New Drug Target for Regulating Cholesterol Metabolism Identified

Researchers studying cholesterol metabolism have identified a mechanism that controls the amount of low-density lipoprotein (LDL) "bad” cholesterol by regulating the number of LDL cell membrane receptors (LDLR).

LDLR is a mosaic protein that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes apolipoprotein B100, which is embedded in the phospholipid outer layer of LDL particles. The receptor also recognizes the apolipoprotein E (apo E) protein found in chylomicron remnants and VLDL remnants.

Investigators from the University of California, Los Angeles (USA) used advanced genetic engineering techniques to study the role of the sterol-responsive nuclear liver X receptor (LXR) in LDL and cholesterol metabolism. They reported in the June 11, 2009, online edition of the journal Science that LXR exerted a modulating effect on LDL metabolism 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.

The investigators genetically engineered a line of mice lacking the gene for Idol (Idol knockdown mice). The liver cells of these mice displayed increased LDLR protein levels, which promoted LDL uptake and reduced the level of circulating LDL. This result implies that a drug that would impede Idol function may be able to help control LDL levels in humans.

"We only know of three pathways that regulate the LDL receptor. The first two are already targeted by existing drugs,” explained senior author Dr. Peter Tontonoz, professor of pathology and laboratory medicine at the University of California, Los Angeles. "Idol is the first mechanism discovered in several years that may lead to a new medication designed to control cholesterol levels.”

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