Abstract
Low-density lipoprotein (LDL) internalization, degradation, and receptor recycling is a fundamental process underlying hypercholesterolemia, a high blood cholesterol concentration, affecting more than 40% of the western population. Membrane contact sites influence endosomal dynamics, plasma membrane lipid composition, and cellular cholesterol distribution. However, if we focus on LDL-related trafficking events we mostly discuss them in an isolated fashion, without cellular context. It is our goal to change this perspective and to highlight that all steps from LDL internalization to receptor recycling are likely associated with dynamic membrane contact sites in which endosomes engage with the endoplasmic reticulum and other organelles.
Highlights
Lipoproteins are transport shuttles in the circulation, delivering cholesterol to different destinations
We focus on how cells take up low-density lipoprotein (LDL) in a regulated process mediated by the LDL receptor (LDLR)
LDLR can join the path to degradation when it does not dissociate from LDL (Davis et al, 1987) or when it is targeted by proprotein convertase
Summary
Lipoproteins are transport shuttles in the circulation, delivering cholesterol to different destinations. Genetic defects in LDLR and proteins associated with LDLR trafficking predispose to a greater CVD risk, even when compared to individuals with similar blood cholesterol levels (Trinder et al, 2020). This is due to life-long exposure to elevated LDL levels or longer residence time of LDL particles in the bloodstream. LDL binds to LDLR on the cell surface and is internalized via clathrin-mediated endocytosis (Brown and Goldstein, 1979). LDLR can join the path to degradation when it does not dissociate from LDL (Davis et al, 1987) or when it is targeted by proprotein convertase
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