[Modification of lipoprotein lipase during its passage through the liver].
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Lipase↗
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Plasma lipoproteins and lipoprotein lipase in young diabetics with and without ketonuria.
Plasma lipoprotein and lipoprotein lipase activity have been evaluated in young diabetics with and without ketonuria and in healthy controls of the same age. Fifteen (age range 7-23 years) newly detected diabetics (8 with ketonuria, 7 non ketonuric) have been examined before starting the treatment. Five healthy medical students (age range 19-21 years) have also been studied. Both ketotic and non ketotic patients showed an impaired insulin and C-peptide response to the glucose load in comparison to controls. Ketotic patients had low lipoprotein lipase activity (p less than 0.01) and high density lipoprotein (p less than 0.01); total plasma Triglycerides and VLDL Triglyceride and Cholesterol were higher than in controls. Plasma Triglyceride and VLDL Triglyceride and Cholesterol were inversely related to lipoprotein lipase activity. Low lipoprotein lipase activity, from adipose tissue and muscle, has been found to be associated with hypertriglyceridemia and reduced HDL Cholesterol in young diabetic patients with ketonuria.
Adolescent↗
Lipoprotein lipase and hepatic lipase activity after heparin administration in abetalipoproteinemia and hypobetalipoproteinemia.
The purpose of this study was to examine whether an absence of triglyceride-rich lipoproteins (chylomicrons and very-low-density lipoproteins) in plasma is associated with any changes in the enzyme activity of lipoprotein lipase or hepatic lipase after heparin administration. To study this, the activities of hepatic lipase and lipoprotein lipase were determined in control subjects, in two patients with heterozygous hypobetalipoproteinemia, and in three patients with phenotypic abetalipoproteinemia after administration of heparin. Both enzymes showed normal activity in the patients with hypobetalipoproteinemia, but showed consistently reduced activity in the patients with abetalipoproteinemia. Hepatic lipase activity in plasma samples from these three patients obtained 15 minutes after intravenous injection of heparin was 55%, 87%, and 46% of that of the controls, whereas corresponding values in plasma samples obtained 30 minutes after heparin were 47%, 70%, and 57%, respectively. Lipoprotein lipase activity in the three patients with abetalipoproteinemia was 46%, 29%, and 34% of that of the controls in the samples obtained 15 minutes after heparin injection, whereas the values obtained after 30 minutes were 53%, 64%, and 47% of that of the controls. We conclude that an inherent absence of triglyceride-rich lipoproteins, as occurs in abetalipoproteinemia, is associated with reduced enzyme activity of both hepatic lipase and lipoprotein lipase in plasma after heparin administration.
Abetalipoproteinemia↗
Interaction of lipoprotein lipase with native and modified heparin-like polysaccharides.
1. Lipoprotein lipase (EC 3.1.1.34), which was previously shown to bind to immobilized heparin, was now found to bind also to heparan sulphate and dermatan sulphate and to some extent to chondroitin sulphate. 2. The relative binding affinities were compared by determining (a) the concentration of NaCl required to release the enzyme from polysaccharide-substituted Sepharose; (b) the concentration of free polysaccharides required to displace the enzyme from immobilized polysaccharides; and (c) the total amounts of enzyme bound after saturation of immobilized polysaccharides. By each of these criteria heparin bound the enzyme most efficiently, followed by heparan sulphate and dermatan sulphate, which were more efficient than chondroitin sulphate. 3. Heparin fractions with high and low affinity for antithrombin, respectively, did not differ with regard to affinity for lipoprotein lipase. 4. Partially N-desulphated heparin (40-50% of N-unsubstituted glucosamine residues) was unable to displace lipoprotein lipase from immobilized heparin. This ability was restored by re-N-sulphation or by N-acetylation; the N-acetylated product was essentially devoid of anticoagulant activity. 5. Partial depolymerization of heparin led to a decrease in ability to displace lipoprotein lipase from heparin-Sepharose; however, even fragments of less than decasaccharide size showed definite enzyme-releasing activity. 6. Studies with hepatic lipase (purified from rat post-heparin plasma) gave results similar to those obtained with milk lipoprotein lipase. However, the interaction between the hepatic lipase and the glycosaminoglycans was weaker and was abolished at lower concentrations of NaCl. 7. The ability of the polysaccharides to release lipoprotein lipase to the circulating blood after intravenous injection into rats essentially conformed to their affinity for the enzyme as evaluated by the experiments in vitro.
Animals↗
Weight reduction increases adipose tissue lipoprotein lipase responsiveness in obese women.
Lipoprotein lipase was measured in gluteal adipose tissue from nine obese (90.6 +/- 2.7 kg) women fasting and after the intravenous infusion of insulin and glucose before, immediately after, and 3 mo subsequent to a 14.0 +/- 1.8% (mean +/- SEM) weight reduction. Fasting adipose tissue lipoprotein lipase activity (ATLPL) decreased from 5.3 to 2.3 nEq FFA/10(6) cells per min (P less than 0.02) immediately after weight reduction, yet after weight maintenance, higher levels were again found (6.1 nEq FFA/10(6) cells per min). Although responsiveness of ATLPL to 40 mU/m2 per min of insulin infusion over 6 h was absent before weight loss, increases were seen immediately after weight loss (delta 0.8, P = 0.05) and more so (delta 7.7, P less than 0.01) after 3 mo. Moreover, whereas before weight loss the ATLPL response to ingested mixed meals (delta 0.9) was minimal, in the maintained reduced-obese state a marked increase was seen (delta 12.6, P = 0.02). Thus, because ATLPL is important to lipid filling in adipose tissue, the maintenance of high levels of fasting ATLPL and the increase in enzyme responsiveness in the reduced-obese state could play an important role in the resumption of the obese state, which so commonly follows weight reduction.
Adipose Tissue↗
The effect of lipoprotein lipase and hepatic lipase on the electrophoretic mobility of lipoprotein-X.
Lipoprotein-X containing plasma from a patient with familial lecithin:cholesterol acyltransferase (LCAT) deficiency, was used as substrate and incubated with postheparin plasma or partly purified lipases. LP-X could not be demonstrated by agar gel electrophoresis after incubation with postheparin plasma from a healthy subject, from a patient with chronic active hepatitis deficient in hepatic lipase, or with partly purified lipoprotein lipase. After incubation a marked increase in free fatty acids (FFA) was observed. In contrast LP-X was still present after incubation when postheparin plasma deficient in lipoprotein lipase or partly purified hepatic lipase was added to the substrate. Only minor changes in the concentration of FFA occurred. After addition of oleic acid to the substrate LP-X could not be demonstrated by agar gel electrophoresis. However, in the isolated low density lipoproteins, LP-X like particles were still present as viewed by electron microscopy. Our results strongly suggest that the change in electrophoretic mobility of LP-X was induced by the release of FFA. This was achieved by lipoprotein lipase, but not by hepatic lipase.
Adult↗
The role of lipoprotein lipase in the metabolism of triglyceride-rich lipoproteins by macrophages.
We have previously shown that cultured macrophages secrete lipoprotein lipase (LPL) into the culture medium. The purpose of these experiments was to determine the role of LPL in the uptake of very low density lipoproteins (VLDL). Both J774 cells and mouse peritoneal macrophages took up and degraded normotriglyceridemic VLDL in a saturable manner. Uptake of VLDL was effectively competed for by rabbit beta-VLDL, human VLDL, but not by native LDL or acetyl LDL. LPL activity accelerated saturable uptake of VLDL but was not a prerequisite for it. This was most clearly seen in experiments with apo-C-II-deficient VLDL. Although no hydrolysis of VLDL triglyceride occurred, saturable uptake and degradation of the C-II-deficient lipoprotein occurred. However, addition of apo-C-II enhanced saturable uptake. Normal VLDL also promoted cellular accumulation of both triglycerides and cholesteryl esters. Accumulation of triglyceride occurred by uptake of intact VLDL particles, by uptake of a triglyceride-depleted particle produced by the action of LPL, and by the direct uptake of free fatty acids generated by the activity of LPL. In turn, the latter process was influenced by the amount of albumin in the medium capable of being an acceptor for free fatty acids. Finally, we have shown that when albumin is present in the medium, the macrophage is capable of mobilizing most of its stored triglyceride over 24 h, even as its cholesteryl ester content remains constant. These studies may be relevant to the ability of VLDL to promote macrophage accumulation of cholesteryl ester, even as triglyceride accumulation is minimized.
Animals↗
Segments in the C-terminal folding domain of lipoprotein lipase important for binding to the low density lipoprotein receptor-related protein and to heparan sulfate proteoglycans.
Lipoprotein lipase (LpL) can mediate cellular uptake of chylomicron and VLDL remnants via binding to heparan sulfate proteoglycans (HSPG) and the endocytic alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2MR/LRP). Whereas it is established that the C-terminal folding domain binds to alpha2MR/LRP, it remains uncertain whether it binds to heparin and to HSPG. To identify segments important for binding to alpha2MR/LRP and to clarify possible binding to heparin, we produced constructs of the human C-terminal folding domain, LpL-(313-448), and of the fragment LpL-(347-448) in Escherichia coli. In addition to binding to alpha2MR/LRP, LpL-(313-448) displayed binding to heparin with an affinity similar to that of the LpL monomer, whereas it bound poorly to lipoprotein particles. Moreover, LpL-(313-448) displayed heparin sensitive binding to normal, but not to HSPG deficient Chinese hamster ovary cells. LpL-(313-448) and LpL-(347-448) showed similar affinities for binding to both purified alpha2MR/LRP and to heparin. Deletion of LpL residues 380-384 abolished the binding to LRP, whereas binding to heparin was unperturbed. The binding to both heparin and alpha2MR/LRP was essentially abolished following deletion of residues 404-430, and pretreatment of CHO cells with the peptide comprising aa 402-423 inhibited the binding of LpL-(313-448). We conclude that the C-terminal folding domain of human LpL has a site for binding to heparin and to HSPG, presumably involving amino acids within residues 404-430. Two segments of the domain are necessary for efficient binding to alpha2MR/LRP, one comprising residues 380-384 and another overlapping the segment important for binding to heparin.
Animals↗
Lipoprotein lipase.
The activity of lipoprotein lipase in the vascular bed represents the major pathway by which triglyceride fatty acid is cleared from the plasma and made available to the epripheral tissues. Recent studies on the properties of the enzyme, both solubilized and membrane-bound have provided new information on the regulation of its activity with the major triglyceride-rich lipoprotein substrates. A key role for this enzyme in the regulation of plasma triglyceride levels is indicated from studies of lipase levels in human adipose tissue and in blood plasma obtained after injection of heparin.
Adipose Tissue↗
The role of lipoprotein lipase in metabolism of normolipidemic very low density lipoprotein by macrophages.
It was demonstrated by using lipoprotein lipase (LPL) inhibitor benzene boronic acid (BBA) that LPL played a major role in the accumulation of triglycerides (TG) in mouse peritoneal macrophages exposed to rabbit normal very low density lipoproteins (N-VLDL). There wwere less free fatty acids (FFA) and much more N-VLDL-TG left in the media containing BBA than in the controls. TG accumulation in the cells was greatly diminished or even prohibited by BBA. Thus, we obtained direct evidence that LPL played a more important role than the receptor did in the uptake of N-VLDL-TG by mouse macrophages. The mechanisms of LPL action were discussed.
Animals↗
Expression and regulation of pOb24 and lipoprotein lipase genes during adipose conversion.
Lipoprotein lipase (LPL) and pOb24 mRNAs are known to be early markers of adipose cell differentiation. Comparative studies of the expression of pOb24 and LPL genes during adipose conversion of Ob1771 preadipocyte cells and in mouse adipose tissue have shown the following: 1) the expression of both genes takes place at confluence; this event can also be triggered by growth arrest of exponentially growing cells at the G1/S stage of the cell cycle; 2) In contrast to glycerol-3-phosphate dehydrogenase mRNA, the emergence of pOb24 and lipoprotein lipase mRNAs requires neither growth hormone or tri-iodothyronine as obligatory hormones nor insulin as a modulating hormone; 3) in mouse adipose tissue, pOb24 mRNA is present at a high level in stromal-vascular cells and at a low level in mature adipocytes, and in contrast LPL mRNAs are preferentially expressed in mature adipocytes. Thus, these two genes do not appear to be regulated in a similar manner, as also shown by the differential inhibition of their expression by tumor necrosis factor (TNF) and transforming growth factor-beta (TGF-beta).
Adipose Tissue↗
Combined effects of lipoprotein lipase and apolipoprotein E polymorphisms on lipid and lipoprotein levels in the Stanislas cohort.
We have genotyped 1101 supposedly healthy subjects from the Stanislas cohort for the lipoprotein lipase (LPL) gene Ser417(C)-->stop (G) polymorphism and/or for the apolipoprotein (apo)E common polymorphism. Genotypic effects of the two polymorphisms on fasting serum triglycerides (TG), total cholesterol (Tchol), high density lipoprotein-cholesterol (HDLc), low density lipoprotein-cholesterol (LDLc), apoB, apoA-I, and apoE levels were studied separately for each polymorphism and in conjunction. epsilon 4 allele and high apoE levels were associated with high levels of LDLc, Tchol, apoB, and TG. The G allele of LPL was significantly associated with low TG levels. We found a clear interaction between the LPL/apoE polymorphisms and apoE levels on serum TG variation. Total variability of TG levels in women and men of 42.31% and 53.62% respectively, were mainly explained by apoE concentration and these two polymorphisms. ApoE and LPL genes simultaneously modulated TG levels.
Adult↗
Lipoprotein lipase and its role in regulation of plasma lipoproteins and cardiac risk.
For over 50 years, biologists and clinicians have studied lipoprotein lipase (LPL) and learned about its structure, function, cellular production, physiology, and human genetics. LPL is the principal enzyme that removes triglyceride from the bloodstream. It also determines plasma levels of high-density lipoprotein. Surprisingly, within the past several years, a number of new and unexpected proteins have been discovered that regulate the actions of LPL. These include the very low-density lipoprotein receptor, angiopoetin-like protein 3, and apolipoprotein A-V. In addition, mouse genetic studies have confirmed tissue culture findings of nonenzymatic roles of LPL both in lipid metabolism and atherogenesis. These basic observations are now being related to new information on human genetic polymorphism in this gene that is likely to affect clinical evaluation of lipoprotein disorders and cardiac risk.
Angiopoietin-Like Protein 3↗
Physical, chemical and immunochemical characterization of a lipoprotein lipase activator protein from pig plasma very low density lipoproteins.
Very low density lipoproteins ere isolated from plasma of swine by ultracentrifugal flotation. After delipidation, the lipid-free proteins were separated by chromatography on Sephadex G-150 AND DEAE-cellulose. A major apoprotein was isolated and shown to activate cows' milk lipoprotein lipase. Since human very low density lipoproteins also contain an activator protein, designated, apoC-II, we have called the pig protein, pig apoC-II. Pig apoC-II had a molecular weight of approximately 10 000 as determined by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. The amino acid composistion showed the absence of histidine, cysteine and tryptophan; there was no evidence for carbohydrate. Treatment of pig apoC-II with carboxypeptidase indicated COOH-terminal serine. Rabbit antisera prepared to the pig protein gave single precipitin lines of complete identity to very low density lipoproteins, apoC-11. Using anti-pig apoC-II, a radioimmunoassay was developed which provides a convenient and reproducible method for measuring 5-1000 ng of apoprotein.
Amino Acids↗
Retroviral-mediated gene transfer and expression of human lipoprotein lipase in somatic cells.
Lipoprotein lipase (LPL) is an enzyme responsible for the hydrolysis of triglyceride-rich circulating lipoproteins. Humans with complete defects in LPL activity present from infancy with failure to thrive, eruptive xanthomas, pancreatitis, and lactescent plasma. In addition, heterozygous carriers for this disorder may be at increased risk for the development of coronary artery disease. In view of a potential strategy for correcting complete or partial LPL deficiency, a 1.56-kb human LPL cDNA was inserted into a series of recombinant myeloproliferative sarcoma virus (MPSV)-based retroviral vectors under transcriptional control of the constitutive MPSV long terminal repeat (LTR). Stable gene transfer and enhanced expression of human LPL was observed at both the RNA and protein level in a variety of somatic cell types in vitro. Genetically modified cell populations included mouse NIH-3T3 fibroblasts and C2C12 myoblasts, primary human fibroblasts, and established human hematopoietic cell lines of erythroid (K562), myelocytic (HL60), and monocytic (U937,THP-1) type. The achieved levels of bioactive human LPL were found to vary widely between the different transduced cell lines, which may be critical to an approach to gene therapy. Transduced primary human fibroblasts yielded maximal elevation of LPL immunoreactive mass and activity of at least 24- and 50-fold, respectively, above constitutively expressed levels for this cell type. Human fibroblasts, therefore, appear to accommodate in vitro the complex processes readily leading to the maturation and secretion of bioactive human LPL and may serve as an effective cellular vehicle for LPL gene delivery and expression in human LPL deficiency.
3T3 Cells↗
The proline 12 alanine substitution in the peroxisome proliferator--activated receptor-gamma2 gene is associated with lower lipoprotein lipase activity in vivo.
Lipoprotein lipase (LPL) plays a key role in lipid metabolism by hydrolyzing triglycerides in circulating lipoproteins. Low LPL activity has been linked to coronary artery disease (CAD), but the factors influencing LPL expression are not completely understood. Peroxisome proliferator--activated receptor (PPAR)-gamma is a nuclear receptor regulating lipid and glucose metabolism, and a PPAR-responsive element is present in the LPL promoter. We determined the Pro12Ala polymorphism in the PPAR-gamma2 gene in 194 male CAD patients because this allele is associated with decreased PPAR activity and reduced LPL promoter activity in vitro. Presence of 12Ala was associated with 20% lower LPL activity in postheparin plasma (141 +/- 58 vs. 177 +/- 77 nmol.ml(-1).min(-1), P < 0.005). Remarkably, the influence of 12Ala on LPL was greater than that of the frequent polymorphisms (HindIII +9%, PvuII +/- 0%, 447stop +12%) in the LPL gene itself. To confirm these results in a different group of patients, we analyzed 100 diabetic patients in whom the 12Ala allele was also associated with lower LPL activity (12Ala: 132 +/- 88 vs. 190 +/- 129 nmol.ml(-1).min(-1), P < 0.05). Our data demonstrate that the Pro12Ala substitution in PPAR-gamma2 is associated with lower LPL activity in vivo and provides a new target for the analysis of genetic influences on LPL activity and CAD risk.
Aged↗
A mutation in the lipoprotein lipase gene associated with hyperlipoproteinemia type I in mink: studies on lipid and lipase levels in heterozygotes.
Severe hypertriglyceridemia was previously observed in mink. Affected animals had no detectable lipoprotein lipase activity, but normal amounts of lipoprotein lipase protein in post-heparin plasma. We have now cloned cDNA for lipoprotein lipase from normal mink and identified a single point mutation in the affected animals which most likely explains the deficiency of active lipase. The mutation is located in exon 6 and results in a Pro214Leu substitution. In heterozygote mink the levels of lipoprotein lipase activity and mass in post-heparin plasma were lower than in normal mink, but could not be used to identify carriers of the mutation. In some tissues (heart, muscle, kidney and lung), lipoprotein lipase activity was decreased to about 50%. In adipose tissue there seemed to be a mechanism to compensate for the mutation, resulting in increased mass and approximately the same activity of lipoprotein lipase as in animals not carrying the mutation. Mink had high lipoprotein lipase activity and mass in kidneys, although the levels of mRNA in kidney were many fold lower than in adipose tissue. Mink had very low levels of cholesteryl ester transfer protein activity in plasma. This may contribute to the high levels of HDL in this animal species.
Adipose Tissue↗
Heparin decreases the degradation rate of lipoprotein lipase in adipocytes.
The mechanism responsible for the stimulation of secretion of lipoprotein lipase by heparin in cultured cells was studied with avian adipocytes in culture. Immunoprecipitation followed by electrophoresis and fluorography were used to isolate and quantitate the radiolabeled enzyme, whereas total lipoprotein lipase was quantitated by radioimmunoassay. Rates of synthesis of lipoprotein lipase were not different for control or heparin treatments as judged by incorporation of L-[35S]methionine counts into lipoprotein lipase during a 20-min pulse. This observation was corroborated in pulse-chase experiments where the calculation of total lipoprotein lipase synthesis, based on the rate of change in enzyme-specific activity during the chase, showed no difference between control (8.13 +/- 3.1) and heparin treatments (9.1 +/- 5.3 ng/h/60-mm dish). Secretion rates of enzyme were calculated from measurements of the radioactivity of the secreted enzyme and the cellular enzyme-specific activity. Degradation rates were calculated by difference between synthesis and secretion rates of enzyme. In control cells 76% of the synthesized enzyme was degraded. Addition of heparin to the culture medium reduced the degradation rate to 21% of the synthetic rate. The presence of heparin in cell media resulted in a decrease in apparent intracellular retention half-time for secreted enzyme from 160 +/- 44 min to 25 +/- 1 min. The above data demonstrate that the increase in lipoprotein lipase protein secretion, observed upon addition of heparin to cultured adipocytes, is due to a decreased degradation rate with no change in synthetic rate. Finally, newly synthesized lipoprotein lipase in cultured adipocytes is secreted constitutively and there is no evidence that it is stored in an intracellular pool.
Adipose Tissue↗