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PubMed1990

Fatty acid control of lipoprotein lipase: a link between energy metabolism and lipid transport.

Lipoprotein lipase (LPL) catalyzes the flux-generating step in transport of fatty acids from lipoprotein triacylglycerols into tissues for use in metabolic reactions. In vitro studies have shown that fatty acids can bind to the enzyme and impede its other interactions. In this study we have searched for evidence of fatty acid control of LPL in vivo by rapid infusion of a triacylglycerol emulsion to healthy volunteers. During infusion the activity of LPL but not of hepatic lipase increased in plasma, but to different degrees in different individuals. The time course for the increase in LPL activity differed from that for triacylglycerols but followed the plasma levels of free fatty acids. This was true during infusions and when the emulsion was given as a bolus injection. In particular there were several instances when plasma triacylglycerol levels were very high but free fatty acids and LPL activity remained low. Model studies with bovine LPL showed that fatty acids displace the enzyme from heparin-agarose. We suggest that in situations when fatty acids are generated more rapidly by LPL than they are used by the local tissue, they cause dissociation of the enzyme from its binding to endothelial heparin sulfate and are themselves released into circulation.

Adult↗
PubMed1997

Mutations at the lipoprotein lipase gene locus in subjects with diabetes mellitus, obesity and lipaemia.

1. The common association of obesity, diabetes mellitus and hyperlipidaemia may have a primary aetiological basis. Insulin resistance has been postulated as a possible cause, but defects in the plasma transport of triacylglycerol or fatty acids could also be primary determinants. 2. We have therefore studied 18 patients with diabetes mellitus, obesity and severe hypertriglyceridaemia for defects of a key protein involved in the clearance of plasma triacylglycerols, lipoprotein lipase. 3. DNA was prepared from leucocytes of 18 patients with the above syndrome, and exons encoding lipoprotein lipase were amplified by PCR. The products were sequenced using the dideoxy chain-termination method. 4. Eight of the subjects were found to possess genetic variants at the lipoprotein lipase gene locus. These were: (a) G579-->A, V108V; (b) G818-->A, G188E; (c) C829-->T, R192; (d) A1127-->G, N291S; (e) C1308-->G, F351L; (f) C1338-->A, T361T; and (g) C1595-->G, S447. Three of these, (c), (e) and (f), have not hitherto been described. Variant (f), appears to be a population polymorphism whose allele frequency in normolipidaemic diabetics was found to be 0.12 (162 chromosomes studied). The others are all rare at frequencies of < 0.01 and may contribute to the phenotype by impairing clearance of plasma triacylglycerols. 5. We conclude that genetic variants at the lipoprotein lipase locus occur commonly in subjects with this syndrome (four out of 18 subjects with probably functional mutants) and may affect the individual's response to obesity and diabetes mellitus for the development of lipaemia.

Adult↗
PubMed1985

Molecular size of bovine lipoprotein lipase as determined by radiation inactivation.

We have determined the size of the functional unit of bovine lipoprotein lipase by radiation inactivation. This was done in five different situations: 1) in a buffer with high salt concentration. In this situation the enzyme is relatively soluble and stable. 2) For an enzyme-heparin complex. This may reflect the physiological state of the enzyme at the vascular endothelium, where it is believed to be bound to a heparin-like molecule. 3) In the presence of lipid substrate and 4) with lipid substrate and activator protein. Here most of the enzyme is adsorbed to the substrate droplets. 5) For an enzyme-detergent complex; another model for enzyme-lipid interaction. In all five situations the enzyme activity decayed as an exponential function of radiation dose, and the target sizes were similar. The target size did not vary with the concentration of lipase protein. The combined data for bovine lipoprotein lipase yield a functional size of 72 kDa which is close to that expected for a dimer, 77 kDa.

Animals↗
PubMed1971

Sites of lipoprotein lipase activity in adipose tissue perfused with chylomicrons. Electron microscope cytochemical study.

Lipoprotein lipase activity was studied in rat parametrial adipose tissue perfused with chylomicrons and in gelatin blocks containing postheparin plasma and chylomicrons. The tissues and blocks were fixed in glutaraldehyde and incubated in 0.035 M CaCl(2)-0.1 M Tris medium (pH 8.3) at 38 degrees C. The doubly labeled chylomicron triglycerides (glycerol-(3)H and palmitate-(14)C) in the tissues and blocks were hydrolyzed during incubation to free fatty acids (FFA) and the FFA remained in the specimens; hydrolysis was inhibited by 0.004 M diethyl paranitrophenyl phosphate (E-600). Incubated blocks and tissue were treated with 0.05 M Pb(NO(3))(2), postfixed in OsO(4), dehydrated with acetone, embedded in Epon, and examined by electron microscopy. The incubated blocks contained electronlucent areas and granular and laminar precipitates at sites of hydrolysis. Similar precipitates were found in incubated tissue, within vacuoles and microvesicles of capillary endothelium, and in the subendothelial space (between the endothelium and pericytes), but not in the capillary lumen or in or near fat cells. The cytochemical reaction was greatly reduced, in blocks and tissues incubated with E-600. It is concluded that plasma glycerides are hydrolyzed by lipoprotein lipase in capillary endothelial cells and in the subendothelial space of adipose tissue and that glycerides across the endothelial cells within a membrane-bounded system.

Adipose Tissue↗
PubMed1999

3-Hydroxy-3-methylglutaryl CoA reductase inhibitors reduce serum triglyceride levels through modulation of apolipoprotein C-III and lipoprotein lipase.

Statins are hypolipidemic drugs which not only improve cholesterol but also triglyceride levels. Whereas their cholesterol-reducing effect involves inhibition of de novo biosynthesis of cellular cholesterol through competitive inhibition of its rate-limiting enzyme 3-hydroxy-3-methylglutaryl CoA reductase, the mechanism by which they lower triglycerides remains unknown and forms the subject of the current study. Treatment of normal rats for 4 days with simvastatin decreased serum triglycerides significantly, whereas it increased high density lipoprotein cholesterol moderately. The decrease in triglyceride concentrations after simvastatin was caused by a reduction in the amount of very low density lipoprotein particles which were of an unchanged lipid composition. Simvastatin administration increased the lipoprotein lipase mRNA and activity in adipose tissue and heart. This effect on lipoprotein lipase was accompanied by decreased mRNA as well as plasma levels of the lipoprotein lipase inhibitor apolipoprotein C-III. These results suggest that the triglyceride-lowering effect of statins involves a stimulation of lipoprotein lipase-mediated clearance of triglyceride-rich lipoproteins.

Animals↗
PubMed1992

The structure and complete nucleotide sequence of the avian lipoprotein lipase gene.

The entire gene for chicken lipoprotein lipase (LPL) has been isolated and characterized by primer extension and sequence analysis. The gene is 17 kilobase pairs long and comprises 10 exons and 9 introns. As determined by primer extension analysis the start sites of transcription map 176, 204 and 218 nucleotides upstream of the initiator methionine codon. The 1947 base pairs of 5' flanking sequence contains several putative regulatory elements including two adjacent Oct I binding elements, four glucocorticoid regulatory elements and a sequence very homologous to the previously described fat specific element at--1402 nt. The first intron is very large (6433 bp) and contains four consensus SpI binding-site sequences. Five polyadenylation signals are found in the 3' untranslated region, the last three of which give predicted mRNA species identical in size to those determined by Northern blot. The 5' flanking sequences of the LPL, pancreatic lipase and hepatic lipase genes do not show homology, however. This may account for the homologous amino acid sequences but dissimilar gene expression of these enzymes.

Amino Acid Sequence↗
PubMed1993

Biotinylation of lipoprotein lipase and hepatic triglyceride lipase: application in the assessment of cell binding sites.

Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HL) were biotinylated using N-hydroxysuccinamide ester of biotin (25-fold molar excess) which was incorporated into the lysine amino groups of the enzyme protein. By assessing enzyme activity and heparin-agarose affinity a biotinylation protocol which did not denature lipases was developed. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis showed that biotinylated LPL (bLPL) has the same mobility as that of unlabeled or iodinated LPL. Receptor binding activity of bLPL was studied in (i) cell binding experiments using cultured bovine aortic endothelial cells and (ii) ligand blotting experiments using endothelial cell plasma membranes. Endothelial cells in culture bound similar amounts of bLPL and 125I-LPL. We previously described a 116-kDa heparin-releasable LPL binding protein (hrp-116) on endothelial cells. Using biotinylated lipases in ligand blotting experiments we now demonstrate that both bLPL and biotinylated HL can bind to hrp-116. bLPL in addition also bound to low-density lipoprotein receptor related protein in ligand blotting. Thus, our protocol has produced biotinylated lipases which are both chemically and biologically active and can be used instead of iodinated lipases.

Animals↗
PubMed1994

Short-term effects of renal transplantation on plasma lipids and lipoprotein lipase in children with congenital nephrosis.

Plasma lipoprotein and apoprotein (apo) A-I, A-II and B concentrations and post-heparin plasma lipoprotein lipase (LPL) activity and mass were measured in 13 children with congenital nephrotic syndrome of the Finnish type (CNF) six months after renal transplantation to determine whether the severe lipid abnormalities documented prior to and during peritoneal dialysis would normalize. Plasma total triglyceride decreased by 52% (p < 0.001), VLDL triglyceride by 55% (p < 0.01) and total cholesterol by 17% (p < 0.01). HDL cholesterol increased by 51% (p < 0.001), whereas no significant change was observed in LDL cholesterol. Despite these improvements, plasma lipoprotein concentrations were still abnormal after transplantation. Total (p < 0.01) and VLDL triglyceride (p < 0.05) as well as total (p < 0.01), VLDL (p < 0.01) and LDL cholesterol (p < 0.01) were higher than in control children. HDL cholesterol normalized. Plasma apo A-I and A-II concentrations were normal, but the apo B concentration remained high (p < 0.01). Post-heparin LPL activity and mass were normal (25.0 +/- 9.1 mumol FFA/ml/h and 227.2 +/- 88.4 ng/ml). The mean cyclosporine dose correlated positively with the serum creatinine concentration (r = +0.72, p < 0.01). Positive correlations were also observed between total (r = +0.68, p < 0.05) and VLDL triglyceride (r = +0.62, p < 0.05) and the serum creatinine concentrations. We conclude that renal transplantation substantially improves the triglyceride and cholesterol abnormalities in CNF but significant abnormalities still persist.

Apolipoprotein A-I↗
PubMed2003

[Study on lipoprotein lipase gene Hind III polymorphism in Chinese type IIb hyperlipoproteinemia].

OBJECTIVE: To investigate whether lipoprotein lipase (LPL) gene Hind III polymorphism is associated with Chinese type IIb hyperlipoproteinemia. METHODS: Lipoprotein lipase gene Hind III polymorphism was studied using polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) in 103 type IIb hyperlipoproteinemia patients and 129 healthy subjects from a population of Chinese Hans in Chengdu area. RESULTS: Both in type IIb hyperlipoproteinemia group and control group, the H+H+ homozygote was the major allelotype. The H+ allelic frequency of type IIb hyperlipoproteinemia group was higher than that of control group (0.864 vs 0.705, P<0.01). But the H- allelic frequency of type IIb hyperlipoproteinemia group was significantly lower than that of control group (0.136 vs 0.295, P<0.01). The plasma triglycerides (TG) level of H+H+ genotype was significantly higher than that of H+H- and H-H- genotypes (P<0.05 and P<0.01); the plasma TC level and TG/HDL C ratio were higher than those of H+H- and H-H- genotypes (P<0.05); apoA II levels of H+H+ and H+H- genotypes were significantly lower than that of H-H- genotype (P<0.01 and P<0.05). CONCLUSION: The Hind III RFLP at intron 8 of LPL gene is associated with type II b hyperlipoproteinemia to some extent in Chinese population.

Adult↗
PubMed1985

[Inhibition of lipoprotein lipolysis by polyarginine and evaluation of the mechanism of its interaction with lipoprotein lipase].

It was found that polyarginine (Mr 40 000-60 000) is a strong inhibitor of the lipoprotein lipase activity in vivo and in vitro. The inhibitory effect in vivo was observed after a single intravenous injection of 0.85-3.5 mg/kg to rabbits, that in vitro at the polypeptide concentration of greater than or equal to 2.5 micrograms/ml. Within the first few hours after intravenous injection of polyarginine hyperlipidemia occurred with an obvious increase in the plasma triglyceride and VLDL fractions and a slight decrease of the LDL and HDL fractions. These changes typical for reduced lipoprotein lipolysis were due to the formation of a polyarginine-heparin complex, on the one hand, and to the formation of a polyarginine-enzyme complex devoid of the lipolytic properties, on the other. The inhibitory effect of polyarginine on lipoprotein lipase is related to the whole polypeptide molecule or its large fragment, since arginine and metformine (bi-guanidine compound) have no effect on the enzyme activity.

Animals↗
PubMed2001

Lipoprotein-stimulated mesangial cell proliferation and gene expression are regulated by lipoprotein lipase.

BACKGROUND: Hyperlipidemia accelerates the progression of glomerular disease, and lipoproteins bind glomerular mesangial cells (MC) and induce proliferation and cytokine expression. In the vessel wall, the binding of lipoproteins to endothelial cells is markedly enhanced by lipoprotein lipase (LpL), synthesized by the underlying smooth muscle cells. While it is known that LpL is localized to the glomerulus, it is not known if and how it modulates the lipoprotein-mesangial interaction. METHODS: Very low-density lipoprotein (VLDL) was isolated from rats and was used to treat cultured primary rat MCs. Binding studies were done with and without LpL and with/without pretreatment with heparanase, which degrades cell surface heparan sulfate proteoglycan (HSPG), known to modulate the LpL-lipoprotein interaction in blood vessels. VLDL/LpL was also used to assess MC proliferation and gene expression of the cytokine platelet-derived growth factor (PDGF). RESULTS: LpL enhanced VLDL binding to MCs by as much as 200-fold, and most of this effect was blocked by pretreatment with heparanase. LpL amplified VLDL-driven MC proliferation and increased VLDL-induced PDGF expression. Heparanase pretreatment of cells eliminated both of these amplifications. LpL alone increased MC proliferation and PDGF gene expression. DISCUSSION: As in the vessel wall, LpL enhances VLDL binding to MCs. MCs respond to LpL binding by proliferating and expressing cytokines such as PDGF. LpL may be a crucial paracrine mediator of the glomerular response to circulating lipoproteins, amplifying a response that includes cytokine elaboration, influx of circulating monocytes, and eventual sclerosis.

Animals↗
PubMed2000

Roles for lipoprotein lipase in Alzheimer's disease: an association study.

Lipoprotein lipase (LPL) assists lipid transport by transferring lipids between lipoprotein particles and cells. LPL binds apolipoprotein E (apoE) lipoprotein particles and a major apoE receptor, low density lipoprotein receptor related protein (LRP). Because apoE and LRP polymorphisms alter Alzheimer's disease (AD) risk, and LPL itself is found in AD amyloid plaques, we examined whether LPL variants also affect AD risk. In case-control studies in the United States and Canada, the frequencies of two LPL alleles known to affect LPL enzymatic activity were measured in Caucasian AD or elderly normal (N) subjects. Pathologically confirmed subjects in both studies exhibited similar trends toward fewer 447Ter and more 291Ser alleles in AD. Combining results from both countries gave allele frequencies for 447Ter of 13.7% (26/190) in N and 9.4% (80/852) in AD (P = 0.10), and for 291Ser of 0.0% (0/184) in N and 1. 3% (8/636) in AD (P = 0.21). The trend appeared even greater for homozygous 447Ter subjects: 4.2% (4/95) of N vs. 1.4% (6/426) of AD (P = 0.09). These trends are consistent with a putative protective effect of 447Ter and causative effect of 291Ser on AD. Furthermore, brains of AD patients with 447Ter showed trends toward fewer plaques, tangles, and glia, and more neurons and cortical thickness than AD patients without 447Ter. Hippocampal plaques were significantly reduced. LPL might affect hippocampal function and thus dementia via its role as supplier of membrane components or antioxidants to neurons. Alternatively, LPL may play a part in plaque formation through its interaction with apoE and LRP.

Aged↗
PubMed2005

Relationship between plasma HDL subclasses distribution and lipoprotein lipase gene HindIII polymorphism in hyperlipidemia.

BACKGROUND: Different high-density lipoprotein (HDL) subclasses have distinct but interrelated metabolic functions. HDL directly influences the atherogenic process, and changes in HDL subclasses distribution may be related to the incidence and prevalence of atherosclerosis. Lipoprotein lipase (LPL) is an important enzyme for hydrolysis of triglyceride-rich lipoproteins, and its activity is positively correlated with the plasma HDL cholesterol level. LPL gene HindIII polymorphism has been found associated with variations in lipid levels, but the impact on HDL subclasses distribution is less clearly established. METHODS: The relative apolipoprotein (apo) A-I contents (% apoA-I) of plasma HDL subclasses were determined by two-dimensional gel electrophoresis coupled with immunodetection and LPL gene HindIII polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 173 hyperlipidemic and 155 normolipidemic subjects. RESULTS: The frequencies of 495TT genotype and allele T were the highest both in the hyperlipidemic and control groups. Compared with the control group, the frequency of 495TT genotype was higher, while the frequencies of 495TG and 495GG genotypes were significantly lower (P<0.05) in the hyperlipidemic group. Two-dimensional gel electrophoresis and immunodetection showed that HDL subclasses distribution was altered in hyperlipidemia, and had a general shift toward smaller size. Compared with the control group, the hyperlipidemic group had significantly higher relative apoA-I contents of prebeta1-HDL, prebeta2-HDL, HDL3b and HDL3a (P<0.05) and lower HDL2a and HDL2b levels (P<0.001). In the hyperlipidemic group, allele T carriers' frequency was higher than that in the control group (P<0.05), and the genotype of 495TT showed higher levels of plasma TG, apoB100, TG/HDL-C ratio, relative apoA-I contents of prebeta1-HDL, HDL3b and lower HDL2a, HDL2b compared with that of the 495GG genotype subgroup (P<0.05). In the control group, the genotype of 495TT had higher plasma TG, HDL3c and lower HDL2a compared with that of 495GG subgroup (P<0.05). CONCLUSIONS: The 495TT genotype of LPL gene HindIII polymorphism was associated with changes of HDL subclasses distribution in Chinese population with hyperlipidemia. The particle size of HDL shifted toward smaller, which, in turn, indicated that RCT might be weakened and HDL maturation might be abnormal in hyperlipidemic subjects with 495TT genotype.

Adult↗
PubMed1996

Oxidation of low density lipoproteins greatly enhances their association with lipoprotein lipase anchored to endothelial cell matrix.

Native and oxidized low density lipoprotein retention within arterial wall endothelial cell matrix (ECM) is an early event in the pathogenesis of atherosclerosis. Previously we showed lipoprotein lipase (LPL) addition to ECM enhanced the retention of apoB-containing lipoproteins. In the present studies we examined whether the oxidation of low density lipoprotein (LDL) increases its retention by LPL-containing ECM. Except where noted, 125I-labeled moderately oxidized LDL (ModOxLDL) was prepared by long term storage of 125I-LDL. Without LPL, 125I-ModOxLDL matrix binding was low and nonsaturable. LPL preanchored to ECM resulted in 125I-ModOxLDL binding that was saturable and 20-fold greater than in the absence of LPL, with an association constant equal to 2.6 nM. Copper-oxidized LDL (Cu-OxLDL) was able to compete with 125I-ModOxLDL, whereas a 60-fold native LDL excess had no effect. Reconstituted apolipoprotein B from Cu-OxLDL also reduced 125I-ModOxLDL to LPL, whereas liposomes derived from the lipid extract of Cu-OxLDL had no effect on binding. These data suggest that the increased binding of oxidized LDL to LPL-ECM may be due to the exposure of novel apoB binding sites and not an oxidized lipid moiety. 125I-ModOxLDL binding was also not affected by either preincubation with a 300-fold molar excess of apoE-poor HDL or an 340-fold molar excess of Cu-Ox-HDL. In contrast, a 4-fold apoE-rich HDL excess (based on protein) totally inhibited 125I-ModOxLDL matrix retention. Positively charged peptides of polyarginine mimicked the effect of apoE-rich HDL in reducing the 125I-ModOxLDL retention; however, polylysine had no effect. We postulate that the oxidation of LDL may be a mechanism that enhances LDL retention by the ECM-bound LPL and that the protective effects of apoE-containing HDL may in part be due to its ability to block the retention of oxidized LDL in vivo.

Animals↗
PubMed1983

Insulin regulation of fat cell ribosomes, protein synthesis, and lipoprotein lipase.

Ribosomes of high purity were isolated from fat cells by discontinuous sucrose gradient centrifugation. Approximately 23% of the ribosomes were membrane bound. A reproducible fraction of ribosomes was recovered as polysomes capable of incorporating [3H]leucine into peptides in a cell-free system. Insulin (0.1-1.0 mU/ml) produced an increase in polysomal activity. Linear sucrose gradient profiles also revealed an increase in the ratio of polysomes to total ribosomes. Coincident with this effect, insulin increased the lipoprotein lipase activity fraction inhibitable by cycloheximide (0.01 mg/ml), and the immunotitratable enzyme activity. Insulin also enhanced the incorporation of labeled amino acids into adipose tissue immunoprecipitable lipoprotein lipase and total fat cell proteins. Cordycepin (0.1 mg/ml) or alpha-amanitin (10 micrograms/ml) partially inhibited insulin effects on ribosomes and protein synthesis but not on lipoprotein lipase. EGTA (1mM) prevented all of the insulin effects, whereas the calcium ionophore A-23187 (2 microM) augmented the hormone actions. The ionophore alone partially mimicked the insulin effects. In adipocytes, insulin increased the size of the protein-synthesizing polysomal pool by a mechanism which, in part, requires nuclear mRNA processing. Insulin, however, increased lipoprotein lipase synthesis independent of nuclear events. Calcium ions may be important for the expression of these insulin effects.

Adipose Tissue↗
PubMed1997

Species differences between chickens and rats in chemical properties of adipose tissue lipoprotein lipase.

Chemical characterization of chicken and rat lipoprotein lipase (LPL) was carried out following purification of LPL. Molecular weight and isoelectric point of both purified enzymes were determined to be 60 KDa and pH 4, while optimum temperature and pH to yield the maximal activity were about 37 degrees C and pH 8.5. Metallic ions, NaCl and protamine sulfate reduced, and heparin increased, both LPL activities. Michaelis constants for LPLs determined with triolein emulsion as the substrate were 0.98 and 1.57, and those of Vmax were 379.2 and 181.3, in chickens and rats, respectively. Triton WR-1339 caused mixed-type inhibition in rat, but inhibited chicken LPL noncompetitively. In LPLs of chickens and rats, values of Ki were 66.7 and 36.4 with triolein emulsion as the substrate, and 832.4 and 66.0 with respective VLDL as the substrate. These results show species difference between chickens and rats in the affinity to lipoproteins of LPL and inhibition of LPL by Triton WR-1339.

Adipose Tissue↗
PubMed1976

Activity of lipoprotein lipase in adipose tissues from steers.

Mean lipoprotein lipase activities (mueq fatty acids released/h per g tissue) and lipid content(%) in adipose tissue of steers from brisket, perirectal, subcutaneous abdominal, and mesenteric areas were 32, 32, 30, 50, and 73, 77, 64, and 85. The enzyme activity was higher in mesenteric tissue than in the other sites which did not differ from each other. Mesenteric adipose tissue had higher and subcutaneous abdominal adipose tissue had lower lipid content than did brisket and perirectal adipose tissue. Lipid content and enzyme activity were correlated .38.

Abdomen↗