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LPL activity plays an important role in preceding the VLDL remnant clearance via the three major apolipoprotein E (apoE)-recognizing receptors: the LDL receptor (LDLr), LDL receptor-related protein (LRP), and VLDL receptor (VLDLr). The aim of this study was to determine whether LPL activity is also important for VLDL remnant clearance irrespective of these receptors and to determine the mechanisms involved in the hepatic remnant uptake. Administration of an adenovirus expressing LPL (AdLPL) into lrp 2 ldlr 2/2 vldlr 2/2 mice reduced both VLDL-triglyceride (TG) and VLDL-total cholesterol (TC) levels. Conversely, inhibition of LPL by AdAPOC1 increased plasma VLDL-TG and VLDL-TC levels. Metabolic studies with radiolabeled VLDL-like emulsion particles showed that the clearance and hepatic association of their 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 2 ldlr 2/2 vldlr 2/2 mice, followed by slow internalization, and involved heparin-releaseable cell surface proteins as well as scavenger receptor class B type I (SR-BI). Collectively, we conclude that hepatic VLDL remnant uptake in the absence of the three classical apoE-recognizing receptors is regulated by LPL activity and involves heparan sulfate proteoglycans and SR-BI.-Hu, L., C. C. van LPL is the key enzyme responsible for the hydrolysis of triglycerides (TGs) in TG-rich lipoproteins such as chylomicrons and VLDL (1, 2). During lipolysis, the lipoproteins are reduced in size and enriched with apolipoprotein E (apoE). Subsequently, their core remnants are taken up mainly by the liver via apoE-recognizing receptors [i.e., the LDL receptor (LDLr) and the LDLr-related protein (LRP)] (2). Therefore, mice deficient for the LDLr and hepatic LRP show marked accumulation of TG-rich lipoprotein remnants (3). Although core remnants may be directly internalized via the LDLr, the binding and internalization via the LRP is thought to involve previous binding of core remnants to heparan sulfate proteoglycans (HSPGs) in the space of Disse via heparin binding proteins such as apoE (4, 5).The third major apoE-recognizing receptor, the VLDL receptor (VLDLr), is expressed abundantly in tissues active in fatty acid metabolism [i.e., heart, skeletal muscle,

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