LXR Regulates Cholesterol Uptake through Idol-dependent Ubiquitination of the LDL Receptor

By N. Zelcer, Cynthia Hong, Rima Boyadjian, P. Tontonoz. Science, 2009

871 citations recorded by the source corpus.

Idolizing Cholesterol Control The low-density lipoprotein receptor (LDLR) removes LDL, the so-called “bad” cholesterol particles, from the blood through a mechanism that involves LDL binding and internalization into liver cells. Because the LDLR plays a pivotal role in heart disease risk, there is substantial interest in understanding how its expression is regulated, and a large body of previous work has established the importance of transcriptional control. A new study identifies a signaling pathway that appears to regulate the LDLR at the level of protein degradation. Zelcer et al. (p. 100, published online 11 June) show that a sterol-responsive transcription factor called LXR induces the expression of Idol (for inducible degrader of the LDLR), a protein that triggers ubiquitination of the receptor and targets it for degradation. Activation of this pathway suppresses cellular uptake of LDL and, in a mouse model, leads to higher plasma LDL levels, raising the possibility that the pathway could be targeted pharmacologically to control plasma cholesterol levels. Cholesterol metabolism is regulated by a signaling pathway that targets the LDL receptor for degradation. 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.

Subfields: Cancer Research, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/da519f1e860f692caea766ce56edc6488a186934

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Citations in the corpus

Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality. (2015, background): “In human ER -negative breast cancer cells (MDA-MB-231) and prostate cancer cell lines however, this downregulation of the LDLR does not occur, and no increase in cholesterol efflux gene transcription occurs, resulting in increased intracellular cholesterol (8, 209).”
Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility (2010, background): “MYLIP (Idol) is a ligase involved in the ubiquitination and degradation of LDL receptors [44,45] and SCD is a stearoyl-CoA desaturase involved in the conversion of saturated into monounsaturated fatty acids that regulates lipid metabolism and may be modulated by dietary intake [46].”
Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR (2012, background): “LXR controls the transcription of inducible degrader of LDLR (IDOL), an E3 ligase that targets LDLR for ubiquitylation and lysosomal degradatio”