LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor

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...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) Vol. 325; no. 5936; p. 100
Main Authors: Zelcer, Noam, Hong, Cynthia, Boyadjian, Rima, Tontonoz, Peter
Format: Journal Article
Language:English
Published: United States 03.07.2009
Subjects:
Animals
Cell Line, Tumor
Cholesterol - metabolism
DNA-Binding Proteins - agonists
DNA-Binding Proteins - metabolism
Homeostasis
Humans
Ligands
Lipoproteins, LDL - blood
Lipoproteins, LDL - metabolism
Liver - metabolism
Liver X Receptors
Mice
Mice, Inbred C57BL
Orphan Nuclear Receptors
Promoter Regions, Genetic
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - metabolism
Receptors, LDL - genetics
Receptors, LDL - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Transcription, Genetic
Ubiquitin-Protein Ligases
Ubiquitination
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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Summary: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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ISSN:1095-9203
1095-9203
DOI:10.1126/science.1168974