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Structure-Function Relationship Of Lipoprotein Lipase-mediated Enhancement Of Very Low Density Lipoprotein Binding And Catabolism By The Low Density Lipoprotein Receptor

S. Salinelli, J. Y. Lo, M. Mims, E. Zsigmond, L. C. Smith, L. Chan
Published 1996 · Chemistry, Medicine

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We examined the structure-function relationship of human lipoprotein lipase (hLPL) in its ability to enhance the binding and catabolism of very low density lipoproteins (VLDL) in COS cells. Untransfected COS cells did not bind to or catabolize normal VLDL. Expression of wild-type hLPL by transient transfection enhanced binding, uptake, and degradation of the VLDL (a property of LPL that we call bridge function). Heparin pretreatment and a monoclonal antibody ID7 that blocks LDL receptor-binding domain of apoE both inhibited binding, and apoE2/E2 VLDL from a Type III hyperlipidemic subject did not bind. However, LDL did not reduce 125I-VLDL binding to the hLPL-expressing cells, whereas rabbit β-VLDL was an effective competitor. By contrast, LDL reduced uptake and degradation of 125I-VLDL to the same extent as excess unlabeled VLDL or β-VLDL. These data suggest that binding occurs by direct interaction of VLDL with LPL but the subsequent catabolism of the VLDL is mediated by the LDL receptor. Mutant hLPLs that were catalytically inactive, S132A, S132D, as well as the partially active mutant, S251T, and S172G, gave normal enhancement of VLDL binding and catabolism, whereas the partially active mutant S172D had markedly impaired capacity for the process; thus, there is no correlation between bridge function and lipolytic activity. A naturally occurring genetic variant hLPL, S447→Ter, has normal bridge function. The catalytic center of LPL is covered by a 21-amino acid loop that must be repositioned before a lipid substrate can gain access to the active site for catalysis. We studied three hLPL loop mutants (LPL-cH, an enzymatically active mutant with the loop replaced by a hepatic lipase loop; LPL-cP, an enzymatically inactive mutant with the loop replaced by a pancreatic lipase loop; and C216S/C239S, an enzymatically inactive mutant with the pair of Cys residues delimiting the loop substituted by Ser residues) and a control double Cys mutant, C418S/C438S. Two of the loop mutants (LPL-cH and LPL-cP) and the control double Cys mutant C418S/C438S gave normal enhancement of VLDL binding and catabolism, whereas the third loop mutant, C216S/C239S, was completely inactive. We conclude that although catalytic activity and the actual primary sequence of the loop of LPL are relatively unimportant (wild-type LPL loop and pancreatic lipase loops have little sequence similarity), the intact folding of the loop, flanked by disulfide bonds, must be maintained for LPL to express its bridge function.
This paper references
Lipoprotein lipase genotypes for a common premature termination codon mutation detected by PCR-mediated site-directed mutagenesis and restriction digestion.
J. Stocks (1992)
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. Chappell (1994)
A carboxyl-terminal fragment of lipoprotein lipase binds to the low density lipoprotein receptor-related protein and inhibits lipase-mediated uptake of lipoprotein in cells.
A. Nykjaer (1994)
10.1006/METH.1996.0038
Natural Killer Cell Subsets and Development
Carson (1996)
Structural and functional roles of highly conserved serines in human lipoprotein lipase. Evidence that serine 132 is essential for enzyme catalysis.
F. Faustinella (1991)
Lipoprotein lipase. Molecular model based on the pancreatic lipase x-ray structure: consequences for heparin binding and catalysis.
H. van Tilbeurgh (1994)
10.1111/J.1432-1033.1994.00975.X
Mouse very-low-density-lipoprotein receptor (VLDLR) cDNA cloning, tissue-specific expression and evolutionary relationship with the low-density-lipoprotein receptor.
K. Oka (1994)
Human lipoprotein lipase: the loop covering the catalytic site is essential for interaction with lipid substrates.
K. Dugi (1992)
10.1128/MCB.6.9.3173
Human growth hormone as a reporter gene in regulation studies employing transient gene expression.
R. Selden (1986)
10.1161/01.ATV.14.7.1090
DNA variants at the LPL gene locus associate with angiographically defined severity of atherosclerosis and serum lipoprotein levels in a Welsh population.
R. Mattu (1994)
Low density lipoprotein receptor internalizes low density and very low density lipoproteins that are bound to heparan sulfate proteoglycans via lipoprotein lipase.
M. Mulder (1993)
10.1161/01.ATV.14.2.235
Overexpression of human lipoprotein lipase enhances uptake of lipoproteins containing apolipoprotein B-100 in transfected cells.
M. Kawamura (1994)
The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds lipoprotein lipase and beta-migrating very low density lipoprotein associated with the lipase.
A. Nykjaer (1993)
10.1093/NAR/13.24.8765
The rapid generation of oligonucleotide-directed mutations at high frequency using phosphorothioate-modified DNA.
J. Taylor (1985)
10.1021/BI00147A002
Functional topology of a surface loop shielding the catalytic center in lipoprotein lipase.
F. Faustinella (1992)
10.1172/JCI113642
Pre-beta-very low density lipoproteins as precursors of beta-very low density lipoproteins. A model for the pathogenesis of familial dysbetalipoproteinemia (type III hyperlipoproteinemia).
D. Chappell (1988)
Lipoprotein lipase domain function.
H. Wong (1994)
10.1016/0959-440X(92)90076-J
Lipases: three-dimensional structure and mechanism of action
L. Smith (1992)
10.1172/JCI116018
Lipoprotein lipase-mediated uptake and degradation of low density lipoproteins by fibroblasts and macrophages.
S. Rumsey (1992)
Lipoprotein lipase and hepatic lipase mRNA tissue specific expression, developmental regulation, and evolution.
C. Semenkovich (1989)
10.1172/JCI116081
Lipoprotein lipase enhances binding of lipoproteins to heparan sulfate on cell surfaces and extracellular matrix.
S. Eisenberg (1992)
In vitro expression and site-specific mutagenesis of the cloned human lipoprotein lipase gene. Potential N-linked glycosylation site asparagine 43 is important for both enzyme activity and secretion.
C. Semenkovich (1990)
10.1006/GENO.1994.1171
Human very-low-density lipoprotein receptor complementary DNA and deduced amino acid sequence and localization of its gene (VLDLR) to chromosome band 9p24 by fluorescence in situ hybridization.
K. Oka (1994)
10.1093/NAR/18.18.5407
Direct detection and automated sequencing of individual alleles after electrophoretic strand separation: identification of a common nonsense mutation in exon 9 of the human lipoprotein lipase gene.
A. Hata (1990)
Effect of cholesterol feeding on the distribution of plasma lipoproteins and on the metabolism of apolipoprotein E in the rabbit.
R. Roth (1983)
10.1126/SCIENCE.3923623
Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins.
G. Wong (1985)
10.1038/343771A0
Structure of human pancreatic lipase
F. Winkler (1990)
Structure and evolution of the lipase superfamily.
Winston A Hide (1992)
Catalytic triad residue mutation (Asp156----Gly) causing familial lipoprotein lipase deficiency. Co-inheritance with a nonsense mutation (Ser447----Ter) in a Turkish family.
F. Faustinella (1991)
10.1073/PNAS.89.19.9252
Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor-like protein with distinct ligand specificity.
S. Takahashi (1992)
The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP.
S. Williams (1994)
Transgenic mice expressing human lipoprotein lipase driven by the mouse metallothionein promoter. A phenotype associated with increased perinatal mortality and reduced plasma very low density lipoprotein of normal size.
E. Zsigmond (1994)
The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor binds and mediates catabolism of bovine milk lipoprotein lipase.
D. Chappell (1992)
10.1016/0005-2760(72)90034-3
The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations.
D. Bilheimer (1972)
Structure-function relationships of lipoprotein lipase: mutation analysis and mutagenesis of the loop region.
H. Henderson (1993)
10.1073/PNAS.88.19.8342
Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein.
U. Beisiegel (1991)
10.1016/S0006-291X(05)80113-5
A heterozygous mutation (the codon for Ser447----a stop codon) in lipoprotein lipase contributes to a defect in lipid interface recognition in a case with type I hyperlipidemia.
J. Kobayashi (1992)
10.7326/0003-4819-114-9-816_3
The Metabolic basis of inherited disease
Charles R.scriver (1989)
Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene.
J. Sakai (1994)
The receptor-binding domain of human apolipoprotein E. Monoclonal antibody inhibition of binding.
K. Weisgraber (1983)
Mutational analysis of human lipoprotein lipase by carboxy-terminal truncation.
K. Kozaki (1993)
10.1016/0076-6879(83)98152-1
Receptor-mediated endocytosis of low-density lipoprotein in cultured cells.
J. Goldstein (1983)
Monoclonal antibodies against bovine milk lipoprotein lipase. Characterization of an antibody specific for the apolipoprotein C-II binding site.
J. Voyta (1985)
10.1006/BBRC.1995.1037
Lipoprotein lipase: role of intramolecular disulfide bonds in enzyme catalysis.
J. Y. Lo (1995)



This paper is referenced by
10.1007/0-387-23226-5_7
The Protective Role of Vitamin E in Vascular Amyloid β-Mediated Damage
F. Muñoz (2005)
10.1016/S0014-5793(97)01456-7
Calcium‐dependence of hydrogen peroxide‐induced c‐fos expression and growth stimulation of multicellular prostate tumor spheroids
H. Sauer (1997)
10.1007/978-1-4615-1087-1_28
Oxidative stress and TNF-alpha induce histone acetylation and NF-kappaB/AP-1 activation in alveolar epithelial cells: potential mechanism in gene transcription in lung inflammation.
I. Rahman (2002)
10.1089/152308604322899422
Distinct roles of Ca2+, calmodulin, and protein kinase C in H2O2-induced activation of ERK1/2, p38 MAPK, and protein kinase B signaling in vascular smooth muscle cells.
A. Blanc (2004)
10.1006/ABBI.1999.1159
Phenyl-N-tert-butylnitrone demonstrates broad-spectrum inhibition of apoptosis-associated gene expression in endotoxin-treated rats.
C. Stewart (1999)
Der LDL-Rezeptor und das LDL-Rezeptor Related Protein als Recyclingrezeptoren für triglyceridreiche Lipoproteine
Universitätskrankenhauses Eppendorf (2000)
10.1097/01.bor.0000133663.37352.4a
Signaling transduction: target in osteoarthritis
F. Berenbaum (2004)
10.1016/S0021-9150(00)00457-3
The LDL receptor is the major pathway for beta-VLDL uptake by mouse peritoneal macrophages.
S. Perrey (2001)
10.1007/978-1-59259-736-9_6
Mechanotransduction Pathways in Cartilage
Qian Chen (2004)
10.1038/510047a
Lipids in health and disease
J. Finkelstein (2014)
10.1074/jbc.272.20.13000
Lipoprotein Lipase Reduces Secretion of Apolipoprotein E from Macrophages*
M. Lucas (1997)
10.1007/978-3-0348-8482-2_10
Reactive oxygen species and the regulation of metalloproteinase expression
Yvonne Y. C. Lo (2000)
10.1006/BBRC.2001.4628
Dual function of troglitazone in ICAM-1 gene expression in human vascular endothelium.
N. Chen (2001)
10.1016/S0076-6879(02)49346-9
Assessment of oxidants in mitogen-activated protein kinase activation.
L. Terada (2002)
10.1201/B14147-4
Reactive Oxygen Species in the Activation and Regulation of Intracellular Signaling Events
F. Chen (2004)
10.1097/01.HJH.0000125456.28861.E4
The S447X polymorphism of the lipoprotein lipase gene is associated with lipoprotein lipid and blood pressure levels in Chinese patients with essential hypertension
Aiping Liu (2004)
10.1006/MCBR.2001.0271
PD98059 attenuates hydrogen peroxide-induced cell death through inhibition of Jun N-Terminal Kinase in HT29 cells.
B. Salh (2000)
10.1194/JLR.M400016-JLR200
The lipoprotein lipase S447X polymorphism and plasma lipids: interactions with APOE polymorphisms, smoking, and alcohol consumption.
J. Lee (2004)
10.1038/ni1096
T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation
S. H. Jackson (2004)
10.1186/1476-511X-8-24
Sex-associated effect of CETP and LPL polymorphisms on postprandial lipids in familial hypercholesterolaemia
K. Anagnostopoulou (2009)
10.1007/s12602-014-9165-3
Antioxidant Lactobacilli Could Protect Gingival Fibroblasts Against Hydrogen Peroxide: A Preliminary In Vitro Study
A. Mendi (2014)
10.1002/jcp.10419
ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species‐mediated induction of osteopontin gene expression by angiotensin II and interleukin‐1β in adult rat cardiac fibroblasts
Z. Xie (2004)
10.1164/AJRCCM.156.4.9702095
Interleukin-1 in ischemia-reperfusion acute lung injury.
D. Chang (1997)
10.1007/978-1-4419-8634-4_22
Map Kinases in Airway Disease: Standing at the Confluence of Basic and Clinical Science
P. Vichi (1998)
10.1089/15230860050192224
The roles of dopamine oxidative stress and dopamine receptor signaling in aging and age-related neurodegeneration.
Y. Luo (2000)
10 Glia Maturation Factor in Brain Function
R. Lim (2006)
10.1002/jcb.20071
Flavonoid quercetin decreases osteoclastic differentiation induced by RANKL via a mechanism involving NFκB and AP‐1
A. Wattel (2004)
10.1046/J.1523-1755.1998.00888.X
DNA binding of activator protein-1 is increased in human mesangial cells cultured in high glucose concentrations.
W. Wilmer (1998)
10.1007/s00432-007-0273-2
Combination of ZD55-MnSOD therapy with 5-FU enhances antitumor efficacy in colorectal cancer
Y. Zhang (2007)
10.1007/s11064-013-1123-z
Reactive Oxygen Species from Human Astrocytes Induced Functional Impairment and Oxidative Damage
W. Sheng (2013)
10.1201/B15608-10
Honey for Cardiovascular Diseases
Tahira Farooqui (2013)
10.1080/14764170802074680
Phospholipids do not have lipolytic activity. A critical review
Pasquale Motolese (2008)
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