Submitted on March 10, 2008
Accepted on March 25, 2008
The hepatic uptake of VLDL in absence of the three major apoE-recognizing receptors is regulated by LPL activity and involves heparan sulfate proteoglycans and scavenger receptor BI
Lihui Hu, Caroline C. Van der Hoogt, Sonia M. S. Espirito Santo, Ruud Out, Kyriakos E. Kypreos, Bart J. M. Van Vlijmen, Theo J.C. Van Berkel, Johannes A. Romijn, Louis M. Havekes, Ko Willems van Dijk, and Patrick C. N. Rensen
Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Zuid-Holland 2300 RC
Corresponding Author: P.C.N.Rensen{at}lumc.nl
Lipoprotein lipase (LPL) activity plays an important role in preceding the remnant clearance via the three major apoE-recognizing receptors, the LDL receptor (LDLr), LDLr related protein (LRP), and VLDL receptor (VLDLr). We recently showed that lrp-ldlr-/-vldlr-/- mice have elevated fasted plasma total cholesterol (TC) and triglyceride (TG), mainly present as VLDL. However, since VLDL is continuously produced by the liver, their core remnants must thus still be cleared to attain steady state lipid levels in plasma. The aim of this study was to determine whether LPL activity is important for the clearance of VLDL core remnants irrespective of these receptors, and to determine the mechanisms involved in the hepatic uptake of these remnants. Administration of an adenovirus expressing LPL (AdLPL) into lrp-ldlr-/-vldlr-/- mice reduced both VLDL-TG and VLDL-TC levels. Conversely, inhibition of LPL by AdAPOC1 increases plasma VLDL-TG and VLDL-TC levels. Metabolic studies with radiolabeled VLDL-like emulsion particles showed that the clearance and hepatic association of their core remnants positively correlated with LPL activity. This hepatic association was independent of the bridging function of LPL and HL, since heparin did not reduce the liver association. In vitro studies demonstrated that VLDL-like emulsion particles avidly bound to the cell surface of primary hepatocytes from lrp-ldlr-/-vldlr-/- mice, followed by slow internalization, and involved heparin-releasable cell surface proteins as well as scavenger receptor BI (SR-BI). Collectively, we conclude that hepatic VLDL remnant uptake in absence of the three classical apoE-recognizing receptors is regulated by LPL activity and involves heparan sulfate proteoglycans and SR-BI.
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