While HDL protects against atherosclerosis due to its role in reducing oxidative damage, preventing inflammation and promoting endothelial function, our lab is very interested in the role that HDL plays in reverse cholesterol transport and whole body cholesterol disposal.

Scavenger receptor class B type I (SR-BI), the most physiologically relevant HDL receptor, is highly expressed in the liver and plays a key role in mediating the delivery of HDL-C to the liver for excretion. This process termed “selective uptake” requires two steps: (i) HDL must bind to the extracellular domain of SR-BI and (ii) lipid alone is transferred from HDL to the plasma membrane, without holoparticle uptake. Genetic mouse models demonstrate that SR-BI protects against atherosclerosis. Further, the recent discovery of SR-BI mutations in patients with high HDL-C levels strongly supports a critical role of SR-BI in facilitating the flux of cholesterol out of the body.

In order to develop novel therapeutic strategies that treat hypercholesterolemia and its associated pathologies such as atherosclerosis, it is critical that we understand the mechanisms that regulate receptor-ligand interactions at the end of reverse cholesterol transport. A better understanding of the interaction between SR-BI and HDL will allow us to gain novel insight into mechanisms that facilitate the efficient clearance of HDL-C via SR-BI-mediated selective uptake of HDL lipids.

To accomplish these goals, our laboratory is currently studying the following:

• The molecular architecture of the extracellular domain of SR-BI (using novel fluorescence strategies and other biochemical techniques);
• The oligomeric properties of SR-BI;
• The mechanisms of HDL-CE delivery and hydrolysis at the plasma membrane
• The impact of modified HDL on selective uptake of HDL lipids.