The focus of the LDL receptor project is to characterize the mechanisms by which the LDL receptor mediates lipoprotein uptake. The LDL receptor is responsible for the clearance of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) from the circulation. LDL and VLDL are the principal serum transporters for cholesterol and fatty acids, respectively. Elevated levels of LDL (hypercholesterolemia) or VLDL (hypertriglyceridemia) result in atherosclerosis and coronary heart disease. Drugs such as statins that increase LDL receptor expression are widely used to reduce LDL and VLDL and thereby protect against atherosclerosis.

Our laboratory has shown that the LDL receptor can distinguish between LDL and VLDL and can operate as a VLDL-only endocytic receptor or as an LDL/VLDL endocytic receptor. For the dual specificity mode, the LDL receptor requires an adaptor protein, either ARH or Dab2. These adaptor proteins bind to the LDL receptor and to clathrin and AP2, two components of the endocytic machinery of clathrin-coated pits. ARH and Dab2 promote targeting of LDL receptors to coated pits thereby facilitating the internalization of LDL. In the absence of either adaptor or in the presence of a mutation in the LDL receptor that prevents ARH and Dab2 binding, the LDL receptor fails to support LDL uptake because the receptor is not constitutively targeted to coated pits. Unlike LDL, VLDL binding to the LDL receptor can drive the receptor-VLDL complex into coated pits where the VLDL-LDL receptor complex is internalized. This VLDL induced internalization process is independent of ARH and Dab2 but still requires clathrin coated pits.

Our current research is examining the mechanism by which VLDL drives LDL receptors into coated pits and the role of ARH in the dual endocytic mode of LDL receptor endocytosis. The characterization of these mechanisms may facilitate novel therapeutic approaches for the treatment of coronary heart disease.