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Cellular catabolism of normal very low density lipoproteins via the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is induced by the C-terminal domain of lipoprotein lipase.
D A Chappell; I Inoue; G L Fry; M W Pladet; S L Bowen; P H Iverius; J M Lalouel; D K Strickland (Profiled Author: Dudley K Strickland)
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242.
The Journal of biological chemistry 1994;269(27):18001-6.
Lipoprotein lipase (LPL) binds to the low density lipoprotein receptor-related protein (LRP)/alpha 2-macroglobulin receptor and induces catabolism of normal human very low density lipoproteins (VLDL) via LRP in vitro. Recent studies showed that the C-terminal domain of LPL can bind LRP in solid phase assays and inhibit cellular catabolism of two LRP ligands, activated alpha 2-macroglobulin and the 39-kDa receptor-associated protein (Williams, S.E., Inoue, I., Tran, H., Fry, G. L., Pladet, M.W., Iverius, P.-H., Lalouel, J.-M., Chappell, D.A., and Strickland, D.K. (1994) J. Biol. Chem. 269, 8653-8658). The current study investigated the potential for this region of LPL to promote cellular catabolism of VLDL via LRP. A fragment comprising the C-terminal domain of LPL (designated LPLC) was expressed in bacteria and found to promote cellular binding, uptake, and degradation of normal human VLDL in a dose-dependent manner. These effects were present whether LPLC was added simultaneously with 125I-VLDL or was prebound to cell surfaces prior to the assay. Mutations involving Lys407, Trp393, Trp394, or deletion of the C-terminal 14 residues reduced the effects of LPLC. Three LRP-binding proteins, the receptor-associated protein, lactoferrin, and a polyclonal antibody against LRP, competed for 125I-VLDL degradation induced by LPLC. Heparin or heparinase treatment of cells prevented LPLC-induced 125I-VLDL catabolism. Thus, cell-surface proteoglycans play an important role in this pathway. Interestingly, either LPLC or LPL when added in excess could block LPL-induced 125I-VLDL degradation presumably by interacting directly with LRP. However, unlabeled VLDL could not prevent catabolism of 125I-labeled LPLC or LPL. These data show that cellular fates for VLDL versus LPLC or LPL are divergent. This is probably due to independent catabolism of the latter via cell-surface proteoglycans. In summary, these in vitro studies indicate that a fragment of LPL corresponding to the C-terminal domain mimics the native enzyme with respect to induction of VLDL catabolism via LRP. Because LPLC lacks the catalytic site of native LPL, these studies establish that lipase activity is not required for LRP-mediated lipoprotein catabolism.
2 Originating Grant
STRICKLAND, DUDLEY K
1 April 1983 - 31 March 1993
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
STRICKLAND, DUDLEY K
This section shows information related to the publication - computed using the fingerprint of the publication - including related publications, related experts and related grants with fingerprints representing significant amounts of overlap between their fingerprint and this publication. The red dots indicate whether those experts or terms appear within the publication, thereby showing potential and actual connections.
D A Chappell; G L Fry; M A Waknitz; P H Iverius; S E Williams; D K StricklandThe Journal of biological chemistry 1992;267(36):25764-7.
M Z Kounnas; D A Chappell; D K Strickland; W S ArgravesThe Journal of biological chemistry 1993;268(19):14176-81.
D A Chappell; I Inoue; G L Fry; M W Pladet; P H Iverius; J M Lalouel; D K Strickland
The carboxy-terminal domain of lipoprotein lipase induces cellular catabolism of normal very low density lipoproteins via the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor.Annals of the New York Academy of Sciences 1994;737():434-8.
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