Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα
Open accessAbstract
LXRα is a nuclear receptor that has previously been shown to regulate the metabolic conversion of cholesterol to bile acids. Here we define a role for this transcription factor in the control of cellular cholesterol efflux. We demonstrate that retroviral expression of LXRα in NIH 3T3 fibroblasts or RAW264.7 macrophages and/or treatment of these cells with oxysterol ligands of LXR results in 7- to 30-fold induction of the mRNA encoding the putative cholesterol/phospholipid transporter ATP-binding cassette (ABC)A1. In contrast, induction of ABCA1 mRNA in response to oxysterols is attenuated in cells that constitutively express dominant-negative forms of LXRα or LXRβ that lack the AF2 transcriptional activation domain. We further demonstrate that expression of LXRα in NIH 3T3 fibroblasts and/or treatment of these cells with oxysterols is sufficient to stimulate cholesterol efflux to extracellular apolipoprotein AI. The ability of oxysterol ligands of LXR to stimulate efflux is dramatically reduced in Tangier fibroblasts, which carry a loss of function mutation in the ABCA1 gene. Taken together, these results indicate that cellular cholesterol efflux is controlled, at least in part, at the level of transcription by a nuclear receptor–signaling pathway. They suggest a model in which activation of LXRs by oxysterols in response to cellular sterol loading leads to induction of the ABCA1 transporter and the stimulation of lipid efflux to extracellular acceptors. These findings have important implications for our understanding of mammalian cholesterol homeostasis and suggest new opportunities for pharmacological regulation of cellular lipid metabolism.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Expression of both ABCA1 and ABCG1 is up-regulated in states of cholesterol excess by LXR.
“The expression of both ABCA1 and ABCG1 are up-regulated in states of cholesterol excess by LXR 9.”
From Control of Cholesterol Metabolism and Plasma High-Density Lipoprotein Levels by microRNA-144 (2013) · cites this paper as [9]
Cited by
Sorted by citations
Khovidhunkit, W., Kim, M.-S., Memon, R. A., Shigenaga, J. K., Moser, A. H., Feingold, K. R., & Grunfeld, C. (2004) · Journal of Lipid Research · doi:10.1194/jlr.r300019-jlr200 · Cited by 1,481 · see citing works
Chinetti, G., Lestavel, S., Bocher, V., Remaley, A. T., Neve, B., Torra, I. P., Teissier, E., Minnich, A., Jaye, M., Duverger, N., et al. (2001) · Nature Medicine · doi:10.1038/83348 · Cited by 1,170 · see citing works
Macrophage death and defective inflammation resolution in atherosclerosis
Tabas, I. (2010) · Nature Reviews Immunology · doi:10.1038/nri2675 · Cited by 1,120 · see citing works
Liver X receptors as integrators of metabolic and inflammatory signaling
Zelcer, N. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27883 · Cited by 978 · see citing works
Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR
Calkin, A. C., & Tontonoz, P. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3312 · Cited by 779 · see citing works
Self-citationLiver X receptors in lipid signalling and membrane homeostasis
Wang, B., & Tontonoz, P. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0037-x · Cited by 722 · see citing works
Self-citationmiR-33 links SREBP-2 induction to repression of sterol transporters
Marquart, T. J., Allen, R. M., Ory, D. S., & Baldán, Á. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1005191107 · Cited by 562 · see citing works
HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells
Tabet, F., Vickers, K. C., Cuesta Torres, L. F., Wiese, C. B., Shoucri, B. M., Lambert, G., Catherinet, C., Prado-Lourenco, L., Levin, M. G., Thacker, S., et al. (2014) · Nature Communications · doi:10.1038/ncomms4292 · Cited by 428 · see citing works
ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease
Oram, J. F., & Vaughan, A. M. (2006) · Circulation Research · doi:10.1161/01.res.0000250171.54048.5c · Cited by 411 · see citing works
Increased Atherosclerosis in Hyperlipidemic Mice With Inactivation of ABCA1 in Macrophages
Aiello, R. J., Brees, D., Bourassa, P.-A., Royer, L., Lindsey, S., Coskran, T., Haghpassand, M., & Francone, O. L. (2002) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000014804.35824.da · Cited by 390 · see citing works
Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation*
Gerin, I., Clerbaux, L.-A., Haumont, O., Lanthier, N., Das, A. K., Burant, C. F., Leclercq, I. A., MacDougald, O. A., & Bommer, G. T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.152090 · Cited by 382 · see citing works
Seo, J. B., Moon, H. M., Kim, W. S., Lee, Y. S., Jeong, H. W., Yoo, E. J., Ham, J., Kang, H., Park, M.-G., Steffensen, K. R., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.8.3430-3444.2004 · Cited by 250 · see citing works
Control of Cholesterol Metabolism and Plasma High-Density Lipoprotein Levels by microRNA-144
Ramírez, C. M., Rotllan, N., Vlassov, A. V., Dávalos, A., Li, M., Goedeke, L., Aranda, J. F., Cirera-Salinas, D., Araldi, E., Salerno, A., et al. (2013) · Circulation Research · doi:10.1161/circresaha.112.300626 · Cited by 217 · see citing works
“The expression of ABCA1 and of ABCG1 is upregulated in states of cholesterol excess by liver X nuclear receptor (LXR).(9) LXRs are activated by oxysterol metabolites of cholesterol and play key roles in regulating multiple components of the reverse cholesterol transport pathway, cholesterol conversion to bile acid, an…”
BackgroundFeedback Regulation of Cholesterol Uptake by the LXR–IDOL–LDLR Axis
Zhang, L., Reue, K., Fong, L. G., Young, S. G., & Tontonoz, P. (2012) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.112.250571 · Cited by 137 · see citing works
Self-citationGromovsky, A. D., Schugar, R. C., Brown, A. L., Helsley, R. N., Burrows, A. C., Ferguson, D., Zhang, R., Sansbury, B. E., Lee, R. G., Morton, R. E., et al. (2018) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.117.309660 · Cited by 115 · see citing works
Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1
Fond, A. M., Lee, C. S., Schulman, I. G., Kiss, R. S., & Ravichandran, K. S. (2015) · Journal of Clinical Investigation · doi:10.1172/jci80300 · Cited by 114 · see citing works
Role of amyloid beta in lipid homeostasis
Grösgen, S., Grimm, M. O. W., Frieß, P., & Hartmann, T. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.05.002 · Cited by 90 · see citing works
Liver X receptors regulate cholesterol homeostasis in oligodendrocytes
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
Glycosphingolipid Accumulation Inhibits Cholesterol Efflux via the ABCA1/Apolipoprotein A-I Pathway
Glaros, E. N., Kim, W. S., Quinn, C. M., Wong, J., Gelissen, I., Jessup, W., & Garner, B. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413862200 · Cited by 75 · see citing works
Cashikar, A. G., Toral-Rios, D., Timm, D., Romero, J., Strickland, M., Long, J. M., Han, X., Holtzman, D. M., & Paul, S. M. (2023) · Journal of Lipid Research · doi:10.1016/j.jlr.2023.100350 · Cited by 72 · see citing works
Chen, J., Tian, J., Ge, H., Liu, R., & Xiao, J. (2017) · Food and Chemical Toxicology · doi:10.1016/j.fct.2016.12.017 · Cited by 69 · see citing works
Efflux and uptake transporters as determinants of statin response
Rodrigues, A. C. (2010) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425251003713519 · Cited by 64 · see citing works
Anuka, E., Gal, M., Stocco, D. M., & Orly, J. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.02.003 · Cited by 60 · see citing works
Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?
Staurenghi, E., Giannelli, S., Testa, G., Sottero, B., Leonarduzzi, G., & Gamba, P. (2021) · Antioxidants · doi:10.3390/antiox10121890 · Cited by 44 · see citing works
Liver X receptor-dependent inhibition of microglial nitric oxide synthase 2
Secor McVoy, J. R., Oughli, H. A., & Oh, U. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0247-2 · Cited by 34 · see citing works
The macrophage LBP gene is an LXR target that promotes macrophage survival and atherosclerosis
Sallam, T., Ito, A., Rong, X., Kim, J., van Stijn, C., Chamberlain, B. T., Jung, M. E., Chao, L. C., Jones, M., Gilliland, T., et al. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m047548 · Cited by 30 · see citing works
Self-citationMicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease
Yoon, H., Flores, L. F., & Kim, J. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.04.020 · Cited by 23 · see citing works
“ABCA1 and ABCG1 expression are regulated by LXR and RXR in the liver [26, 27].”
BackgroundLinden, A. K., Affaneh, A., Aylward, A., Wong, Y., Kessler, J. A., & Peng, C.-Y. (2025) · doi:10.64898/2025.12.14.694212 · Cited by 1 · see citing works
- Authors
- Venkateswaran, A., Laffitte, B. A., Joseph, S. B., Mak, P. A., Wilpitz, D. C., Edwards, P. A., & Tontonoz, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Edwards, Peter A.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2000-10-17
- Volume
- 97
- Issue
- 22
- Pages
- 12097-12102
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC17300
- OpenAlex
- W2093296161
- Cited by
- 1,005
- References
- 0
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 25 · 2023: 25 · 2022: 29 · 2021: 35 · 2020: 36 · 2019: 43 · 2018: 28 · 2017: 29 · 2016: 27 · 2015: 45 · 2014: 43 · 2013: 43 · 2012: 43
- FWCI
- 54.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (30568)
- University of California, Los Angeles
- National Heart, Lung, and Blood Institute (HL3 0568, P01HL030568)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- liver X receptor alpha, nuclear receptors, cholesterol efflux, ABCA1, oxysterols, apolipoprotein A-I, cholesterol homeostasis, Tangier disease, macrophages, fibroblasts, transactivation domain, lipid metabolism
- MeSH terms
- Liver X Receptors, Animals, Biological Transport, Cells, Cultured, Cholesterol, DNA-Binding Proteins, Humans, Macrophages, Monocytes, 3T3 Cells, Receptors, Cytoplasmic and Nuclear, Mice, Orphan Nuclear Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
