LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor
Open accessAbstract
Cellular cholesterol levels reflect a balance between uptake, efflux, and endogenous synthesis. Here we show that the sterol-responsive nuclear liver X receptor (LXR) helps maintain cholesterol homeostasis, not only through promotion of cholesterol efflux but also through suppression of low-density lipoprotein (LDL) uptake. LXR inhibits the LDL receptor (LDLR) pathway through transcriptional induction of Idol (inducible degrader of the LDLR), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduces, whereas LXR knockout increases, LDLR protein levels in vivo in a tissue-selective manner. Idol knockdown in hepatocytes increases LDLR protein levels and promotes LDL uptake. Conversely, adenovirus-mediated expression of Idol in mouse liver promotes LDLR degradation and elevates plasma LDL levels. The LXR-Idol-LDLR axis defines a complementary pathway to sterol response element-binding proteins for sterol regulation of cholesterol uptake.
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There are no antibodies capable of detecting endogenous IDOL protein due to its autocatalytic proteosomal turnover.
“There are no antibodies capable of detecting endogenous IDOL protein due to its autocatalytic proteosomal turnover (Zelcer et al., 2009).”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Zelcer et al., 2009
The passage labeled Abstract (page unavailable) says some Idol levels were too low for the authors’ antibody to detect and that Idol may catalyze its own degradation. Another passage there reports that a proteasome blocker stabilized Idol. The paper does not establish that no antibody can detect endogenous Idol or that autocatalytic proteasomal turnover is the confirmed reason. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe intracellular tail of the LDLR is both required and sufficient for IDOL-dependent degradation.
“We have previously reported that the intracellular tail of the LDLR is both required and sufficient for IDOL-dependent degradation (11,13).”
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 [11]
The mutational-analysis passage (labeled Abstract; page unavailable) reports that IDOL had no effect on an LDLR lacking its intracellular domain, supporting that the tail is required. Our copy does not show that the tail alone is sufficient to confer IDOL-dependent degradation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOverexpression of IDOL strongly reduces LDLR, VLDLR, and APOER2 protein levels in vitro and in vivo, whereas IDOL knockdown results in the opposite outcome.
“Briefly, overexpression of IDOL strongly reduces LDLR, VLDLR, and APOER2 protein levels in vitro and in vivo, whereas IDOL knockdown results in the opposite outcome.”
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 [11]
The passages on cell experiments (Fig. 2E and Fig. 3A–B) report that IDOL expression lowers LDLR protein and IDOL knockdown raises it; the mouse experiment (Fig. 5E) also reports reduced hepatic LDLR after IDOL expression. But the paper says APOER2 was only marginally affected, does not report the claimed VLDLR effect, and does not show the opposite knockdown outcome for all three receptors in vivo. (LLM, conf=0.90)
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 [11]
The paper says LXR-induced Idol expression is not secondary to SREBP-1c and describes the LXR–Idol pathway as independent of SREBPs (copy section labeled Abstract; no page supplied). That supports SREBP-independent induction, but does not establish that SREBP never regulates IDOL or the claimed contrast with both LDLR and PCSK9. (LLM, conf=0.84)
Experimental — accuracy not yet measuredModulation of LDLR family receptor levels by IDOL is a post-transcriptional event.
“Importantly, modulation of the levels of these receptors by IDOL is a post-transcriptional event.”
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 [11]
The indexed copy (section labeled Abstract; page unavailable) reports that Idol knockdown changed LDLR protein levels without affecting LDLR mRNA, supporting post-transcriptional regulation of LDLR. It does not support extending that effect to LDLR family receptors generally: Lrp4 and SorLA were unaffected, and ApoER2 was only marginally affected. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Knockdown of MYLIP expression in human cultured cells increases LDLR protein levels.
“Knockdown of MYLIP expression in human cultured cells increases LDLR protein levels (4); however, the effect of loss of MYLIP expression in vivo has not been investigated.”
From The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans (2011) · cites this paper as [4]
The passage describing the Idol shRNA experiments (indexed under Abstract; page unavailable) reports increased LDLR protein after knockdown in cultured mouse embryonic fibroblasts and rat McR-H7777 cells. It does not report that result in human cells; the human-cell experiments described there involved Idol expression rather than knockdown. (LLM, conf=0.90)
Experimental — accuracy not yet measuredLoss of LXRα and LXRβ does not lead to complete loss of Idol expression.
“However, it is important to keep in mind that loss of LXRα and LXRβ does not lead to complete loss of Idol expression (15).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [15]
IDOL is an E3 ubiquitin ligase that ubiquitinates LDLR, triggering its lysosomal degradation.
“IDOL is an E3 ubiquitin ligase that ubiquitinates LDLR, thereby triggering its lysosomal degradation. 19”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [19]
IDOL induces post-translational modifications by ubiquitinating its substrates.
“IDOL induces post‐translational modifications by ubiquitinating its substrates, 19 , 53 but neuronal Idol deletion may also result in transcriptomic changes.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [19]
LXRs respond to excess cellular cholesterol by promoting ABCA1- and ABCG1-dependent cholesterol efflux and by inhibiting LDLR protein expression through induction of the E3 ubiquitin ligase IDOL.
“LXRs respond to excess cellular cholesterol by promoting ABCA1- and ABCG1-dependent cholesterol efflux and by inhibiting LDLR protein expression through induction of the E3 ubiquitin ligase IDOL (27).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [27]
LXR agonists may be highly beneficial because of their ability to coordinately target two of the three aspects of cholesterol regulation.
“LXR agonists may be highly beneficial because of their ability to coordinately target two of the three aspects of cholesterol regulation (27).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [27]
PCSK9 and IDOL are well-established post-translational regulators of LDLR turnover.
“Although PCSK9 (ref. 8) and IDOL 9 are well-established post-translational regulators of LDLR turnover, the mechanisms controlling LDLR trafficking and degradation are not yet fully understood, especially in response to high dietary cholesterol.”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [9]
Overexpression of Idol reduces LDLR protein levels in vitro and in vivo and inhibits LDL uptake.
“Overexpression of Idol potently reduces LDLR protein levels in vitro and in vivo and inhibits LDL uptake.”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [13]
Idol is not regulated by SREBPs.
“Unlike the LDLR and PCSK9 genes, Idol is not regulated by SREBPs.”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [13]
Idol is a transcriptional target of LXRs and a post-transcriptional regulator of the LDLR pathway.
“We have recently identified the E3 ubiquitin ligase Idol (inducible degrader of the LDLR) as a transcriptional target of LXRs and a post-transcriptional regulator of the LDLR pathway (13).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [13]
LXR null mice have substantially reduced Idol expression.
“Because the formation of vertical processes emanating from these cells requires proper Reelin signaling (39) and the LXR null mice have substantially reduced Idol expression (13), it remains to be seen whether Idol contributes to the observed migratory defect.”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [13]
These observations are consistent with Idol-dependent lysosomal degradation of the VLDLR.
“These observations are consistent with Idol-dependent lysosomal degradation of the VLDR as we recently proposed for the LDLR (13).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [13]
Idol triggers ubiquitination of the LDLR on conserved residues in its intracellular tail, leading to degradation of the receptor.
“Idol triggers ubiquitination of the LDLR on conserved residues in its intracellular tail, leading to degradation of the receptor.”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [13]
A mutant LDLR lacking the intracellular domain is resistant to IDOL-mediated degradation.
“We have previously found that a mutant LDLR lacking the intracellular domain is resistant to IDOL-mediated degradation (13).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [13]
Knockdown of Idol expression increases LDLR protein and LDL uptake.
“Conversely, knockdown of Idol expression leads to an increase in LDLR protein and LDL uptake.”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [13]
An inactivating point mutation in the IDOL RING domain (C387A) abrogates the effect of IDOL on VLDLR and ApoER2.
“Introducing an inactivating point mutation in the IDOL RING domain (C387A) (13) abrogated the effect on these receptors.”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [13]
IDOL is an E3 ubiquitin ligase whose expression is transcriptionally controlled by liver X receptors in cell types such as hepatocytes and macrophages.
“Inducible Degrader of the LDL receptor (IDOL; encoded by the Mylip gene), an E3 ubiquitin ligase whose expression is transcriptionally controlled by liver X receptors in (LXRs) in cell types such as hepatocytes and macrophages (Zelcer et al., 2009).”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Zelcer et al., 2009
Expression of an inactive mutant (C387A) fails to recapitulate the effects of IDOL on synaptogenesis.
“as expression of an inactive mutant (C387A)(Zelcer et al., 2009) failed to recapitulate these effects (Figure 2C).”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Zelcer et al., 2009
IDOL triggers ubiquitination and subsequent degradation of the LDLR.
“Acting as an E3 ubiquitin ligase, IDOL triggers ubiquitination and subsequent degradation of the low density lipoprotein receptor (LDLR).”
Ubiquitination of these receptors by IDOL marks them for subsequent lysosomal degradation.
“Ubiquitination of these receptors by IDOL marks them for subsequent lysosomal degradation.”
Knocking down endogenous IDOL expression increases abundance of the LDLR and LDL uptake into cells, indicating that receptor endocytosis remains intact.
“Knocking down endogenous IDOL expression increases abundance of the LDLR and LDL uptake into cells indicating that receptor endocytosis remains intact (11).”
IDOL promotes the appearance of ubiquitinated LDLR in cells.
“We have previously demonstrated that IDOL promotes appearance of ubiquitinated LDLR in cells (11).”
IDOL 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).”
The LXR-MYLIP-LDLR pathway provides a complementary pathway to sterol regulatory element-binding proteins for the feedback inhibition of cholesterol uptake.
“Thus, the LXR-MYLIP-LDLR pathway provides a complementary pathway to sterol regulatory element-binding proteins for the feedback inhibition of cholesterol uptake (4,5).”
From The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans (2011) · cites this paper as [4]
The E3 ubiquitin ligase MYLIP (also known as IDOL) is a regulator of the LDL receptor pathway for cellular cholesterol uptake.
“We previously identified the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also known as IDOL) as a regulator of the LDL receptor (LDLR) pathway for cellular cholesterol uptake (4).”
From The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans (2011) · cites this paper as [4]
MYLIP stimulates ubiquitination of the LDLR on its cytoplasmic tail, thereby directing its degradation.
“MYLIP stimulates ubiquitination of the LDLR on its cytoplasmic tail, thereby directing its degradation.”
From The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans (2011) · cites this paper as [4]
MYLIP is a direct target for regulation by LXR, and its expression is coordinately regulated with the ATP-binding cassette transporter in multiple cell types.
“MYLIP is a direct target for regulation by the nuclear receptor liver X receptor (LXR), and its expression is coordinately regulated with the ATP-binding cassette transporter in multiple cell types (4).”
From The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans (2011) · cites this paper as [4]
Expression of Mylip in mouse liver by means of an adenoviral vector dramatically reduces LDLR protein levels and raises LDL-C levels.
“Expression of Mylip in mouse liver by means of an adenoviral vector dramatically reduces LDLR protein levels and raises LDL-C levels (4).”
From The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans (2011) · cites this paper as [4]
The LXR-MYLIP pathway is conserved in human cells.
“The LXR-MYLIP pathway is conserved in human cells, but its role in human cholesterol metabolism remains to be addressed.”
From The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans (2011) · cites this paper as [4]
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- Authors
- Zelcer, N., Hong, C., Boyadjian, R., & Tontonoz, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zelcer, Noam
- Tontonoz, Peter
- Venue
- Science
- Published
- 2009-07-03
- Volume
- 325
- Issue
- 5936
- Pages
- 100-104
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2777523
- OpenAlex
- W2030341081
- Cited by
- 848
- References
- 1
- Citations by year
- 2026: 37 · 2025: 56 · 2024: 45 · 2023: 70 · 2022: 47 · 2021: 52 · 2020: 49 · 2019: 42 · 2018: 50 · 2017: 36 · 2016: 36 · 2015: 56 · 2014: 55 · 2013: 55 · 2012: 63
- FWCI
- 54.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (HL030568, P01HL090553, HL066088, P01HL030568, HL090553, R01HL066088)
- 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, LDL receptor, idols, E3 ubiquitin ligase, LDL receptor degradation, cholesterol absorption, cholesterol homeostasis, hepatocytes, nuclear receptor signaling
- MeSH terms
- Liver X Receptors, Animals, Cholesterol, DNA-Binding Proteins, Homeostasis, Humans, Ligands, Lipoproteins, LDL, Liver, Mice, Inbred C57BL, Promoter Regions, Genetic, Receptors, LDL, RNA, Messenger, Transcription, Genetic, Receptors, Cytoplasmic and Nuclear, Ubiquitin-Protein Ligases, Cell Line, Tumor, Mice, Ubiquitination, Orphan Nuclear Receptors
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