Hepatic lipase mediates the uptake of chylomicrons and beta-VLDL into cells via the LDL receptor-related protein (LRP).
The uptake of triglyceride-rich lipoproteins has been described as being mediated by apolipoprotein E and lipoprotein lipase (LpL). Proteoglycans, the LDL-receptor, and the LDL receptor-related protein (LRP) are the cellular acceptors. In addition to LpL, hepatic lipase (HL) has been shown to bind to LRP. In this study, the role of HL in lipoprotein uptake was investigated. Human chylomicrons and rabbit beta-VLDL were used as ligands for human hepatoma cells, primary human hepalocytes, normal and proteoglycan-deficient Chinese hamster ovary (CHO) cells, and normal and LDL receptor-deficient human fibroblasts. We show that HL induces stimulation of the uptake of chylomicrons and beta-VLDL into the different cell lines. HL is known to bind to heparan sulfate, and experiments on normal and proteoglycan-deficient CHO cells showed that cell surface proteoglycans are essential for HL-mediated uptake of lipoproteins. To exclude LDL receptor-mediated uptake. we performed experiments on LDL receptor-deficient fibroblasts that demonstrated that the LDL receptor was not important for the HL-mediated uptake of lipoproteins. Crosslinking experiments confirmed the binding of HL to LRP on the cell surface. To identify the region of HL involved in the interaction with LRP, we used a C-terminal fragment of LpL, known to inhibit LpL-mediated uptake. HL-mediated lipoprotein uptake was suppressed by this fragment. Our experiments indicate that HL, like LpL, can mediate the uptake of lipoproteins into cells, most probably via a C-terminal binding site. The uptake, initiated by proteoglycan binding, is mediated by LRP.
Krapp
A
A
Medical Clinic, University Hospital Hamburg, Germany.
Ahle
S
S
Kersting
S
S
Hua
Y
Y
Kneser
K
K
Nielsen
M
M
Gliemann
J
J
Beisiegel
U
U
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002914:Chylomicrons / Q000378:metabolism*; D006224:Cricetinae; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008049:Lipase / Q000502:physiology*; D008074:Lipoproteins / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins / Q000378:metabolism; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism; D011817:Rabbits; D011971:Receptors, Immunologic / Q000502:physiology*; D011973:Receptors, LDL; D014407:Tumor Cells, Cultured
D002914:Chylomicrons; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins; D011509:Proteoglycans; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D008049:Lipase