Abstract
Lipoprotein lipase (LPL), the major enzyme responsible for the hydrolysis of plasma triglycerides, promotes binding and catabolism of triglyceride-rich lipoproteins by various cultured cells. Recent studies demonstrate that LPL binds to three members of the low density lipoprotein (LDL) receptor family, including the LDL receptor-related protein (LRP), GP330/LRP-2, and very low density lipoprotein (VLDL) receptors and induces receptor-mediated lipoprotein catabolism. We show here that LDL receptors also bind LPL and mediate LPL-dependent catabolism of large VLDL with Sf 100-400. Up-regulation of LDL receptors by lovastatin treatment of normal human foreskin fibroblasts (FSF cells) resulted in an increase in LPL-induced VLDL binding and catabolism to a level that was 10-15-fold greater than in LDL receptor-negative fibroblasts, despite similar LRP activity in both cell lines. This indicates that the contribution of LRP to LPL-dependent degradation of VLDL is small when LDL receptors are maximally up-regulated. Furthermore studies in LRP-deficient murine embryonic fibroblasts showed that the level of LPL-dependent degradation of VLDL was similar to that in normal murine embryonic fibroblasts. LPL also promoted the internalization of protein-free triglyceride emulsions; lovastatin-treatment resulted in 2-fold higher uptake in FSF cells, indicating that LPL itself could bind to LDL receptors. However, the lower induction of emulsion catabolism as compared with native VLDL suggests that LPL-induced catabolism via LDL receptors is only partially dependent on receptor binding by LPL and instead is primarily due to activation of apolipoproteins such as apoE. A fusion protein between glutathione S-transferase and the catalytically inactive carboxyl-terminal domain of LPL (GST-LPLC) also induced binding and catabolism of VLDL. However GST-LPLC was not as active as native LPL, indicating that lipolysis is required for a maximal LPL effect. Mutations of critical tryptophan residues in GST-LPLC that abolished binding to VLDL converted the protein to an inhibitor of lipoprotein binding to LDL receptors. In solid-phase assays using immobilized receptors, LDL receptors bound to LPL in a dose-dependent manner. Both LPL and GST-LPLC promoted binding of VLDL to LDL receptor-coated wells. These results indicate that LPL binds to LDL receptors and suggest that the carboxyl-terminal domain of LPL contributes to this interaction.
Highlights
Lipoprotein lipase (LPL), the major enzyme responsible for the hydrolysis of plasma triglycerides, promotes binding and catabolism of triglyceride-rich lipoproteins by various cultured cells
Half-maximal LPL-induced 125IVLDL binding to cell surfaces at 4 °C shifted to a ϳ5-fold lower LPL concentration when low density lipoprotein (LDL) receptors were up-regulated by lovastatin (Fig. 1A)
The very low density lipoprotein (VLDL) receptor and GP330/LDL receptor-related protein (LRP)-2 are implicated in the process as well (10 –13)
Summary
Blasts and human monocyte-derived macrophages via LDL receptors They suggest that LPL’s lipolytic activity is necessary for its ability to enhance LDL degradation, but they did not study the effect of LPL on the catabolism of VLDL, which is a better substrate for LPL than LDL [25]. Several investigators determined that LPL-mediated LDL degradation is independent of the LDL receptor and is not regulated by factors affecting LDL receptor expression (20 –22) These studies focused on the effect of LPL on LDL rather than VLDL catabolism. Mulder et al [23] concluded that internalization of LPL1⁄7VLDL complexes in HepG2 cells was mediated by LDL receptors, since it was negligible in LDL receptor-lacking fibroblasts They did not study lipoprotein degradation or the ability of LPL itself to bind to LDL receptors. Both solid-phase assays using immobilized LDL receptors and internalization studies using protein-free lipid emulsions demonstrate that LPL binds directly to LDL receptors and thereby may contribute to the catabolism of native VLDL via the LDL receptor pathway
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