Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 325 (5936): 100-104

Copyright © 2009 by the American Association for the Advancement of Science

LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor

Noam Zelcer,* Cynthia Hong, Rima Boyadjian, Peter Tontonoz{dagger}

Abstract: 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.

Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.

* Present address: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300RA Leiden, Netherlands.

{dagger} To whom correspondence should be addressed. E-mail: ptontonoz{at}mednet.ucla.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-{gamma}-Induced Inflammatory Responses and LXR-Dependent Gene Expression.
M. Pascual-Garcia, L. Rue, T. Leon, J. Julve, J. M. Carbo, J. Matalonga, H. Auer, A. Celada, J. C. Escola-Gil, K. R. Steffensen, et al. (2013)
J. Immunol. 190, 6520-6532
   Abstract »    Full Text »    PDF »
Control of Cholesterol Metabolism and Plasma High-Density Lipoprotein Levels by microRNA-144.
C. M. Ramirez, N. Rotllan, A. V. Vlassov, A. Davalos, M. Li, L. Goedeke, J. F. Aranda, D. Cirera-Salinas, E. Araldi, A. Salerno, et al. (2013)
Circ. Res. 112, 1592-1601
   Abstract »    Full Text »    PDF »
Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice.
K. S. Bura, C. Lord, S. Marshall, A. McDaniel, G. Thomas, M. Warrier, J. Zhang, M. A. Davis, J. K. Sawyer, R. Shah, et al. (2013)
J. Lipid Res. 54, 1567-1577
   Abstract »    Full Text »    PDF »
S-nitrosylation of ARH is required for LDL uptake by the LDL receptor.
Z. Zhao, S. Pompey, H. Dong, J. Weng, R. Garuti, and P. Michaely (2013)
J. Lipid Res. 54, 1550-1559
   Abstract »    Full Text »    PDF »
PCSK9-mediated degradation of the LDL receptor generates a 17 kDa C-terminal LDL receptor fragment.
K. Tveten, T. B. Strom, K. E. Berge, and T. P. Leren (2013)
J. Lipid Res. 54, 1560-1566
   Abstract »    Full Text »    PDF »
Both K63 and K48 ubiquitin linkages signal lysosomal degradation of the LDL receptor.
L. Zhang, M. Xu, E. Scotti, Z. J. Chen, and P. Tontonoz (2013)
J. Lipid Res. 54, 1410-1420
   Abstract »    Full Text »    PDF »
Identification of a loss-of-function inducible degrader of the low-density lipoprotein receptor variant in individuals with low circulating low-density lipoprotein.
V. Sorrentino, S. W. Fouchier, M. M. Motazacker, J. K. Nelson, J. C. Defesche, G. M. Dallinga-Thie, J. J. P. Kastelein, G. Kees Hovingh, and N. Zelcer (2013)
Eur. Heart J. 34, 1292-1297
   Abstract »    Full Text »    PDF »
IDOL Stimulates Clathrin-Independent Endocytosis and Multivesicular Body-Mediated Lysosomal Degradation of the Low-Density Lipoprotein Receptor.
E. Scotti, M. Calamai, C. N. Goulbourne, L. Zhang, C. Hong, R. R. Lin, J. Choi, P. F. Pilch, L. G. Fong, P. Zou, et al. (2013)
Mol. Cell. Biol. 33, 1503-1514
   Abstract »    Full Text »    PDF »
Quantitative fluorescence imaging reveals point of release for lipoproteins during LDLR-dependent uptake.
S. Pompey, Z. Zhao, K. Luby-Phelps, and P. Michaely (2013)
J. Lipid Res. 54, 744-753
   Abstract »    Full Text »    PDF »
High-Throughput Screening of Small Molecules Identifies Hepcidin Antagonists.
E. Fung, P. Sugianto, J. Hsu, R. Damoiseaux, T. Ganz, and E. Nemeth (2013)
Mol. Pharmacol. 83, 681-690
   Abstract »    Full Text »    PDF »
The Expression of Cholesterol Metabolism Genes in Monocytes From HIV-Infected Subjects Suggests Intracellular Cholesterol Accumulation.
E. R. Feeney, N. McAuley, J. A. O'Halloran, C. Rock, J. Low, C. S. Satchell, J. S. Lambert, G. J. Sheehan, and P. W. G. Mallon (2013)
The Journal of Infectious Disease 207, 628-637
   Abstract »    Full Text »    PDF »
Adrenal-Specific Scavenger Receptor BI Deficiency Induces Glucocorticoid Insufficiency and Lowers Plasma Very-Low-Density and Low-Density Lipoprotein Levels in Mice.
M. Hoekstra, R. J. van der Sluis, M. Van Eck, and T. J. C. Van Berkel (2013)
Arterioscler Thromb Vasc Biol 33, e39-e46
   Abstract »    Full Text »    PDF »
Caenorhabditis elegans reveals a FxNPxY-independent low-density lipoprotein receptor internalization mechanism mediated by epsin1.
Y.-L. Kang, J. Yochem, L. Bell, E. B. Sorensen, L. Chen, and S. D. Conner (2013)
Mol. Biol. Cell 24, 308-318
   Abstract »    Full Text »    PDF »
Modulation of Cholesterol Transport by Insulin-Treated Gestational Diabetes Mellitus in Human Full-Term Placenta.
E. Dube, M. Ethier-Chiasson, and J. Lafond (2013)
Biol Reprod 88, 16
   Abstract »    Full Text »    PDF »
SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion.
X.-W. Chen, H. Wang, K. Bajaj, P. Zhang, Z.-X. Meng, D. Ma, Y. Bai, H.-H. Liu, E. Adams, A. Baines, et al. (2013)
eLife Sci 2, e00444
   Abstract »    Full Text »    PDF »
Liver X receptor agonists decrease ENaC-mediated sodium transport in collecting duct cells.
S. Soodvilai, Z. Jia, S. Fongsupa, V. Chatsudthipong, and T. Yang (2012)
Am J Physiol Renal Physiol 303, F1610-F1616
   Abstract »    Full Text »    PDF »
Feedback Regulation of Cholesterol Uptake by the LXR-IDOL-LDLR Axis.
L. Zhang, K. Reue, L. G. Fong, S. G. Young, and P. Tontonoz (2012)
Arterioscler Thromb Vasc Biol 32, 2541-2546
   Abstract »    Full Text »    PDF »
Lipid Metabolism and Neuroinflammation in Alzheimer's Disease: A Role for Liver X Receptors.
J. Kang and S. Rivest (2012)
Endocr. Rev. 33, 715-746
   Abstract »    Full Text »    PDF »
Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR.
Y. Wang, Y. Huang, H. H. Hobbs, and J. C. Cohen (2012)
J. Lipid Res. 53, 1932-1943
   Abstract »    Full Text »    PDF »
Liver X Receptor Activation Reduces Angiogenesis by Impairing Lipid Raft Localization and Signaling of Vascular Endothelial Growth Factor Receptor-2.
A. Noghero, A. Perino, G. Seano, E. Saglio, G. L. Sasso, F. Veglio, L. Primo, E. Hirsch, F. Bussolino, and F. Morello (2012)
Arterioscler Thromb Vasc Biol 32, 2280-2288
   Abstract »    Full Text »    PDF »
Blockade of cholesterol absorption by ezetimibe reveals a complex homeostatic network in enterocytes.
L. J. Engelking, M. R. McFarlane, C. K. Li, and G. Liang (2012)
J. Lipid Res. 53, 1359-1368
   Abstract »    Full Text »    PDF »
The Oxysterol 24(S),25-Epoxycholesterol Attenuates Human Smooth Muscle-Derived Foam Cell Formation Via Reduced Low-Density Lipoprotein Uptake and Enhanced Cholesterol Efflux.
M. M. Beyea, S. Reaume, C. G. Sawyez, J. Y. Edwards, C. O'Neil, R. A. Hegele, J. G. Pickering, and M. W. Huff (2012)
JAHA 1, e000810
   Abstract »    Full Text »    PDF »
Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia.
M. M. Motazacker, J. Pirruccello, R. Huijgen, R. Do, S. Gabriel, J. Peter, J. A. Kuivenhoven, J. C. Defesche, J. J. P. Kastelein, G. K. Hovingh, et al. (2012)
Eur. Heart J. 33, 1360-1366
   Abstract »    Full Text »    PDF »
Fibroblast Growth Factor-21 (FGF21) Regulates Low-density Lipoprotein Receptor (LDLR) Levels in Cells via the E3-ubiquitin Ligase Mylip/Idol and the Canopy2 (Cnpy2)/Mylip-interacting Saposin-like Protein (Msap).
H. T. Do, T. V. Tselykh, J. Makela, T. H. Ho, V. M. Olkkonen, B. C. Bornhauser, L. Korhonen, N. Zelcer, and D. Lindholm (2012)
J. Biol. Chem. 287, 12602-12611
   Abstract »    Full Text »    PDF »
Nuclear Hormone Receptors Enable Macrophages and Dendritic Cells to Sense Their Lipid Environment and Shape Their Immune Response.
L. Nagy, A. Szanto, I. Szatmari, and L. Szeles (2012)
Physiol Rev 92, 739-789
   Abstract »    Full Text »    PDF »
Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial.
D. I. Chasman, F. Giulianini, J. MacFadyen, B. J. Barratt, F. Nyberg, and P. M. Ridker (2012)
Circ Cardiovasc Genet 5, 257-264
   Abstract »    Full Text »    PDF »
Liver X Receptor Modulation of Gene Expression Leading to Proluteolytic Effects in Primate Luteal Cells.
R. L. Bogan, A. E. DeBarber, and J. D. Hennebold (2012)
Biol Reprod 86, 89
   Abstract »    Full Text »    PDF »
Heritability of submaximal exercise heart rate response to exercise training is accounted for by nine SNPs.
T. Rankinen, Y. J. Sung, M. A. Sarzynski, T. K. Rice, D. C. Rao, and C. Bouchard (2012)
J Appl Physiol 112, 892-897
   Abstract »    Full Text »    PDF »
FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors.
A. C. Calkin, B. T. Goult, L. Zhang, L. Fairall, C. Hong, J. W. R. Schwabe, and P. Tontonoz (2011)
PNAS 108, 20107-20112
   Abstract »    Full Text »    PDF »
Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk.
S. Calandra, P. Tarugi, H. E. Speedy, A. F. Dean, S. Bertolini, and C. C. Shoulders (2011)
J. Lipid Res. 52, 1885-1926
   Abstract »    Full Text »    PDF »
An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR-Dependent Pathway.
D. Guo, F. Reinitz, M. Youssef, C. Hong, D. Nathanson, D. Akhavan, D. Kuga, A. N. Amzajerdi, H. Soto, S. Zhu, et al. (2011)
Cancer Discovery 1, 442-456
   Abstract »    Full Text »    PDF »
Lysosomal Acid Lipase Deficiency Impairs Regulation of ABCA1 Gene and Formation of High Density Lipoproteins in Cholesteryl Ester Storage Disease.
K. L. Bowden, N. J. Bilbey, L. M. Bilawchuk, E. Boadu, R. Sidhu, D. S. Ory, H. Du, T. Chan, and G. A. Francis (2011)
J. Biol. Chem. 286, 30624-30635
   Abstract »    Full Text »    PDF »
Distinct Functional Domains Contribute to Degradation of the Low Density Lipoprotein Receptor (LDLR) by the E3 Ubiquitin Ligase Inducible Degrader of the LDLR (IDOL).
V. Sorrentino, L. Scheer, A. Santos, E. Reits, B. Bleijlevens, and N. Zelcer (2011)
J. Biol. Chem. 286, 30190-30199
   Abstract »    Full Text »    PDF »
The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor.
L. Zhang, L. Fairall, B. T. Goult, A. C. Calkin, C. Hong, C. J. Millard, P. Tontonoz, and J. W. R. Schwabe (2011)
Genes & Dev. 25, 1262-1274
   Abstract »    Full Text »    PDF »
Cross-talk between the Androgen Receptor and the Liver X Receptor: IMPLICATIONS FOR CHOLESTEROL HOMEOSTASIS.
J. R. Krycer and A. J. Brown (2011)
J. Biol. Chem. 286, 20637-20647
   Abstract »    Full Text »    PDF »
Targeted Disruption of the Idol Gene Alters Cellular Regulation of the Low-Density Lipoprotein Receptor by Sterols and Liver X Receptor Agonists.
E. Scotti, C. Hong, Y. Yoshinaga, Y. Tu, Y. Hu, N. Zelcer, R. Boyadjian, P. J. de Jong, S. G. Young, L. G. Fong, et al. (2011)
Mol. Cell. Biol. 31, 1885-1893
   Abstract »    Full Text »    PDF »
Research Resource: Nuclear Receptor Atlas of Human Retinal Pigment Epithelial Cells: Potential Relevance to Age-Related Macular Degeneration.
M. A. Dwyer, D. Kazmin, P. Hu, D. P. McDonnell, and G. Malek (2011)
Mol. Endocrinol. 25, 360-372
   Abstract »    Full Text »    PDF »
Transcriptional and Posttranscriptional Control of Cholesterol Homeostasis by Liver X Receptors.
P. Tontonoz (2011)
Cold Spring Harb Symp Quant Biol 76, 129-137
   Abstract »    Full Text »    PDF »
Binding Preferences for GPIHBP1, a Glycosylphosphatidylinositol-Anchored Protein of Capillary Endothelial Cells.
P. Gin, A. P. Beigneux, C. Voss, B. S. J. Davies, J. A. Beckstead, R. O. Ryan, A. Bensadoun, L. G. Fong, and S. G. Young (2011)
Arterioscler Thromb Vasc Biol 31, 176-182
   Abstract »    Full Text »    PDF »
Commentary: The Year in Nuclear Receptor Control of Metabolism.
D. J. Mangelsdorf (2010)
Mol. Endocrinol. 24, 2075-2080
   Abstract »    Full Text »    PDF »
Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease.
D. M. Waterworth, S. L. Ricketts, K. Song, L. Chen, J. H. Zhao, S. Ripatti, Y. S. Aulchenko, W. Zhang, X. Yuan, N. Lim, et al. (2010)
Arterioscler Thromb Vasc Biol 30, 2264-2276
   Abstract »    Full Text »    PDF »
Genome-Wide Association Studies Identify New Targets in Cardiovascular Disease.
A. C. Calkin and P. Tontonoz (2010)
Science Translational Medicine 2, 48ps46
   Full Text »    PDF »
Reduced VLDL clearance in Apoe-/-Npc1-/- mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels.
M. Ishibashi, D. Masson, M. Westerterp, N. Wang, S. Sayers, R. Li, C. L. Welch, and A. R. Tall (2010)
J. Lipid Res. 51, 2655-2663
   Abstract »    Full Text »    PDF »
PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain.
M. Liu, G. Wu, J. Baysarowich, M. Kavana, G. H. Addona, K. K. Bierilo, J. S. Mudgett, G. Pavlovic, A. Sitlani, J. J. Renger, et al. (2010)
J. Lipid Res. 51, 2611-2618
   Abstract »    Full Text »    PDF »
Mitotic Down-regulation of p190RhoGAP Is Required for the Successful Completion of Cytokinesis.
S. A. S. Manchinelly, J. A. Miller, L. Su, T. Miyake, L. Palmer, M. Mikawa, and S. J. Parsons (2010)
J. Biol. Chem. 285, 26923-26932
   Abstract »    Full Text »    PDF »
Liver X Receptor Signaling Pathways and Atherosclerosis.
A. C. Calkin and P. Tontonoz (2010)
Arterioscler Thromb Vasc Biol 30, 1513-1518
   Abstract »    Full Text »    PDF »
miR-33 links SREBP-2 induction to repression of sterol transporters.
T. J. Marquart, R. M. Allen, D. S. Ory, and A. Baldan (2010)
PNAS 107, 12228-12232
   Abstract »    Full Text »    PDF »
Meeting Report: Nuclear Receptors: Transcription Factors and Drug Targets Connecting Basic Research with Translational Medicine.
J. Tuckermann, W. Bourguet, and S. Mandrup (2010)
Mol. Endocrinol. 24, 1311-1321
   Abstract »    Full Text »    PDF »
The E3 Ubiquitin Ligase IDOL Induces the Degradation of the Low Density Lipoprotein Receptor Family Members VLDLR and ApoER2.
C. Hong, S. Duit, P. Jalonen, R. Out, L. Scheer, V. Sorrentino, R. Boyadjian, K. W. Rodenburg, E. Foley, L. Korhonen, et al. (2010)
J. Biol. Chem. 285, 19720-19726
   Abstract »    Full Text »    PDF »
Chronic social defeat stress disrupts regulation of lipid synthesis.
J. C. Chuang, H. Cui, B. L. Mason, M. Mahgoub, A. L. Bookout, H. G. Yu, M. Perello, J. K. Elmquist, J. J. Repa, J. M. Zigman, et al. (2010)
J. Lipid Res. 51, 1344-1353
   Abstract »    Full Text »    PDF »
Liver X receptor activation promotes macrophage-to-feces reverse cholesterol transport in a dyslipidemic hamster model.
F. Briand, M. Treguier, A. Andre, D. Grillot, M. Issandou, K. Ouguerram, and T. Sulpice (2010)
J. Lipid Res. 51, 763-770
   Abstract »    Full Text »    PDF »
Liver X receptor in cholesterol metabolism.
C. Zhao and K. Dahlman-Wright (2010)
J. Endocrinol. 204, 233-240
   Abstract »    Full Text »    PDF »
Sent to Destroy: The Ubiquitin Proteasome System Regulates Cell Signaling and Protein Quality Control in Cardiovascular Development and Disease.
M. S. Willis, W. H. D. Townley-Tilson, E. Y. Kang, J. W. Homeister, and C. Patterson (2010)
Circ. Res. 106, 463-478
   Abstract »    Full Text »    PDF »
Nuclear Receptor DHR96 Acts as a Sentinel for Low Cholesterol Concentrations in Drosophila melanogaster.
M. Bujold, A. Gopalakrishnan, E. Nally, and K. King-Jones (2010)
Mol. Cell. Biol. 30, 793-805
   Abstract »    Full Text »    PDF »
Cholesterol Worships a New Idol.
I. G. Schulman (2009)
J Mol Cell Biol 1, 75-76
   Abstract »    Full Text »    PDF »
New Idol for Cholesterol Reduction?.
T. Sawamura (2009)
Clin. Chem. 55, 2082-2084
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882