Scratching the surface: Regulation of cell surface receptors in cholesterol metabolism

Elevated plasma levels of low density lipoprotein cholesterol (LDL) are an established risk factor for the development of atherosclerosis and cardiovascular diseases. The LDL-Receptor is a key determinant in regulating LDL levels in plasma, and current lipid-lowering strategies aim to increase its cell surface expression. My PhD research has largely focused on the characterization of novel post-translational regulators of the LDL-Receptor. Mainly, I studied the Liver X Receptor (LXR) responsive E3 ubiquitin ligase, the Inducible Degrader of the LDL-Receptor (IDOL), which negatively regulates the LDL-Receptor and attenuates LDL uptake into cells. Through genetic, molecular and biochemical characterization, we identified novel mechanisms and components that regulate IDOL-mediated degradation of the LDL-Receptor. Specifically, I was involved in investigating the endocytic trafficking route of this degradation pathway, identifying a deubiquitlyase (DUB) that attenuates IDOL activity, describing a novel transcriptional regulatory mechanism, as well as characterizing a rare IDOL variant in individuals with low circulating LDL-cholesterol levels. These findings suggest that IDOL inhibition would be beneficial for developing new lipid lowering strategies, and thus, have laid the foundation for ongoing research aimed at solving the structure of IDOL as well as characterizing its physiological impact in vivo. Collectively, my research resulted in the publication of 7 articles in peer-reviewed journals and 2 articles currently in submission.