The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells. Next to the LDLR, IDOL also promotes degradation of two related receptors, the very LDL receptor (VLDLR) and apolipoprotein E receptor 2 (APOER2), which have important signaling functions in the brain. We review here the emerging role of IDOL in lipoprotein and energy metabolism, neurodegenerative diseases, and the potential for therapeutic targeting of IDOL.
Genetic studies suggest an association between IDOL and lipoprotein metabolism in humans. Studies in rodents and nonhuman primates support an in-vivo role for IDOL in lipoprotein metabolism, and also uncovered an unexpected role in whole-body energy metabolism. Recent evaluation of IDOL function in the brain revealed a role in memory formation and progression of Alzheimer's disease. The report of the first IDOL inhibitor may facilitate further investigations on therapeutic strategies to target IDOL.
IDOL is emerging as an important determinant of lipid and energy metabolism in metabolic disease as well as in Alzheimer's disease. IDOL targeting may be beneficial in treating these conditions.
aDepartment of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
bMedicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki
cMinerva Foundation Institute for Medical Research, Biomedicum-2, Helsinki, Finland
Correspondence to Noam Zelcer, PhD, Department of Medical Biochemistry, K1-260, Academic Medical Center of the University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands. Tel: +31 20 5665131; e-mail: email@example.com