The mechanisms of scavenger receptor (SR)-BI-mediated lipid uptake from high density lipoprotein

2001

Stephen T. Thuahnai, Sissel Lund-Katz, Michael C. Phillips

Abstract

Scavenger receptor class B, type I (SR-BI) is the first molecularly defined receptor for high density lipoprotein (HDL). Cholesteryl esters from HDL enter cells in a selective manner without whole particle uptake. The mechanism of this selective uptake pathway remained largely unknown until the discovery of SR-BI. Lipid uptake via SR-BI involves two steps. The first step is the binding of the lipid donor particle to SR-BI and the second step is the movement of lipids from the SR-BI-bound lipid donor particle to the cell. In this dissertation, the molecular mechanisms of SR-BI-mediated HDL lipid uptake were examined. There were three specific aims in the project: Aim 1 examined the binding of various components of HDL to the receptor; Aim 2 compared the selectivity of the receptor for various HDL lipids: and Aim 3 focused on the consequence of lipid uptake from apolipoprotein-free lipid donor particles. The results show that the binding of a lipid donor particle to SR-BI and the movement of lipid into cells are linked processes. Quantitative comparison of various HDL components show that binding to the receptor can be mediated either by the lipid or protein component of the lipoprotein. Examination of binding using apolipoprotein A-I peptides and synthetic peptides show that a recognition motif on HDL is the amphipathic [alpha]-helix in apolipoproteins. Selective transfer of lipid from the SR-BI-bound lipid donor particle requires these amphipathic [alpha]-helices. If the binding to the receptor is mediated by an apolipoprotein-free lipid donor particle (e.g. phospholipid unilamellar vesicles, lipid emulsion), then the lipid movement into the cells via SR-BI is stoichiometric (i.e. non-selective transfer occurs), consistent with fusion of the lipid donor particle with the cell membrane. A low activation energy for CE selective uptake from the SR-BI-bound HDL to the cell membrane suggests that a non-aqueous channel is involved in this process. The putative hydrophobic channel created by SR-BI is able to accommodate the movement of all the major HDL lipids into cells with the relative rates of uptake of lipids being in the order cholesterol > cholesterol esters > triglycerides > phospholipids. Overall, these results provide new insights into the molecular mechanism of the last stage of the reverse cholesterol transport pathway, by which HDL returns cholesterol from the periphery to the liver.

Abstract

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