In macrophages, LXR stimulates the transcription of genes encoding transporters involved in cholesterol efflux, which may limit the transformation of these cells into foam cells in response to lipid loading. Here, we report that natural and synthetic LXR ligands induce the expression of the LXRalpha gene in primary human macrophages and differentiated THP-1 macrophages. This regulation was not observed in primary human adipocytes or hepatocytes, a human intestinal cell line, or in any mouse tissue or cell line examined. The human LXRalpha gene was isolated, and the transcription initiation site delineated. Analysis of the LXRalpha promoter revealed a functional LXR/RXR binding site approximately 2.9 kb upstream of the transcription initiation site. We conclude that LXRalpha regulates its own expression in human macrophages and that this response is likely to amplify the effects of oxysterols on reverse cholesterol transport. These findings underscore the importance of LXR as a potential therapeutic target for the treatment of atherosclerosis.
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LXRα is found at high levels in cholesterol-metabolizing tissues and its expression is acutely regulated.
“LXR␣ is found at high levels in cholesterol-metabolizing tissues and its expression is acutely regulated (Whitney et al., 2001)”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Whitney et al., 2001
The introductory passage (labeled Abstract in our copy; page unavailable) says LXRα is abundant in the liver, kidney, spleen, intestine, and macrophages. The Abstract and Results show that LXR ligands induce LXRα expression in human macrophages, but not in the other tested cell types or mouse tissues. They do not establish that its expression is acutely regulated across cholesterol-metabolizing tissues. (LLM, conf=0.87)
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Li, A. C., & Glass, C. K. (2004) · Journal of Lipid Research · doi:10.1194/jlr.r400010-jlr200 · Cited by 357 · see citing works
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Terwel, D., Steffensen, K. R., Verghese, P. B., Kummer, M. P., Gustafsson, J.-Å., Holtzman, D. M., & Heneka, M. T. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6546-10.2011 · Cited by 181 · see citing works
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Nelissen, K., Mulder, M., Smets, I., Timmermans, S., Smeets, K., Ameloot, M., & Hendriks, J. J. A. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.22743 · Cited by 80 · see citing works
- Authors
- Whitney, K. D., Watson, M. A., Goodwin, B., Galardi, C. M., Maglich, J. M., Wilson, J. G., Willson, T. M., Collins, J. L., & Kliewer, S. A.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Kliewer, Steven A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-11
- Volume
- 276
- Issue
- 47
- Pages
- 43509-43515
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2099765837
- Cited by
- 154
- References
- 1
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 7 · 2017: 1 · 2016: 3 · 2015: 8 · 2014: 2 · 2013: 3 · 2012: 14
- FWCI
- 11.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- liver X receptor alpha, macrophages, oxysterols, reverse cholesterol transport, cholesterol efflux, foam cells, transcriptional regulation, atherosclerosis, THP-1 macrophages, LXR ligands
- MeSH terms
- Liver X Receptors, Animals, Base Sequence, Cell Line, DNA, DNA-Binding Proteins, Gene Expression Regulation, Humans, Macrophages, Male, Mice, Inbred C57BL, Receptors, Thyroid Hormone, Mutagenesis, Site-Directed, Sequence Homology, Amino Acid, Receptors, Cytoplasmic and Nuclear, Receptors, Retinoic Acid, Mice, Orphan Nuclear Receptors
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