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

TLDR

The low‑density lipoprotein receptor (LDLR) clears LDL cholesterol from the bloodstream, and its transcriptional regulation is a key factor in cardiovascular disease risk. The study investigates a signaling pathway that regulates LDLR via protein degradation. LXR activation induces Idol, which ubiquitinates LDLR, reducing LDL uptake and raising plasma LDL levels in mice, suggesting a pharmacological target for cholesterol control. Zelcer et al.

Abstract

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.