Targeted disruption of the idol gene alters cellular regulation of the low-density lipoprotein receptor by sterols and liver x receptor agonists
Open accessAbstract
Previously, we identified the E3 ubiquitin ligase Idol (inducible degrader of the low-density lipoprotein [LDL] receptor [LDLR]) as a posttranscriptional regulator of the LDLR pathway. Idol stimulates LDLR degradation through ubiquitination of its C-terminal domain, thereby limiting cholesterol uptake. Here we report the generation and characterization of mouse embryonic stem cells homozygous for a null mutation in the Idol gene. Cells lacking Idol exhibit markedly elevated levels of the LDLR protein and increased rates of LDL uptake. Furthermore, despite an intact sterol responsive element-binding protein (SREBP) pathway, Idol-null cells exhibit an altered response to multiple regulators of sterol metabolism, including serum, oxysterols, and synthetic liver X receptor (LXR) agonists. The ability of oxysterols and lipoprotein-containing serum to suppress LDLR protein levels is reduced, and the time course of suppression is delayed, in cells lacking Idol. LXR ligands have no effect on LDLR levels in Idol-null cells, indicating that Idol is required for LXR-dependent inhibition of the LDLR pathway. In line with these results, the half-life of the LDLR protein is prolonged in the absence of Idol. Finally, the ability of statins and PCSK9 to alter LDLR levels is independent of, and additive with, the LXR-Idol pathway. These results demonstrate that the LXR-Idol pathway is an important contributor to feedback inhibition of the LDLR by sterols and a biological determinant of cellular LDL uptake.
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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 Scotti et al., 2011
The Results and Discussion report that the LXR-IDOL pathway regulates LDL receptor levels and LDL uptake in mouse embryonic stem cells, supporting its role in cellular cholesterol regulation. The paper does not report an effect on plasma LDL levels in primates; its discussion of raised plasma LDL concerns mice, not primates. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPCSK9 is still able to stimulate LDLR degradation in cells lacking IDOL, indicating that IDOL and PCSK9 function in complementary but independent pathways.
“Furthermore, PCSK9 is still able to stimulate LDLR degradation in cells lacking IDOL, indicating that IDOL and PCSK9 function in complementary but independent pathways.32”
From Feedback Regulation of Cholesterol Uptake by the LXR–IDOL–LDLR Axis (2012) · cites this paper as [32]
Cells lacking IDOL expression exhibit higher basal levels of LDLR protein and internalize LDL more readily than wild-type cells, and LXR agonists have no effect on LDLR protein or LDL uptake in IDOL-null ES cells.
“Cells lacking IDOL expression exhibit higher basal levels of LDLR protein and internalize LDL more readily than wild-type cells.32”
From Feedback Regulation of Cholesterol Uptake by the LXR–IDOL–LDLR Axis (2012) · cites this paper as [32]
The LXR-IDOL-LDLR mechanism for feedback inhibition of cholesterol uptake is independent of and complementary to the SREBP pathway.
“The LXR–IDOL–LDLR mechanism for feedback inhibition of cholesterol uptake is independent of and complementary to the SREBP pathway.”
From Feedback Regulation of Cholesterol Uptake by the LXR–IDOL–LDLR Axis (2012) · cites this paper as [32]
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 [5]
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Cites
Hong, C., Duit, S., Jalonen, P., Out, R., Scheer, L., Sorrentino, V., Boyadjian, R., Rodenburg, K. W., Foley, E., Korhonen, L., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.123729 · Cited by 142 · see citing works
Self-citationCholesterol-independent Effects of Statins and New Therapeutic Targets: Ischemic Stroke and Dementia
Miida, T., Hirayama, S., & Nakamura, Y. (2004) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.11.253 · Cited by 97 · see citing works
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Research works printed but not linked: 4
- Janowski, B. A., et al. 1999. Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc. Natl. Acad. Sci.
- Laffitte, B. A., et al. 2001. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc. Natl. Acad. Sci.
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Mechanisms and regulation of cholesterol homeostasis
Luo, J., Yang, H., & Song, B.-L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0190-7 · Cited by 1,980 · see citing works
Feedback 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-citationThe LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice
Hong, C., Marshall, S. M., McDaniel, A. L., Graham, M., Layne, J. D., Cai, L., Scotti, E., Boyadjian, R., Kim, J., Chamberlain, B. T., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.001 · Cited by 87 · see citing works
Self-citationWeissglas-Volkov, D., Calkin, A. C., Tusie-Luna, T., Sinsheimer, J. S., Zelcer, N., Riba, L., Tino, A. M. V., Ordoñez-Sánchez, M. L., Cruz-Bautista, I., Aguilar-Salinas, C. A., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45504 · Cited by 66 · see citing works
Self-citationGao, J., Marosi, M., Choi, J., Achiro, J. M., Kim, S., Li, S., Otis, K., Martin, K. C., Portera-Cailliau, C., & Tontonoz, P. (2017) · eLife · doi:10.7554/elife.29178 · Cited by 30 · see citing works
Self-citationIDOL regulates systemic energy balance through control of neuronal VLDLR expression
Lee, S. D., Priest, C., Bjursell, M., Gao, J., Arneson, D. V., Ahn, I. S., Diamante, G., van Veen, J. E., Massa, M. G., Calkin, A. C., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0127-7 · Cited by 26 · see citing works
Self-citationKarahan, H., Hartigan, K., Al‐Amin, M. M., John, S. K., McCord, B., Wijeratne, H. R. S., Acri, D. J., Smith, D. C., Dabin, L. C., Cordero, H. M. R., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70949 · Cited by 2 · see citing works
“5XFAD mice 21 (Stock# 34840-JAX), Idol f/f (also known as Mylip f/f ) 22 (Stock# 034728, generated by Dr. Peter Tontonoz, HHMI), Cx3cr1-CreERT2 23 (Stock# 021160), and Camk2a-Cre 24 (Stock# 005359) were purchasedfromTheJacksonLaboratory.”
- Authors
- Scotti, E., Hong, C., Yoshinaga, Y., Tu, Y., Hu, Y., Zelcer, N., Boyadjian, R., de Jong, P. J., Young, S. G., Fong, L. G., & Tontonoz, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Children's Hospital of Oakland Research Institute, Oakland, California
- University of California, Los Angeles (US)
- Corresponding author
- Tontonoz, Peter
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2011-05-01
- Volume
- 31
- Issue
- 9
- Pages
- 1885-1893
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3133228
- OpenAlex
- W2110543371
- Cited by
- 77
- References
- 2
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 2 · 2015: 8 · 2014: 12 · 2013: 8 · 2012: 9
- FWCI
- 10.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Università degli Studi di Milano
- National Institutes of Health (HL090553, DK-063491, HL030568)
- National Heart, Lung, and Blood Institute (HL030568, P01HL090553, HL066088, P01HL030568, HL090553, R01HL066088)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, P30DK063491)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- idols, LDL receptor, liver X receptor agonist, oxysterols, sterol metabolism, LDL uptake, protein degradation, ubiquitination, statins, PCSK9, cholesterol absorption, SREBP pathway, mouse embryonic stem cells
- MeSH terms
- Proprotein Convertase 9, Liver X Receptors, Animals, Cells, Cultured, Lipoproteins, LDL, Liver, Mice, Inbred C57BL, Mutation, Receptors, LDL, Serine Endopeptidases, Sterols, Gene Expression, Proprotein Convertases, Ubiquitin-Protein Ligases, Mice, Embryonic Stem Cells, Gene Knockout Techniques, Orphan Nuclear Receptors
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