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PMID:19520913

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Citation

Zelcer, N, Hong, C, Boyadjian, R and Tontonoz, P (2009) LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325:100-4

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.

Links

PubMed PMC2777523 Online version:10.1126/science.1168974

Keywords

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; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Promoter Regions, Genetic; RNA, Messenger/genetics; RNA, Messenger/metabolism; Receptors, Cytoplasmic and Nuclear/agonists; Receptors, Cytoplasmic and Nuclear/metabolism; Receptors, LDL/genetics; Receptors, LDL/metabolism; Transcription, Genetic; Ubiquitin-Protein Ligases; Ubiquitination

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MYLIP

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

  • has_input:(MGI:MGI:96765)

Seeded From UniProt

complete

MOUSE:MYLIP

involved_in

GO:0032803: regulation of low-density lipoprotein particle receptor catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MYLIP

involved_in

GO:0031648: protein destabilization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MYLIP

involved_in

GO:0010989: negative regulation of low-density lipoprotein particle clearance

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MYLIP

involved_in

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MYLIP

involved_in

GO:0071404: cellular response to low-density lipoprotein particle stimulus

ECO:0000305: curator inference used in manual assertion

GO:0032803

P

Seeded From UniProt

complete

MOUSE:MYLIP

involved_in

GO:0045732: positive regulation of protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MYLIP

involved_in

GO:0042632: cholesterol homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MYLIP

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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