Abstract
Scavenger receptor BI (SR-BI) mediates the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE), a process by which HDL CE is taken into the cell without internalization and degradation of the HDL particle. The biochemical mechanism by which SR-BI mediates the selective uptake of HDL CE is poorly understood. Given that CE transfer will occur to some extent from HDL to protein-free synthetic membranes, one hypothesis is that the role of SR-BI is primarily to tether HDL close to the cell surface to facilitate CE transfer from the particle to the plasma membrane. In the present study, this hypothesis was tested by comparing the selective uptake of HDL CE mediated by mouse SR-BI (mSR-BI) with that mediated by rat CD36 (rCD36), a closely related class B scavenger receptor. Both mSR-BI and rCD36 bind HDL with high affinity, and both receptors mediate HDL CE selective uptake. However, SR-BI mediates selective uptake of HDL CE with a 7-fold greater efficiency than rCD36. HDL CE selective uptake mediated by rCD36 is dependent on HDL binding to the receptor, since a mutation that blocks HDL binding also blocks HDL CE selective uptake. These data lead us to hypothesize that one component of HDL CE selective uptake is the tethering of HDL particles to the cell surface. To explore the molecular domains responsible for the greater efficiency of selective uptake by mSR-BI, we compared binding and selective uptake among mSR-BI, scavenger receptor BII, and various chimeric receptors formed from mSR-BI and rCD36. The results show that the extracellular domain of mSR-BI is essential for efficient HDL CE uptake, but the C-terminal cytoplasmic tail also has a major influence on the selective uptake process.
Highlights
From the Departments of ‡Pharmacological Sciences and ¶Physiology and Biophysics, University Medical Center, State University at Stony Brook, Stony Brook, New York, 11794-8651 and §Geriatric Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304
Despite extensive studies of the high density lipoprotein (HDL) CE selective uptake process over the past 18 years, the molecular mechanism by which hydrophobic cholesteryl esters are transferred from the HDL particle to the plasma membrane has remained elusive
We have examined the mechanism of mouse SR-BI (mSR-BI)-mediated HDL CE selective uptake by comparing mSR-BI with the closely related class B scavenger receptor, rat CD36 (rCD36), and with chimeric receptors formed from mSR-BI and rCD36
Summary
Vol 274, No 1, Issue of January 1, pp. 41–47, 1999 Printed in U.S.A. Comparison of Class B Scavenger Receptors, CD36 and Scavenger Receptor BI (SR-BI), Shows That Both Receptors Mediate High Density Lipoprotein-Cholesteryl Ester Selective Uptake but SR-BI Exhibits a Unique Enhancement of Cholesteryl Ester Uptake*. This hypothesis was tested by comparing the selective uptake of HDL CE mediated by mouse SR-BI (mSR-BI) with that mediated by rat CD36 (rCD36), a closely related class B scavenger receptor. Inactivation of the SR-BI gene in mice alters plasma HDL metabolism and reduces adrenal gland CE accumulation, results consistent with a major role for SR-BI in cholesterol metabolism in vivo [13] Taken together, these studies indicate that SR-BI is a physiologically relevant receptor for the selective uptake of HDL CE. Comparison of SR-BI, SR-BII, CD36, and chimeric receptors showed that the extracellular domain of mSR-BI is essential for efficient HDL CE uptake, but the C-terminal cytoplasmic tail has a major influence on the selective uptake process
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