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

Lutz, Erlo; Merkel, Martin; Kako, Yuko; Melford, Kristan; Radner, H.; Breslow, Jan L.; Bensadoun, André; Goldberg, Ira J.

doi:10.1172/jci11774

Cited by 53 publications

(46 citation statements)

References 40 publications

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“…It should be noted that unlike hHL, the post-heparin activity of which is negatively correlated with plasma HDL concentrations, post-heparin plasma LPL activity is directly correlated with HDL cholesterol levels (42). Expression of a heparin binding-deficient human LPL in mice results in elevated triglyceride and cholesterol associated with very low density lipoproteins (49). Thus, the mode of action is distinct between LPL and HL in regulating plasma lipoproteins including HDL.…”

Section: Discussionmentioning

confidence: 99%

Severe Hypoalphalipoproteinemia in Mice Expressing Human Hepatic Lipase Deficient in Binding to Heparan Sulfate Proteoglycan

Brown

Gauthier

Parks

et al. 2004

Journal of Biological Chemistry

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Unlike human hepatic lipase (hHL) that is mainly cell surface-anchored via binding to heparan sulfate proteoglycans (HSPG), mouse HL (mHL) has a low affinity to HSPG and thus is largely blood-borne. The reduced HSPG binding of mHL is attributable to the C-terminal amino acids. To determine the functions of HSPG binding of hHL in vivo, we created adenovirus vectors encoding hHL or a chimeric protein (designated hHLmt) in which the C-terminal HSPG-binding sequences were replaced with the corresponding mouse sequences. Injecting hHLmt-expressing virus into C57BL/6J mice (1.8 ؋ 10 10 virus particles/mouse) resulted in a 3-fold increase in pre-heparin HL activity, whereas infection with an identical dose of hHL virus did not change pre-heparin HL activity. In hHLmt-expressing mice, the concentration of total cholesterol and phospholipids was inversely related to the hHL activity in pre-heparin plasma in a dose-and time-dependent manner, and the decrease was mainly attributable to high density lipoproteins (HDL) cholesterol and HDL phospholipids. The expression of hHL exhibited no change in plasma total cholesterol or phospholipid levels as compared with control mice infected with luciferase or injected with saline. The reduced HDL lipids in the hHLmt-expressing mice were accompanied by markedly decreased plasma and hepatic apolipoprotein (apo) A-I. In primary hepatocytes isolated from hHLmt-expressing mice, the concentration of cell-associated and secreted apoA-I was decreased by 2-3-fold as compared with hepatocytes isolated from control mice, whereas the levels of apoB and apoE were unaltered. Infection of primary hepatocytes with hHLmt virus ex vivo also resulted in reduced apoA-I secretion but had no effect on cell-associated apoA-I. These results suggest that expression of HSPG binding-deficient hHL has a profound HDL-lowering effect.

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Section: Discussionmentioning

confidence: 99%

Severe Hypoalphalipoproteinemia in Mice Expressing Human Hepatic Lipase Deficient in Binding to Heparan Sulfate Proteoglycan

Brown

Gauthier

Parks

et al. 2004

Journal of Biological Chemistry

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“…The Arg405, Arg407, and Lys409 residues of avian LPL, which correspond to the Lys403, Arg405, and Lys407 residues, respectively, in the C-terminal domain of human LPL, have been demonstrated to be responsible for heparin binding [22]. In another study with transgenic mice expressing a human LPL with Asn residues substituted for basic amino acids at positions 403, 405, and 407, the mutant LPL displayed normal enzyme activity but with a reduced affinity for heparin [23]. The investigators of the latter study concluded that HSPG binding at the cell surface is required for maintaining LPL stability.…”

mentioning

confidence: 99%

Molecular modeling of the dimeric structure of human lipoprotein lipase and functional studies of the carboxyl‐terminal domain

Kobayashi

Nakajima

Inoue

2002

European Journal of Biochemistry

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Lipoprotein lipase (LPL) plays a key role in lipid metabolism. Molecular modeling of dimeric LPL was carried out using INSIGHT II based upon the crystal structures of human, porcine, and horse pancreatic lipase. The dimeric model reveals a saddle-shaped structure and the key heparinbinding residues in the amino-terminal domain located on the top of this saddle. The models of two dimeric conformations -a closed, inactive form and an open, active form -differ with respect to how surface-loop positions affect substrate access to the catalytic site. In the closed form, the surface loop covers the catalytic site, which becomes inaccessible to solvent. Large conformational changes in the open form, especially in the loop and carboxyl-terminal domain, allow substrate access to the active site. To dissect the structure-function relationships of the LPL carboxylterminal domain, several residues predicted by the model structure to be essential for the functions of heparin binding and substrate recognition were mutagenized. Arg405 plays an important role in heparin binding in the active dimer. Lys413/Lys414 or Lys414 regulates heparin affinity in both monomeric and dimeric forms. To evaluate the prediction that LPL forms a homodimer in a Ôhead-to-tailÕ orientation, two inactive LPL mutants -a catalytic site mutant (S132T) and a substrate-recognition mutant (W390A/W393A/ W394A) -were cotransfected into COS7 cells. Lipase activity could be recovered only when heterodimerization occurred in a head-to-tail orientation. After cotransfection, 50% of the wild-type lipase activity was recovered, indicating that lipase activity is determined by the interaction between the catalytic site on one subunit and the substraterecognition site on the other.Keywords: lipoprotein lipase; dimeric model structure; heparin binding; substrate recognition; catalytic activity.Lipoprotein lipase (LPL) belongs to a mammalian lipase family that includes pancreatic lipase (PL), hepatic lipase (HL), gastric lipase, and endothelial lipase [1,2]. The primary function of LPL is triglyceride hydrolysis in triglyceride-rich lipoproteins, such as chylomicron and very low density lipoprotein (VLDL) particles, which are converted to remnants. LPL is secreted from a variety of tissues, such as adipocyte, macrophage, and muscle cells, and is bound to the capillary bed of endothelium via cellular surface heparan sulfate proteoglycans (HSPG), a function reflected in LPL's strong affinity for heparin. LPL deficiencies in humans are manifested as severe hypertriglyceridemia [3-5] and arteriosclerosis [6]. Genetically engineered mice lacking LPL also exhibit hypertriglyceridemia. In addition to lipolytic activity, LPL functions as a ligand for lipoprotein receptors, such as low density lipoprotein (LDL) receptor, LDL receptor related protein (LRP), GP330/ LRP-2, and VLDL receptor [7][8][9][10][11].A model structure of LPL had previously been constructed, based on the crystal structure of human PL as a template [12]. The model structure exhibited two domainsa large N-t...

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“…Studies with cells deficient in HS showed, however, that HS is not required for the intracellular processing and secretion of LPL (10). Secretion of LPL to the culture medium from HS-deficient cells was even higher than from wild type cells, which is in line with that HS may also have a role as co-receptor in internalization and catabolism of LPL (11)(12)(13)(14).…”

Section: Heparan Sulfates (Hs)mentioning

confidence: 77%

“…This family of triglyceride lipases contain two domains with the catalytic site located in a pocket of the N-terminal domain. In LPL, four clusters of basic amino acids are exposed on the opposite side of the molecule compared with the entrance to the catalytic site, and at least two, located in the N-terminal domain, seem to be important for HS binding (14,16,17). Participation of positive regions also in the C-terminal domain of LPL have been demonstrated (17)(18)(19).…”

Section: Heparan Sulfates (Hs)mentioning

confidence: 99%

Isolation and Characterization of Low Sulfated Heparan Sulfate Sequences with Affinity for Lipoprotein Lipase

Spillmann

Lóokene

Olivecrona

2006

Journal of Biological Chemistry

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Lipoprotein lipase (LPL), which is an important enzyme in lipid metabolism, binds to heparan sulfate (HS) proteoglycans. This interaction is crucial for several aspects of LPL function, such as intracellular/extracellular transport and high capacity attachment to cell surfaces. Retention of LPL on the capillary walls, and elsewhere, via HS chains is most likely affected by the quality and quantity of HS present. Earlier studies have demonstrated that LPL interacts with highly sulfated HS and heparin oligosaccharides. Since such structures are relatively rare in endothelial HS, we have re-addressed the question of physiological ligand structures for LPL by affinity purification of endlabeled oligosaccharides originating from heparin and HS on immobilized LPL. By a combination of chemical modification and fragmentation of the bound material we identified that the bound fraction contained modestly sulfated oligosaccharides with an average sulfation of one O-sulfate per disaccharide unit and tolerates N-acetylated glucosamine residues. Therefore LPL, containing several clusters of positive charges on each subunit, may constitute an ideal structure for a protein that needs to bind with reasonable affinity to a variety of modestly sulfated sequences of the type that is abundant in HS chains.

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

Cited by 53 publications

References 40 publications

Severe Hypoalphalipoproteinemia in Mice Expressing Human Hepatic Lipase Deficient in Binding to Heparan Sulfate Proteoglycan

Severe Hypoalphalipoproteinemia in Mice Expressing Human Hepatic Lipase Deficient in Binding to Heparan Sulfate Proteoglycan

Molecular modeling of the dimeric structure of human lipoprotein lipase and functional studies of the carboxyl‐terminal domain

Isolation and Characterization of Low Sulfated Heparan Sulfate Sequences with Affinity for Lipoprotein Lipase

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