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Heparin-binding defective lipoprotein lipase is unstable and causes abnormalities in lipid delivery to tissues
E. Peer Lutz, … , André Bensadoun, Ira J. Goldberg
E. Peer Lutz, … , André Bensadoun, Ira J. Goldberg
Published May 1, 2001
Citation Information: J Clin Invest. 2001;107(9):1183-1192. https://doi.org/10.1172/JCI11774.
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Article

Heparin-binding defective lipoprotein lipase is unstable and causes abnormalities in lipid delivery to tissues

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Abstract

Lipoprotein lipase (LpL) binding to heparan sulfate proteoglycans (HSPGs) is hypothesized to stabilize the enzyme, localize LpL in specific capillary beds, and route lipoprotein lipids to the underlying tissues. To test these hypotheses in vivo, we created mice expressing a human LpL minigene (hLpLHBM) carrying a mutated heparin-binding site. Three basic amino acids in the carboxyl terminal region of LpL were mutated, yielding an active enzyme with reduced heparin binding. Mice expressing hLpLHBM accumulated inactive human LpL (hLpL) protein in preheparin blood. hLpLHBM rapidly lost activity during a 37°C incubation, confirming a requirement for heparin binding to stabilize LpL. Nevertheless, expression of hLpLHBM prevented the neonatal demise of LpL knockout mice. On the LpL-deficient background hLpLHBM expression led to defective targeting of lipids to tissues. Compared with mice expressing native hLpL in the muscle, hLpLHBM transgenic mice had increased postprandial FFAs, decreased lipid uptake in muscle tissue, and increased lipid uptake in kidneys. Thus, heparin association is required for LpL stability and normal physiologic functions. These experiments confirm in vivo that association with HSPGs can provide a means to maintain proteins in their stable conformations and to anchor them at sites where their activity is required.

Authors

E. Peer Lutz, Martin Merkel, Yuko Kako, Kristan Melford, Herbert Radner, Jan L. Breslow, André Bensadoun, Ira J. Goldberg

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Figure 4

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LpL stability. (a) Media from CHO cells expressing nonmutated hLpL (fill...
LpL stability. (a) Media from CHO cells expressing nonmutated hLpL (filled squares) and hLpLHBM (open circles) were assayed for LpL activity before and at the indicated time points during incubation at 37°C. The activity before the incubation is set as 100%. (b) 5 U heparin/ml were added to the cell culture media, then the experiment was performed as in a. (c) The stability of hLpLHBM (open bars) associated with the cell surface of CHO cells was compared with hLpL (filled bars). The initial cell-associated LpL activity was determined by incubating the cells with 20 U/ml of heparin for 30 minutes at 4°C. This was set as 100%. Then LpL activity in heparin-free media after a 4-hour incubation at 4°C with the cells is shown. The third bar indicates the activity released from the cell surface with heparin after the 4-hour incubation described before. (d) Stability of postheparin plasma from hLpLHBM/LpL0 was compared with hLpL/LpL0. The samples were assayed for LpL activity before incubation at 37°C and at the indicated time points. The initial activity was set to 100%.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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