Regulation of cholesterol metabolism: An IDOL-dependent pathway to degrade the LDL-receptor

The central theme of this thesis is the functional and molecular characterization of the LXR-IDOL-LDLR nexus, a novel post-translational regulative pathway of the LDL receptor, complementary to the SREBP-driven transcriptional control of LDLR for sterol regulation of LDL uptake in the cell. In addition to this, genetic evidence is included in support of a possible physiological role of the E3-ubiquitin ligase IDOL in regulating whole-body cholesterol homeostasis, and the identification of USP2 and the ESCRT as new modulators of this pathway is described. E3-ubiquitin ligases are the most numerous members of the Ubiquitin-Proteasome System, and due to their exquisite substrate specificity, object of investigation for highly specific drug design. In view of IDOLʼs unique role in controlling the LDLR pathway via its E3-ubiquitin ligase activity, the mechanistic understanding of IDOL function and regulation illustrated in this thesis supports the concept that inhibition of IDOL could be used to integrate the current statin-based treatment of hypercholesterolemia.