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PubMed2000

The release of lipoprotein lipase from 3T3-L1 adipocytes is regulated by microvessel endothelial cells in an insulin-dependent manner.

Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of serum triglycerides associated with the lipoprotein particles very low density lipoprotein and chylomicrons. The cell biology of LPL is complex. It functions while tethered to the extracellular matrix of the capillary endothelium. LPL is synthesized, however, in the parenchymal cells (for example, adipocytes or muscle cells) subtending the endothelium. Thus, after synthesis in and release by the parenchymal cell, LPL must move to the endothelial cell and across this cell monolayer before expression at its physiologically relevant location. LPL expression on the endothelium is regulated by insulin. The intent of this study was to ascertain the role of microvessel endothelial cells in the release of LPL from 3T3-L1 adipocytes and to ascertain whether insulin regulates the function of the endothelial cells. Endothelial cells were treated with insulin, and the resultant culture medium conditioned by the endothelial cells was placed on 3T3-L1 adipocytes. The release of LPL from the adipocytes induced by the endothelial cell-conditioned medium was then quantitated. Insulin concentrations as low as 100 pM stimulated the release of a factor from the endothelial cells. This factor, when added to adipocytes, caused the quantitative release of LPL from the plasma membrane of the adipocytes. The effect of insulin on the endothelial cells was maximal within 15 min of insulin addition to the endothelial cells. Repeated challenges of the endothelial cells with insulin resulted in the repeated release of the LPL release factor from the endothelial cells if the challenges were separated by periods of 2-3 h. However, if the endothelial cells were chronically stimulated with insulin for 18 h, a subsequent acute stimulation with insulin did not generate any LPL release factor. Thus, microvessel endothelial cells regulate the mobilization of LPL from adipocytes in an insulin-dependent manner.

3T3 Cells↗
PubMed1998

Comparison of RRR-alpha- and all-rac-alpha-tocopherol uptake by permanent rat skeletal muscle myoblasts (L6 cells): effects of exogenous lipoprotein lipase.

The purpose of the present investigation was to test whether permanent skeletal muscle cells (rat L6 cells) could serve as an in vitro model for alpha-tocopherol (alphaTocH) biodiscrimination studies. L6 cells were incubated in the presence of high density lipoprotein (HDL), low density lipoprotein (LDL), and very low density lipoprotein (VLDL) labeled in the lipid moiety with either all-rac- or RRR-[14C]alphaTocH. These incubations were performed either in the absence or in the presence of exogenously added bovine lipoprotein lipase (LPL) since skeletal muscle is one of the major expression sites of LPL in vivo. Time-dependent uptake studies (up to 24 h) in the absence of LPL have shown that equipotent doses of all-rac- and RRR-[14C]alphaTocH (1.36:1) led to almost identical accumulation of the tracer, independent of the lipoprotein class used as alphaTocH carrier. With regard to alphaTocH donor capacity, it appeared that HDL is the most potent alphaTocH donor, followed by LDL and VLDL. In the presence of LPL, all-rac- and RRR-[14C]alphaTocH uptake was significantly enhanced (between two- and tenfold). Biodiscrimination studies using chiral high-performance liquid chromatographic analysis with radiometric detection of the corresponding methyl ether derivatives on a Chiralcel OD column have demonstrated that the 2S-and 2R-isomers of alphaTocH were taken up in a 1:1 ratio by L6 cells independent of the absence or presence of LPL. In addition, we have not observed biodiscrimination between the four 2R-isomers, i.e., there was no preferential accumulation of the RRR-isomer. These data suggest that L6 cells do not discriminate between different alphaTocH isomers and that the addition of endogenous LPL significantly enhances the uptake of RRR- and all-rac-alphaTocH.

Animals↗
PubMed1981

Lipoprotein lipase activity in adipose tissue and skeletal muscle of human diabetics during insulin deprivation and restoration.

Twelve insulin-dependent diabetic patients were deprived of insulin for 12 h, and thereafter given an 8-h i.v. infusion of insulin. Lipoprotein lipase (LPL) activity was determined from heparin eluates of adipose tissue and skeletal muscle before and after insulin infusion. In spite of development of marked hyperglycemia and hyperketonaemia during the insulin deprivation the LPL activity of the two tissues remained mostly within normal range. During the subsequent insulin administration the LPL activity of adipose tissue increased by 36% (p less than 0.05) whereas the skeletal muscle LPL remained unchanged. The result is compatible with the view that human adipose tissue LPL is more sensitive to insulin than the corresponding enzyme of muscle.

3-Hydroxybutyric Acid↗
PubMed1992

Lipoprotein lipase genotypes for a common premature termination codon mutation detected by PCR-mediated site-directed mutagenesis and restriction digestion.

We have developed a procedure for the determination of a common mutation in exon 9 of the human lipoprotein lipase (LPL) gene. The mutation is due to a C-G transversion which creates a premature termination codon (Ser447-Ter) and results in a truncated LPL molecule lacking the C-terminal dipeptide SER-GLY. The mutation can be detected by polymerase chain reaction (PCR) amplification of exon 9 using a modified 3' amplimer that produces a 140 bp product containing a site for the restriction enzyme Hinf-1 in the presence of the mutation (G allele). The G allele was in strong linkage disequilibrium with a Hind-III restriction fragment length polymorphism (RFLP) allele in intron 8. Genotype determinations for the mutation can be performed by PCR amplification of genomic DNA, digestion with Hinf-1, and analysis of the products by polyacrylamide gel electrophoresis. The allelic frequency of the Ser447-Ter mutation in normal male Caucasian controls was 0.11. The frequency of the mutation was lower in a group of subjects with primary hypertriglyceridemia compared to normolipidemic controls.

Adult↗
PubMed1986

Protein kinase activation of heparin-releasable lipoprotein lipase in rat heart.

An attempt was made to activate the capillary-bound fraction of lipoprotein lipase (LPL) with cAMP-dependent protein kinase catalytic subunit (PKC). Following a 30s washout period, hearts were perfused for 1 min with buffer containing heparin. Medium was collected during the second 30s of heparin perfusion. Addition of PKC+Mg-ATP to this capillary bed perfusate increased LPL activity from 6.84 +/- 0.72 nmol/ml/min to 13.76 +/- 1.12 nmol/ml/min (P less than 0.001). A similar 2-fold increase in activity was observed when results were expressed on a mg protein basis. Removal of serum from, or addition of 1.0M NaCl to, the assay system inhibited PKC-stimulated LPL activity approximately 85%. These results indicate that capillary alkaline LPL can be activated by PKC assayed under experimental conditions free of other TG lipases. Moreover, these findings suggest that the intracellular fraction of LPL can be activated by cAMP and that this activation is mediated through protein phosphorylation by cAMP-dependent protein kinase.

Adenosine Triphosphate↗
PubMed2001

Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice.

Previous studies with hypertriglyceridemic APOC3 transgenic mice have suggested that apolipoprotein C-III (apoC-III) may inhibit either the apoE-mediated hepatic uptake of TG-rich lipoproteins and/or the lipoprotein lipase (LPL)-mediated hydrolysis of TG. Accordingly, apoC3 knockout (apoC3(-/-)) mice are hypotriglyceridemic. In the present study, we attempted to elucidate the mechanism(s) underlying these phenomena by intercrossing apoC3(-/-) mice with apoE(-/-) mice to study the effects of apoC-III deficiency against a hyperlipidemic background. Similar to apoE(+/+) apoC3(-/-) mice, apoE(-/-)apoC3(-/-) mice exhibited a marked reduction in VLDL cholesterol and TG, indicating that the mechanism(s) by which apoC-III deficiency exerts its lipid-lowering effect act independent of apoE. On both backgrounds, apoC3(-/-) mice showed normal intestinal lipid absorption and hepatic VLDL TG secretion. However, turnover studies showed that TG-labeled emulsion particles were cleared much more rapidly in apoC3(-/-) mice, whereas the clearance of VLDL apoB, as a marker for whole particle uptake by the liver, was not affected. Furthermore, it was shown that cholesteryl oleate-labeled particles were also cleared faster in apoC3(-/-) mice. Thus the mechanisms underlying the hypolipidemia in apoC3(-/-) mice involve both a more efficient hydrolysis of VLDL TG as well as an enhanced selective clearance of VLDL cholesteryl esters from plasma. In summary, our studies of apoC3(-/-) mice support the concept that apoC-III is an effective inhibitor of VLDL TG hydrolysis and reveal a potential regulating role for apoC-III with respect to the selective uptake of cholesteryl esters.

Animals↗
PubMed1996

Postprandial serum lipids and tissue lipoprotein lipase are acutely altered in rats by the alpha-glucosidase inhibitor acarbose.

The purpose of this study was to evaluate the consequences of the acarbose-induced attenuation of postprandial glycemia and insulinemia on plasma lipid concentrations and on tissue lipoprotein lipase (LPL) activity. Rats were fed a high-sucrose diet ad libitum for two weeks. On the day of the experiment, half of the animals were given a high-sucrose meal, whereas the other half were given acarbose (10 mg/kg body weight) mixed with the meal. Serum lipids and tissue LPL activity were assessed in samples collected one hour after meal intake. Glycemia was comparable in both groups, whereas serum insulin in acarbose-fed rats was half that of control animals. The main effects of acarbose on postprandial lipids consisted of a lowering of triacylglycerols (-50%) and non-high density lipoprotein cholesterol. LPL was not altered by acarbose in white and brown adipose tissues, but was higher in the heart (+33%). The effects of acarbose on postprandial serum lipids are consistent with a slower rate of de novo lipogenesis from carbohydrate precursors and a consequent lowering of very-low density lipoprotein secretion into the circulation. In addition, the acarbose-induced dampening of the postprandial excursion of insulin may have maintained higher LPL activity in the heart, which would be liable to participate in the hypotriacylglycerolemic action of the inhibitor.

Acarbose↗
PubMed1999

Mutations in the lipoprotein lipase gene associated with ischemic heart disease in men. The Copenhagen city heart study.

The aim of this study was to test the hypothesis that the Asp9Asn substitution and the T(-93)-->G mutation in the promoter of the lipoprotein lipase gene affect plasma lipid levels and thereby the risk of ischemic heart disease (IHD). We genotyped 9033 men and women from a general population sample and 940 patients with IHD. The frequency of both the G allele and the Asn9 allele in the general population sample was approximately 0.015 for both men and women. These 2 mutations appeared together in 95% of carriers. The average triglyceride-raising effect associated with double heterozygosity for the T(-93)-->G mutation and the Asp9Asn substitution was 0.28 mmol/L (P=0.004) and 0.16 mmol/L (P=0.10) in men and women, respectively. On logistic regression analysis allowing for age, the risk of IHD for double heterozygous men and women was increased 90% (95% confidence interval [CI], 20% to 200%) and 30% (95% CI, -40% to 170%), respectively, compared with noncarriers. When, in addition, other conventional cardiovascular risk factors were allowed for, the risk of IHD for double heterozygous men and women was increased 70% (95% CI, 0% to 190%) and 20% (95% CI, -50% to 180%), respectively. Of the overall risk of IHD in men in the general population, the fraction attributable to double heterozygosity was 3%, similar to the 5% attributable to diabetes mellitus. These results demonstrate that the Asp9Asn substitution is in linkage disequilibrium with the T(-93)-->G mutation and that the double-heterozygous carrier status is associated with elevated plasma triglycerides and an increased risk of IHD in men.

Adult↗
PubMed1990

Effects of omega-3 fish oils on plasma lipids, lipoprotein composition, and postheparin lipoprotein lipase in women with IDDM.

Because the apparent reduction in cardiovascular risk noted in nondiabetic populations that ingest diets rich in marine lipids containing omega-3 fatty acids is believed to result in part from their capacity to modify the composition and physicochemical behavior of lipoproteins, we sought to determine whether dietary supplementation with marine lipids might favorably affect lipoprotein composition in insulin-dependent diabetes mellitus (IDDM). Eight normolipidemic IDDM women (mean +/- SD age 29.8 +/- 4.7 yr) were studied before and 3 mo after receiving a marine-lipid concentrate (Super-EPA) containing 6 g omega-3 fatty acids and a total of 12 mg of cholesterol daily. Weight, insulin requirements, and glycosylated hemoglobin remained stable. After treatment, mean +/- SD plasma triglyceride (TG) levels fell (before, 81.7 +/- 22 mg/dl; after, 69.19 +/- 17; P less than 0.025). High-density lipoprotein2 (HDL2) cholesterol (before, 10.98 +/- 5.45 mg/dl; after, 18.43 +/- 7.93; P less than 0.01), its major apolipoprotein A-I (apoAI), and the major phospholipids (sphingomyelin and lecithin) all rose significantly. ApoB and plasma and low-density lipoprotein cholesterol levels and HDL3 composition were unchanged. Postheparin hepatic and lipoprotein lipase activities were unaffected by marine lipids. These data indicate that women with IDDM experience apparently beneficial effects on TG and HDL2 from dietary supplementation with omega-3 fatty acids administered in a low-cholesterol-containing oil without adversely affecting overall diabetes management. If these changes in lipoprotein concentration and composition prove to have antiatherogenic consequences and are free of long-term toxicity, these agents may have a role in the therapy of IDDM patients.

Adult↗
PubMed1992

Inhibition of myocardial lipoprotein lipase by U-57,908 (RHC 80267).

U-57,908 (RHC 80267) was shown to inhibit lipoprotein lipase (LPL) activity in cardiac myocytes from rat hearts; the concentrations required for inhibition to 50% of control activity were 1.1 microM and 2.5 microM for myocyte homogenates and a post-heparin medium preparation, respectively. The inhibition of LPL activity by U-57,908 was not changed when the concentration of the triolein substrate and apolipoprotein CII activator in the assay was reduced. The availability of U-57,908 as a potent and selective LPL inhibitor may provide a useful experimental approach in studies on lipoprotein metabolism.

Animals↗
PubMed1992

The lipoprotein lipase Gly188----Glu mutation in South Africans of Indian descent: evidence suggesting common origins and an increased frequency.

Lipoprotein lipase (LPL) plays a crucial role in the hydrolysis of the triglyceride core of circulating chylomicrons and very low density lipoproteins (VLDL) and also has a major effect on the levels and lipid composition of high density lipoproteins (HDL). LPL deficiency is inherited as an autosomal recessive trait and most commonly presents with chylomicronaemia, abdominal pain, and eruptive xanthomata. We have previously described a mutation in exon 5 of the LPL gene which results in a substitution of glutamic acid for glycine at amino acid 188. We have now assessed 16 South African LPL deficient patients from nine separate kindreds for this mutation. Nine of these probands were homozygous for the mutation and were from four families, all of Indian descent. The ancestors of these probands have their origins in villages close to Bombay, India, which suggests a common ancestral mutation for the four Indian kindreds, particularly as the mutant allele in each family carried the identical restriction fragment length polymorphism (RFLP) haplotype. The presence of at least nine affected subjects in this small community around Cape Town is evidence for a higher than expected gene frequency for LPL deficiency in this population.

Base Sequence↗
PubMed2000

Influence of bovine growth hormone and growth hormone-releasing factor on messenger RNA abundance of lipoprotein lipase and stearoyl-CoA desaturase in the bovine mammary gland and adipose tissue.

Our objective was to determine the influence of bovine growth hormone (bGH) and bovine growth hormone-releasing factor (bGRF) administration on the mRNA abundance of lipoprotein lipase (LpL) and stearoyl-CoA desaturase (SCD). Primiparous Holstein cows received bGH, bGRF, or no treatment from 118 to 181+/-1 d postpartum. We hypothesized that bGH and bGRF treatment would increase the mRNA abundance of both SCD and LpL in the mammary gland with a corresponding reduction in adipose tissue. Milk yield significantly increased but milk fat percentage did not change as a result of bGH or bGRF treatment. Short-, medium-, and long-chain fatty acid concentrations in milk were not affected by either bGH or bGRF treatments, with the exception of a modest, but significant, increase in C16:1 and C18:1 following bGH treatment. Analysis was conducted on the genes encoding LpL (E.C. 3.3.1.34), a key enzyme involved in the uptake of fatty acids into tissues, and SCD (E.C. 1.14.99.5), which is the enzyme responsible for introducing delta9 double bonds in fatty acids of 16 and 18 carbons in length. In adipose tissue, treatment with bGH and bGRF reduced the mRNA abundance of LpL to 14.6 and 25.7% respectively, of that observed for control animals. Similarly, these treatments reduced the SCD mRNA abundance to undetectable levels in adipose tissue. In mammary gland, bGH and bGRF had no significant impact on LpL mRNA abundance. Bovine GH did not significantly affect SCD mRNA abundance in the mammary gland, and bGRF reduced SCD mRNA abundance. From this study to examine the role of bGH and bGRF on the expression of the genes encoding these key lipogenic enzymes in cattle, we conclude that the increased substrate required for enhanced milk fatty acid yield may have been provided through redirection of nutrients to the mammary gland away from adipose tissue and through overall increased metabolism in the mammary gland.

Adipose Tissue↗
PubMed1990

Lipoprotein lipase activity in the liver of starved pregnant rats.

We have previously described the appearance of lipoprotein lipase (LPL)-like activity in the liver of 24-hour-starved 21-day pregnant rat, but it is not known up to what point the appearance of this activity depends on the gestation stage and/or the length of the starvation period. We found that 24 h of starvation resulted in the appearance of LPL-like activity in the liver of 21-day-pregnant but not in 17-day- or nonpregnant rats. This appearance was found only after 24 h but not after 48 or 72 h of starvation. We demonstrate that this activity actually corresponds to LPL, since it is inhibited by either 1.5 M NaCl or 1.5 mg/ml protamine sulfate, is serum-dependent, and could be separated from hepatic lipase activity by using heparin-Sepharose affinity chromatography. The possible relationship between the appearance of LPL activity in the liver and the enhanced metabolic response to starvation in pregnant rats at term is discussed. It is suggested that the presence of this enzyme in the liver would allow the direct uptake by the liver of circulating triacylglycerols.

Adipose Tissue↗
PubMed1985

Studies on inactivation of lipoprotein lipase: role of the dimer to monomer dissociation.

Sedimentation equilibrium analysis demonstrated that preparations of bovine lipoprotein lipase contain a complex mixture of dimers and higher oligomers of enzyme protein. Enzyme activity profiles from sedimentation equilibrium as well as from gel filtration indicated that activity is associated almost exclusively with the dimer fraction. To explore if the enzyme could be dissociated into active monomers, 0.75 M guanidinium chloride was used. Sedimentation velocity measurements demonstrated that this treatment led to dissociation of the lipase protein into monomers. Concomitant with dissociation, there was an irreversible loss of catalytic activity and a moderate change in secondary structure as detected by circular dichroism. The rate of inactivation increased with decreasing concentrations of active lipase, but addition of inactive lipase protein did not slow down the inactivation. This indicates that reversible interactions between active species precede the irreversible loss of activity. The implication is that dissociation initially leads to a monomer form which is in reversible equilibrium with the active dimer, but which decays rapidly into an inactive form, and is therefore not detected as a stable component in the system.

Animals↗
PubMed2003

A common truncated variant of lipoprotein lipase in the Japanese population is characterized by pattern B phenotype.

To investigate the relationship between the lipoprotein lipase Ser447Ter (S447X) mutation, lipid profiles and risk of atherosclerotic disease, we studied two groups of Japanese subjects. These groups consisted of a dyslipidemic group (triglyceride (TG) > 1.69 mmol/l and high-density lipoprotein-cholesterol (HDL-C) < or = 0.91 mmol/l; n = 106) and a control group (TG < or = 1.69 mmol/l and HDL-C > or = 1.16 mmol/l; n = 106). All subjects in the control group were confirmed to the pattern A phenotype (normal low-density lipoprotein (LDL) pattern), and 21 individuals in this group were heterozygous for the S447X mutation, but not homozygous. In the patient group, pattern A was shown by 44 of 106 patients. The rest were of the pattern B phenotype, which is associated with an increased risk of coronary heart disease. Homozygosity was concentrated in the patient group (p < 0.05) and in those with the pattern B phenotype (p < 0.05). In contrast, heterozygosity between both groups was not statistically significant. In conclusion, heterozygous and homozygous status with respect to the LPL S447X mutation appears to have different meanings with respect to biochemical and clinical phenotypes of atherosclerosis.

Adolescent↗
PubMed1985

The mechanism of activation of lipoprotein lipase by apolipoprotein C-II. The formation of a protein-protein complex in free solution and at a triacylglycerol/water interface.

The binding of lipoprotein lipase to a fluorescently labelled apolipoprotein C-II in free solution has been followed by measuring fluorescence anisotropy. The formation of a weak, binary complex in which a single apolipoprotein C-II molecule associates non-cooperatively with each subunit of the dimeric enzyme was observed. The dissociation constant for this complex in 0.05 M NaCl is 0.2 X 10(-6) M and it is weakened markedly by raising the salt concentration and by the binding of heparin to the enzyme. The assembly of the same protein-protein complex on the surface of glycerol trioleate globules has been monitored by steady-state and pre-steady-state kinetics. In these circumstances the lipoprotein lipase-apolipoprotein C-II interaction is much tighter (Kd = (7-10) X 10(-9) M) and is insensitive to salt and heparin. The mechanism of activation of the enzyme at low concentrations of apolipoprotein C-II is described by a kinetic model in which apolipoprotein C-II binds preferentially to the form of the enzyme which is associated with the triacylglycerol substrate. This preference leads to a stabilization of the enzyme-substrate complex, thus reducing the apparent Ks.

Apolipoprotein C-II↗