J. Lipid Res.
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A more recent version of this article appeared on January 1, 2008

Papers In Press, published online ahead of print October 22, 2007
J. Lipid Res., doi:10.1194/jlr.M700355-JLR200
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Submitted on August 9, 2007
Revised on October 19, 2007
Accepted on October 21, 2007

Scavenger receptor BI facilitates the metabolism of very-low-density lipoproteins in vivo

Miranda Van Eck, Menno Hoekstra, Ruud Out, I. Sophie T. Bos, J. Kar Kruijt, Reeni B. Hildebrand, and Theo J. C. Van Berkel

Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden 2333CC

Corresponding Author: m.eck{at}lacdr.leidenuniv.nl

Scavenger receptor class B type I (SR-BI) functions as an HDL receptor that promotes the selective uptake of cholesteryl esters (CE). The physiological role of SR-BI in very-low-density lipoprotein (VLDL) metabolism, however, is largely unknown. SR-BI deficiency resulted in elevated VLDL cholesterol levels, both on chow diet and upon challenge with high cholesterol diets. The increase in VLDL cholesterol levels could not be explained by increased VLDL production, altered lipase activity, or reduced expression of the LDL receptor and LRP1, two important receptors for VLDL removal. To specifically elucidate the role of SR-BI in VLDL metabolism, the plasma clearance and hepatic uptake of 125I-betaVLDL were studied in SR-BI+/+ and SR-BI-/- mice. At 20 min after injection, 66±2% of the injected dose was taken up by the liver in SR-BI+/+ mice, as compared to only 22±4% (p=0.0007) in SR-BI-/- mice. Similar results were obtained using 3H-CE-betaVLDL, indicating that SR-BI does not mediate the selective uptake of cholesteryl esters from betaVLDL in vivo. In vitro studies using isolated hepatocytes established that the Bmax of 125I-betaVLDL binding was reduced from 469±30 ng/mg in SR-BI+/+ animals to 305±20 ng/mg (p=0.01) in SR-BI-/- mice. In agreement with the data obtained in vivo, also limited to no selective uptake of cholesteryl esters from betaVLDL was found in vitro. Interestingly, HDL effectively competed for the association of betaVLDL in the presence as well as in the absence of SR-BI, indicating a second common recognition site. In conclusion, in addition to its function as an HDL receptor, SR-BI plays an important physiological role in the metabolism of VLDL (remnants).


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