The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice
Open accessAbstract
The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR-IDOL axis are both tissue and species specific. In mice, LXR agonist induces Idol transcript levels in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues, but not in the liver. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a potential strategy for LDL lowering in humans.
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IDOL plays a primary role in regulating brain LDLR protein and has a limited effect on hepatic LDLR levels in mice.
“IDOL plays a primary role in regulating brain LDLR protein and has a limited effect on hepatic LDLR levels in mice”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Hong et al 2014
The Introduction and Results report that hepatic LDLR protein in mice is relatively resistant to loss of IDOL activity, with only a subtle increase after a prolonged high-cholesterol diet. The Results identify effects in heart, spleen, macrophages, and other peripheral tissues, but our copy does not establish a primary role for IDOL in regulating brain LDLR protein (searched: brain and brain tissue LDLR). (LLM, conf=0.87)
Experimental — accuracy not yet measuredLoss of Idol expression in mice has little effect on hepatic LDLR.
“By contrast, loss of Idol expression in mice has little effect on hepatic LDLR (13).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [13]
LXR-IDOL-LDLR pathway is highly active in primates.
“We previously reported that the LXR-IDOL-LDLR pathway is highly active in primates (13), but further studies will be needed to translate the current findings to humans.”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [13]
Previous studies suggested Idol inhibition may have beneficial effects on plasma LDL in primates.
“Previous studies have suggested that Idol inhibition may have beneficial effects on plasma LDL in primates (13).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [13]
The LXR-IDOL pathway regulates cellular cholesterol levels and impacts plasma LDL levels in primates.
“Prior studies have shown that the LXR-IDOL pathway regulates cellular cholesterol levels and impacts plasma LDL levels in primates (Hong et al., 2014; Scotti et al., 2011).”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Hong et al., 2014
IDOL and LXR signaling regulate lipoprotein receptors in a cell type-specific manner.
“since IDOL and LXR signaling regulate lipoprotein receptors in a cell type-specific manner (Hong et al., 2014)”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Hong et al., 2014
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- Authors
- Hong, C., Marshall, S. M., McDaniel, A. L., Graham, M., Layne, J. D., Cai, L., Scotti, E., Boyadjian, R., Kim, J., Chamberlain, B. T., Tangirala, R. K., Jung, M. E., Fong, L., Lee, R., Young, S. G., Temel, R. E., & Tontonoz, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Wake Forest University Health Sciences (US)
- Ionis Pharmaceuticals (United States) (US)
- University of Kentucky (US)
- University of California, Los Angeles (US)
- California NanoSystems Institute (US)
- Atrium Health Wake Forest Baptist (US)
- Corresponding author
- Temel, Ryan E.
- Tontonoz, Peter
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 20
- Issue
- 5
- Pages
- 910-918
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4261644
- OpenAlex
- W2124416452
- Cited by
- 87
- References
- 29
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 9 · 2023: 7 · 2022: 4 · 2021: 10 · 2020: 9 · 2019: 9 · 2018: 4 · 2017: 9 · 2016: 6 · 2015: 11
- FWCI
- 8.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Wake Forest University
- Tulane University
- National Institutes of Health (5r00hl088528-05)
- Wake Forest School of Medicine
- National Heart, Lung, and Blood Institute (P01HL090553, R01HL111932, HL066088, R00-HL088528, T32HL091797, HL111932, HL090553, K99HL088528, R01HL066088, HL088528)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK041301)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- liver X receptor, idols, E3 ubiquitin ligase, LDL receptor, species differences, Macaca fascicularis, LXR agonists, antisense oligonucleotides, LDL-C lowering therapy, lipid metabolism
- MeSH terms
- Liver X Receptors, Animals, Haplorhini, Cells, Cultured, Humans, Cholesterol, LDL, Liver, Macaca fascicularis, Male, Mice, Inbred C57BL, Receptors, LDL, Species Specificity, Signal Transduction, Ubiquitin-Protein Ligases, Mice, Orphan Nuclear Receptors
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