Cholesteryl Esters in Lipoproteins Can Be Selectively Taken Up by the Receptor SRBI

Findings from studies of HDL metabolism led to the discovery of a second, distinct mechanism of receptor-facilitated uptake of lipoprotein lipids. In these studies, experimental animals were injected with purified HDL particles in which the apolipoproteins were labeled with 125I and the core cho-lesteryl esters were labeled with 3H. The liver and steroid hormone-producing (steroidogenic) tissues in injected animals accumulated substantial amounts of the labeled cholesterol but not the associated labeled apolipoproteins. Conversely, a large amount of the 125I label, but not the 3H label, was ultimately found in the kidneys, where the apolipoproteins are degraded. These findings are inconsistent with receptor-mediated endocytosis of the entire particle. Rather, liver and steroidogenic cells selectively take up cho-lesteryl esters from the cores of HDL particles without accumulating the components of the outer shells.

depleted HDL particle rapidly dissociates from the receptor 4 and eventually returns to the circulation 5. [See C. Glass et al., 1983, Proc. Nat'l. Acad. Sci. USA 80:5435; Y Stein et al., 1983, Biochim. Biophys. Acta 752:98; and M. Krieger, 1999, Ann. Rev. Biochem. 68:523.]

depleted HDL particle rapidly dissociates from the receptor 4 and eventually returns to the circulation 5. [See C. Glass et al., 1983, Proc. Nat'l. Acad. Sci. USA 80:5435; Y Stein et al., 1983, Biochim. Biophys. Acta 752:98; and M. Krieger, 1999, Ann. Rev. Biochem. 68:523.]

Figure 18-16 depicts a model for the selective uptake of cholesteryl esters by a cell-surface receptor called sSR-BI (scavenger receptor, class B, type I). SR-BI binds HDL, LDL, and VLDL and can mediate selective uptake from all of these lipoproteins. The detailed mechanism of selective lipid uptake has not yet been elucidated, but it may entail hemifusion of the outer phospholipid monolayer of the lipoprotein and the exoplasmic leaflet of the plasma membrane. The cholesteryl esters initially enter the hydrophobic center of the plasma membrane, are subsequently transferred across the inner leaflet, and are eventually hy-drolyzed by cytosolic, not lysosomal, cholesteryl esterases. The lipid-depleted particles remaining after lipid transfer dissociate from SR-BI and return to the circulation; they can then extract more phospholipid and cholesterol from other cells by means of the ABCA1 protein or other cell-surface transport proteins (see Figure 18-13c). Eventually, small lipid-depleted HDL particles circulating in the bloodstream are filtered out by the kidney and bind to a different receptor on renal epithelial cells. After these particles have been internalized by receptor-mediated endocytosis, they are degraded by lysosomes.

The receptor SR-BI differs in two important respects from the LDL receptor. First, SR-BI clusters on microvilli and in cell-surface lipid rafts (Chapter 5), not in coated pits as does the LDL receptor. Second, SR-BI mediates the transfer of lipids across the membrane, not endocytosis of entire LDL particles as mediated by the LDL receptor. A multifunctional receptor, SR-BI can mediate the selective uptake from lipopro-teins of diverse lipids (e.g., cholesteryl esters, vitamin E); it also functions in the reverse direction to facilitate the export of unesterified cholesterol from cells to bound lipoproteins. SR-BI has a structure similar to that of the fatty acid transporter CD36, and they both belong to the superfamily of scavenger receptors; as discussed later, some of these receptors apparently play a role in the onset of atherosclerosis.

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