Liver X receptors as integrators of metabolic and inflammatory signaling
Open accessAbstract
The liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. LXRs function as nuclear cholesterol sensors that are activated in response to elevated intracellular cholesterol levels in multiple cell types. Once activated, LXRs induce the expression of an array of genes involved in cholesterol absorption, efflux, transport, and excretion. In addition to their function in lipid metabolism, LXRs have also been found to modulate immune and inflammatory responses in macrophages. Synthetic LXR agonists promote cholesterol efflux and inhibit inflammation in vivo and inhibit the development of atherosclerosis in animal models. The ability of LXRs to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in human metabolic disease.
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LXRα and LXRβ control expression of an array of genes important for cholesterol metabolism, which may exert independent effects on development of amyloidosis and neuroinflammation.
“Furthermore, LXRα and LXRβ control the expression of an array of genes important for cholesterol metabolism, which may exert independent effects on the development of amyloidosis and neuroinflammation (51).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [51]
Figure 1 describes LXRs as transcription factors that induce cholesterol-related target genes, and the section ‘LXRs as regulators of macrophage inflammatory signaling’ reports anti-inflammatory activity for both isoforms. The cited paper does not address amyloidosis or neuroinflammation, so it does not support the proposed effects on those conditions. The available passages have no page numbers. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCholesterol metabolism in mammals is controlled through the coordinated action of SREBP and LXR transcription factors.
“Cholesterol metabolism in mammals is controlled through the coordinated action of SREBP and LXR transcription factors (24–26).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [25]
The section “LXRs are master regulators of whole-body cholesterol homeostasis” supports LXR’s role in cholesterol metabolism. “LXR signaling in intermediary metabolism and energy balance” says LXR upregulates SREBP-1c, but describes that relationship as regulating hepatic lipogenesis, not coordinated control of cholesterol metabolism by both factors. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPharmacokinetic and toxicity studies have demonstrated that GW3965 may induce elevated hepatic triglycerides.
“Pharmacokinetic and toxicity studies have demonstrated that GW3965 may induce elevated hepatic triglycerides (25).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [25]
The section “LXR signaling in intermediary metabolism and energy balance” (page unavailable) reports that synthetic LXR agonists elevate liver triglycerides in mice. It does not identify GW3965 or describe pharmacokinetic and toxicity studies, so it supports the general risk but not the compound-specific attribution. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIDOL is a direct transcriptional target of LXR and is induced by LXR when cellular cholesterol levels rise.
“IDOL is a direct transcriptional target of the nuclear receptors liver X receptors (LXR) (NR1H2 and NR1H3) and is induced by these transcription factors when cellular cholesterol levels rise (11,12).”
From Distinct Functional Domains Contribute to Degradation of the Low Density Lipoprotein Receptor (LDLR) by the E3 Ubiquitin Ligase Inducible Degrader of the LDLR (IDOL) (2011) · cites this paper as [12]
Figure 1 and the section on macrophage cholesterol metabolism describe LXR-induced gene expression when cholesterol levels rise, but identify other targets, not IDOL. Searches for “IDOL” and “inducible degrader of LDL receptor” found no passage establishing that IDOL is a direct LXR target or is induced under those conditions. (LLM, conf=0.73)
Experimental — accuracy not yet measuredUnlike the LDLR and Pcsk9, IDOL is not regulated by SREBP.
“Unlike the LDLR and Pcsk9, IDOL is not regulated by SREBP.”
From Distinct Functional Domains Contribute to Degradation of the Low Density Lipoprotein Receptor (LDLR) by the E3 Ubiquitin Ligase Inducible Degrader of the LDLR (IDOL) (2011) · cites this paper as [12]
The passages on LXR signaling in intermediary metabolism and energy balance and on LXRs as potential drug targets discuss SREBP-1c regulation, but not whether SREBP regulates IDOL. Searches for IDOL and for LDLR, Pcsk9, and SREBP together found no passage addressing the claimed contrast. Page numbers were not available in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured
LXR activation attenuates LPS-induced expression of pro-inflammatory molecules and inhibits profibrotic pathways, mainly by inhibition of NF-κB.
“Via this pathway, LXR activation e.g.attenuates the LPSinduced expression of pro-inflammatory molecules and inhibits profibrotic pathways, mainly by inhibition of NF-κB.[163]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [163]
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Bifidobacteria can protect from enteropathogenic infection through production of acetate
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ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · see citing works
Self-citationTranscriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR
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“The LXR Agonist GW3965 Promotes GBM Cell Death In Vitro with Enhanced Efficacy in EGFRvIIIExpressing Tumor Cells Intracellular cholesterol levels can be regulated through (1) uptake of LDL through LDLR (40, 41), (2) efflux of cholesterol through ABCA1 or ABCG1 transporters (25, 42), and (3) hydroxymethylglutaryl-CoA r…”
BackgroundPivotal role of the mineralocorticoid receptor in corticosteroid‐induced adipogenesis
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Transcriptional coregulators in the control of energy homeostasis
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Cholesterol in islet dysfunction and type 2 diabetes
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The genomic landscapes of inflammation
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“ABCA1 is transcriptionally regulated by liver X receptors (LXRs) (Zelcer and Tontonoz, 2006).”
BackgroundNeuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease
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Nuclear receptors as therapeutic targets in liver disease: are we there yet?
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Self-citationFrom a glucocentric to a lipocentric approach towards metabolic syndrome
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Bone circuitry and interorgan skeletal crosstalk
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The macrophage LBP gene is an LXR target that promotes macrophage survival and atherosclerosis
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- Authors
- Zelcer, N.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zelcer, N.
- ORCID
- Zelcer, N.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-03-01
- Volume
- 116
- Issue
- 3
- Pages
- 607-614
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1386115
- OpenAlex
- W2058205407
- Cited by
- 978
- References
- 102
- Citations by year
- 2026: 29 · 2025: 40 · 2024: 33 · 2023: 36 · 2022: 26 · 2021: 47 · 2020: 40 · 2019: 41 · 2018: 29 · 2017: 48 · 2016: 39 · 2015: 52 · 2014: 54 · 2013: 65 · 2012: 60
- FWCI
- 14.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (30568, HL30568)
- University of California, Los Angeles
- National Heart, Lung, and Blood Institute (HL3 0568, P01HL030568, R01HL066088, HL66088)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- liver X receptor, nuclear receptors, cholesterol sensing, lipid metabolism, cholesterol efflux, cholesterol absorption, inflammation, macrophages, atherosclerosis, LXR agonists, metabolic disorders
- MeSH terms
- Liver X Receptors, Animals, Cholesterol, DNA-Binding Proteins, Humans, Inflammation, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Orphan Nuclear Receptors
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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.
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