HEPARAN-SULFATE PROTEOGLYCANS PARTICIPATE IN HEPATIC LIPASE-MEDIATED AND APOLIPOPROTEIN-E-MEDIATED BINDING AND UPTAKE OF PLASMA-LIPOPROTEINS, INCLUDING HIGH-DENSITY-LIPOPROTEINS

High density lipoprotein (HDL) particles and HDL cholesteryl esters ar e taken up by both receptor-mediated and non-receptor-mediated pathway s. Here we show that cell surface heparan sulfate proteoglycans (HSPG) participate in hepatic lipase (HL)- and apolipoprotein (apo) E-mediat ed binding and uptake of mouse and human HDL by cultured hepatocytes. The HL secreted by HL-transfected McA-RH7777 cells enhanced both HDL b inding at 4 degrees C (similar to 2-4-fold) and HDL uptake at 37 degre es C (similar to 2-5-fold). The enhanced binding and uptake of HDL wer e partially inhibited by the 39-kDa protein, an inhibitor of low densi ty lipoprotein receptor-related protein (LRP), but were almost totally blocked by heparinase, which removes the sulfated glycosaminoglycan c hains from HSPG. Therefore, HL may mediate the uptake of HDL by two pa thways: an HSPG-dependent LRP pathway and an HSPG-dependent but LRP-in dependent pathway. The HL-mediated binding and uptake of HDL were only minimally reduced when catalytically inactive HL or LRP binding-defec tive HL was substituted for mild-type HL, indicating that much of the HDL uptake required neither HL binding to the LRP nor lipolytic proces sing. To study the role of HL in facilitating the selective uptake of cholesteryl esters, we used HDL into which radiolabeled cholesteryl et her had been incorporated. HL increased the selective uptake of HDL ch olesteryl ether; this enhanced uptake was reduced by more than 80% by heparinase but was unaffected by the 39-kDa protein. Like HL, apoE enh anced the binding and uptake of HDL (similar to 2-fold) but had little effect on the selective uptake of HDL cholesteryl ether. In the prese nce of HL, apoE did not further increase the uptake of HDL, and at a h igh concentration apoE impaired or decreased the HL-mediated uptake of HDL. Therefore, HL and apoE may utilize similar (but not identical) b inding sites to mediate HDL uptake. Although the relative importance o f cell surface HSPG in the overall metabolism of HDL in vivo remains t o be determined, cultured hepatocytes clearly displayed an HSPG-depend ent pathway that mediates the binding and uptake of HDL. This study al so demonstrates the importance of HL in enhancing the binding and upta ke of remnant and low density lipoproteins via an HSPG-dependent pathw ay.