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PubMed2000

Substitution of asparagine for aspartic acid at residue 9 (D9N) of lipoprotein lipase markedly augments risk of ischaemic heart disease in male smokers.

Genetic variants of lipoprotein lipase (LPL), a key enzyme in the hydrolysis of triglyceride (TG)-rich particles, may contribute to ischaemic heart disease (IHD) risk. We have examined the risk of IHD in carriers of two common LPL variants, asparagine substitution for aspartic acid at residue 9 (D9N) and serine for asparagine at residue 291 (N291S) in 2708 middle-aged healthy European men, followed for over 6 years. The carrier frequencies were 2.6% for N9, and 3.9% for S291. Both variants were associated with higher plasma TG at baseline of 9% and 14%, respectively. At baseline, 28% of men were current smokers and smoking was unrelated to genotype. Associations between LPL variants and disease outcome, according to smoking status, were assessed by Cox's proportional hazards analysis. S291 carriers showed no increased risk of IHD compared to non-carriers, while there was strong evidence of interaction between D9N genotype and smoking status (P = 0.0003) in determining the risk of IHD. In 2248 non-carriers of N9, smoking increased the risk of an IHD event by 1.6 (95% CI: 1.1-2.4%) times. Among 58 N9 carriers, no IHD events occurred in 42 who were non-smokers, whereas five events were reported in 16 who smoked. The combined effect of smoking and N9 allele was to increase the risk of an IHD event by 10.4 (95% CI: 4.7-22.8%) times compared with D9 non-smokers. These findings could not be explained by confounding effects of baseline TG. Carriers of N9 appear to be especially vulnerable to the adverse effects of cigarette smoking on IHD risk, but this susceptibility is unrelated to the influence of this variant on plasma TG levels.

Asparagine↗
PubMed1999

A corepressor and chicken ovalbumin upstream promoter transcriptional factor proteins modulate peroxisome proliferator-activated receptor-gamma2/retinoid X receptor alpha-activated transcription from the murine lipoprotein lipase promoter.

Complex physiological stimuli differentially regulate the tissue-specific transcription of the lipoprotein lipase (LPL) gene. A conserved DNA recognition element (-171 to -149 bp) within the promoter functions as a transcriptional enhancer when bound by the peroxisome proliferator-activated receptor-gamma2 (PPARgamma2)/retinoid X receptor alpha (RXRalpha) heterodimer, but serves as a transcriptional silencer in the presence of unidentified double and single stranded DNA-binding proteins. To address this apparent paradox, the current study examined the effect of two classes of candidate comodulatory proteins, COUP-TF (chicken ovalbumin upstream promoter transcriptional factor) and the corepressor SMRT (silencing mediator of retinoic acid receptor and thyroid receptor). The expression of COUP-TF was detected by Western and Northern blots in a preadipocyte 3T3-L1 cell model during periods corresponding to increased LPL transcription. Cotransfection of COUP-TF expression constructs in the renal epithelial 293T cell line significantly increased transcription from the LPL promoter in synergy with PPARgamma2/RXRalpha heterodimers. The COUP-TFII (ARP-1) protein specifically bound the LPL PPAR recognition element inelectromobility shift assays and interacted directly with the ligand-binding domain of PPARgamma in pull-down experiments. In contrast, cotransfection of SMRT repressed PPARgamma2/ RXRalpha-mediated LPL transcription in the absence or presence of COUP-TFII (ARP-1). The interaction between PPARgamma2 and SMRT localized to the receptor-interactive domain 2 (amino acids 1260-1495) of the SMRT protein based on cotransfection and pull-down assays. These in vitro data indicate that COUP-TF proteins and SMRT modulate PPARgamma-mediated LPL transcription in the 293T cell line.

3T3 Cells↗
PubMed2002

Autoantibodies to lipoprotein lipase and dyslipidemia in systemic lupus erythematosus.

OBJECTIVE: To demonstrate the binding of bovine lipoprotein lipase (LPL) by IgG from sera obtained from patients with systemic lupus erythematosus (SLE) and other rheumatic diseases, and the relationship of anti-LPL to triglyceride levels in SLE. METHOD: Binding of LPL by IgG from sera obtained from patients with SLE and other rheumatic diseases was measured by an enzyme-linked immunosorbent assay technique. Lipid profiles for fasting blood samples obtained from SLE patients and control subjects were determined. RESULTS: Sera obtained from 105 patients with SLE were assessed for reactivity with LPL, and 49 (47%) of the results were positive. Sera obtained from patients with rheumatoid arthritis (RA) (n = 80), Sjögren's syndrome (n = 30), polymyositis and dermatomyositis (n = 30), and progressive systemic sclerosis (n = 31) were also studied, and 10 (13%), 3 (10%), 12 (40%), and 13 (42%), respectively, were positive for reactivity with LPL. It was determined that all affinity-purified anti-double-stranded DNA (dsDNA) antibodies and 4 of 5 monoclonal anti-dsDNA antibodies bound to LPL. The binding of IgG depleted of anti-dsDNA to LPL indicates a second anti-LPL activity in SLE. Measurements of fasting lipid levels in SLE patients with anti-LPL revealed a strong positive correlation of antibody levels and total serum triglycerides, apolipoprotein B, and apolipoprotein E concentrations. CONCLUSION: Antibodies to LPL occurred in 47% of SLE patients and in a similar percentage of patients with polymyositis or systemic sclerosis. The prevalence of these antibodies was less in patients with RA or Sjögren's syndrome. It is hypothesized that the elevated triglyceride levels in SLE patients are in part attributable to anti-LPL, and this lipid abnormality could contribute to the premature atherosclerosis known to be present in patients with SLE.

Apolipoproteins B↗
PubMed1978

Adipose tissue lipoprotein lipase in chronic hemodialysis: role in plasma triglyceride metabolism.

The role of adipose tissue lipoprotein lipase (LPL) in the pathogenesis of hypertriglyceridemia in uremic patients receiving maintenance hemodialysis was evaluated. The fasting level of adipose tissue LPL activity was reduced below normal (3.4 +/- 2.5 microU/106 cells; n = 23; mean +/- SD) in hypertriglyceridemic dialysis patients (1.5 +/- 0.8; P less than 0.01; n = 15) and did not differ from normal in normotriglyceridemic dialysis patients (2.5 +/- 2.4; P = NS; n = 13). The enzyme activity increased as a function of relative body weight in normotriglyceridemic hemodialysis patients (r = 0.21; P less than 0.05) but not in the hypertriglyceridemic group (r = 0.21; P = NS). There was an abnormal response of LPL to feeding in the hypertriglyceridemic dialysis patients. The postprandial level of LPL was significantly lower in hypertriglyceridemic dialysis patients (2.2 +/- 1.0; n = 9) than in normotriglyceridemic dialysis patients (3.9 +/- 1.9; P less than 0.05; n = 10) or normal controls (4.8 +/- 1.8; P less than 0.01; n = 12). Whereas the postprandial change in LPL was inversely related to the fasting enzyme activity in normotriglyceridemic dialysis patients (r = 0.74; P less than 0.02; n = 10) and in normal controls (r = 0.58; P less than 0.05; n = 12), no such relationship existed in hypertriglyceridemic dialysis patients (r = 0.17; P = NS; n = 9). Furthermore, fasting plasma triglyceride levels in the entire group of dialysis patients were a function of the postprandial level of LPL activity (rs = 0.574; P less than 0.02; n = 19). Since the level of LPL 1) is below normal in both the fasted and fed state in the hypertriglyceridemic hemodialysis patients, 2) is normal in both the fasted and fed state in the normotriglyceridemic hemodialysis patients, and 3) in the fed state is inversely correlated with the fasting plasma triglyceride concentration in the entire group of hemodialysis patients, it is proposed that adipose tissue LPL plays a role in the etiology of hypertriglyceridemia in hemodialysis patients.

Adipose Tissue↗
PubMed1993

Changes in lipoprotein lipase activities in adipose tissue, heart and skeletal muscle during continuous or interrupted feeding.

Lipoprotein lipase (LPL) activities in parametrial and interscapular adipose tissue, soleus and adductor longus muscles and hearts of female rats were measured during progressive starvation, chow re-feeding after 24 h starvation and throughout dark and light phases in rats permitted unrestricted access to chow. Adipose-tissue LPL activities declined by 50% after 6 h starvation and continued to fall as the starvation period was extended to 24 h. Skeletal-muscle LPL activities dramatically increased between 9 and 12 h of starvation. Cardiac LPL activities increased 2.5-fold within 6 h of starvation, reaching a maximum after 12 h of starvation. Adipose-tissue LPL activities increased rapidly within 2 h of re-feeding chow ad libitum after 24 h starvation, achieving 'fed ad libitum' values after 6 h. Oxidative-skeletal-muscle LPL activities also increased after 2 h of refeeding and exceeded 'fed ad libitum' values throughout the 6 h re-feeding period. Cardiac LPL activities remained up-regulated for the 6 h of re-feeding. Adipose-tissue LPL activities exceeded those of cardiac or skeletal muscle throughout both light and dark phases. The lowest adipose-tissue LPL activities were observed at 9 h into the light phase. In contrast, cardiac LPL activity declined throughout the dark phase, with a minimum at 9 h into the dark phase. No such variation was observed for skeletal-muscle LPL activities. A diurnal nadir in plasma triacylglycerol (TG) concentrations coincided with the peak in cardiac LPL activities. The results demonstrate that, during unrestricted feeding and re-feeding after prolonged starvation, changes in skeletal-muscle and adipose-tissue LPL activities are neither reciprocal nor co-ordinate. Regulation of cardiac LPL activity during the diurnal cycle may be an important aspect of both of cardiac fuel selection and whole-body TG metabolism.

Adipose Tissue↗
PubMed2004

Lipoprotein lipase gene polymorphisms and blood pressure levels in the Northern Chinese Han population.

The lipoprotein lipase (LPL) gene has been investigated extensively in linkage studies and in studies of its association with lipid profiles and coronary artery disease (CAD), and this gene has also been reported to have an association with hypertension. In our previous linkage study on 148 Chinese hypertensive families, the regions at or near the LPL gene were found to be associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP). Thus the LPL gene is a logical candidate gene for involvement in the underlying cause of essential hypertension (EH). In the present study, we identified 22 sequence variants by directly sequencing 10 exons and flanking regions of the LPL gene, and investigated the occurrence of 3 of these variants, IVS4-214C>T, 7754C>A and S447X, in a case-control study including 501 normotensive (NT) subjects and 497 EH subjects. In males, the frequencies of the genotypes of each of the 3 variants did not differ significantly between the NT and EH groups. Among the EH group in females, ANCOVA revealed no significant difference in blood pressure levels according to the 7754C>A genotype. However, in female, the distribution of the 7754C>A genotype and the frequency of the A allele of 7754C>A differed significantly between the NT and EH groups (p=0.032 and p=0.027, respectively) with 0.78 (95% confidence interval (CI): 0.56 to 1.07; p=0.12) of odds ratio for the A allele. Moreover, haplotype analysis revealed that T-A-C and T-C-G haplotypes (in the order of IVS4-214C>T, 7754C>A and S447X) were statistically more frequent in the NT group than in the EH group in females and males, respectively. Our indivisual single nucleotide polymorphism (SNP) analysis did not provide substantial evidence of an association between polymorphisms in the LPL gene and hypertension status and/or blood pressure levels in this cohort, but the more powerful haplotypes analysis suggested an association between the LPL gene and hypertension.

Adult↗
PubMed2003

Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in focal glomerulosclerosis.

BACKGROUND: Imai rats exhibit spontaneous focal glomerulosclerosis (FGS) with progressive proteinuria and hyperlipidemia leading to renal insufficiency by age 34 weeks. Recently, we reported marked down-regulations of skeletal muscle and adipose tissue lipoprotein lipase (LPL) and very low-density lipoprotein (VLDL) receptor in male Imai rats at 32 weeks of age. Dietary protein restriction and oral adsorbent AST-120 (AST) have been shown to slow progression of renal disease and attenuate hyperlipidemia in the Imai rats. This study tested the hypothesis that amelioration of proteinuria by protein restriction or use of oral adsorbent AST-120 beginning at 10 weeks of age may improve renal disease and LPL and VLDL receptor deficiencies in Imai rats. METHODS: Ten-week-old male Imai rats were randomly assigned to those fed either a regular diet, low protein diet (LPD), or regular diet containing the adsorbent preparation, AST-120. Ten-week-old male Sprague-Dawley rats served as controls. The animals were observed for 24 weeks. Six rats were included in each group. All diets were prepared in powder form. RESULTS: The untreated 34-week-old Imai rats showed severe proteinuria, hypoalbuminemia, 50% reduction in creatinine clearance, hypercholesterolemia, hypertriglyceridemia, and elevated plasma VLDL concentration. This was associated with significant reductions in plasma post-heparin LPL activity, hepatic lipase activity, as well as adipose tissue and skeletal muscle immunodetectable LPL and VLDL receptor proteins. Protein restriction mitigated the decline in creatinine clearance, ameliorated proteinuria, hypoalbuminemia, hypertension, and hypercholesterolemia, lowered plasma VLDL, and improved plasma postheparin LPL activity, hepatic lipase activity, LPL, and VLDL receptor proteins in skeletal muscle and adipose tissue. Similar improvements were observed in all parameters with AST administration. CONCLUSION: Moderate protein restriction and use of oral adsorbent can slow progression of renal disease and, thereby, ameliorate LPL, hepatic lipase, and VLDL receptor deficiencies and the associated hyperlipidemia in rats with spontaneous FGS.

Adsorption↗
PubMed1988

Lipoprotein lipase in adipose tissues of rats running during cold exposure.

This study evaluated the individual and combined effects of exercise training and intermittent cold exposure of similar energy cost on serum lipids and lipoprotein lipase (LPL) activity on epididymal white (WAT) and interscapular brown (BAT) adipose tissues of the rat. The animals were subjected daily to 2 h of treadmill running at 24 degrees C or for the same period of time at -5 degrees C, with or without exercise, for 28 days. Exercise training lowered serum triglycerides (P less than 0.01), whereas serum cholesterol was reduced by cold exposure (P less than 0.05). Cholesterol lowering occurred in the lipoproteins of lower densities. WAT weight was diminished by both treatments. Exercise training had an overall lowering effect on WAT total LPL activity (P less than 0.05), whereas cold exposure did not affect enzyme activity significantly. Exercise and intermittent cold interacted on BAT weight. Cold increased total BAT LPL activity (P less than 0.03), whereas simultaneous exercise in the cold greatly diminished this effect. Serum insulin levels were not affected by either treatment. Thus, in WAT, intermittent exposure to cold did not have any lasting effect on LPL activity, whereas exercise training decreased the latter. In contrast, exercise did not influence LPL in BAT of rats not exposed to cold but prevented the stimulation of enzyme activity induced by repeated cold exposure. These results support the notion that the regulation of LPL is tissue specific.

Adipose Tissue↗
PubMed1992

Molecular studies on primary lipoprotein lipase (LPL) deficiency. One base deletion (G916) in exon 5 of LPL gene causes no detectable LPL protein due to the absence of LPL mRNA transcript.

We have systematically investigated a genetic defect resulting in a primary lipoprotein lipase (LPL) deficiency in a proband TN and his affected brother SN, both manifesting familial hyperchylomicronemia. Neither LPL activity nor immunoreactive LPL mass was detected in postheparin plasma from the two patients. Immunocytochemical and biosynthetic studies on the proband's monocyte-derived macrophages with rabbit anti-human LPL antiserum revealed that no immunochemically detectable LPL protein was found in either the cells or culture medium, whereas LPL having a molecular mass of 61 kD was detected in normal cells. No detectable LPL mRNA was identified from poly(A)+RNA of the proband's macrophages by Northern blot analysis, and grossly visible LPL gene rearrangement was not observed by Southern blot analysis. Sequence analysis of polymerase chain reaction-amplified LPL gene exons detected one base deletion of G (first position of Ala221) at base 916 in exon 5 which leads to a premature termination by a frameshift. This mutation, designated as LPLArita and resulting in the loss of an AluI restriction enzyme site, was newly identified. We further analyzed the LPL gene from the two patients and their family members by digestion with AluI. Both patients were homozygous for LPLArita allele, while their spouses did not have this mutation. As genetically expected, their children were all heterozygous for LPLArita. We conclude that primary LPL deficiency in the proband was caused by a lack of enzyme synthesis due to the absence of LPL mRNA resulting from one base deletion of G in exon 5, and that heterozygous LPLArita deficient subjects show almost half value of control LPL mass.

Adult↗
PubMed1993

Lipoprotein lipase regulation in the cyclophosphamide-treated rabbit: dependence on nutritional status.

Cyclophosphamide injection into the fasted rabbit induces a hypertriglyceridemia (4.6 mM vs. 0.8 mM in controls) and a defect of lipoprotein lipase (LPL), as measured in post-heparin plasma (PHP). In contrast, administration of the drug into fed animals tends to increase PHP-LPL. The effects of cyclophosphamide on LPL activity and synthesis, depending on the nutritional state, were thus studied in two sites: periepididymal adipose tissue and heart. In adipose tissue, fasting decreased LPL activity to 45.2 mIU/g (P < 0.001) compared to 667.9 mIU/g in fed animals. PHP-LPL activity was also decreased by 45% upon starvation. These modulations appeared to be related to plasma insulin levels. The relative rate of synthesis of fat tissue LPL was decreased from 0.32% total protein synthesis in fed animals to 0.10% in fasted rabbits, concordant with a reduction in the expression of LPL specific mRNA. Cyclophosphamide administration to the fed rabbit led to decreases of LPL activity and synthesis in the adipose tissue, similar to those observed upon starvation. However, when injected into fasted animals, the drug did not further depress fat tissue LPL. Fasting did not change heart LPL activity (288.3 mIU/g vs. 239.3 in fed animals) nor its relative rate of synthesis (0.21% of total protein synthesis). However, cyclophosphamide induced opposite effects, depending on the nutritional state: after injection into fed animals, heart LPL activity increased up to 477.2 mIU/g (P < 0.01) with a concomitant increase in the LPL synthesis rate. Conversely, drug administration into fasted rabbits led to a decrease of heart LPL activity to 133.9 mIU/g. Similar qualitative variations were recorded in postheparin plasma. Hence, although insensitive to nutritional modulations, heart LPL responded differently to cyclophosphamide, depending on the nutritional state. In spite of those different modulations of heart and adipose tissue LPL, the enzyme isolated from these two sources displayed similar molecular mass, immunoreactivity, and catalytic properties. The effects of cyclophosphamide injection on very low density lipoprotein (VLDL)-triacylglycerol (TG) synthesis were also investigated, as a possible determinant of hypertriglyceridemia. The drug stimulated TG synthesis in both nutritional states, and maximally by 45% in fed animals. Hence, a defect of heart and postheparin plasma LPL appears as a major determinant of hypertriglyceridemia in cyclophosphamide-treated fasted rabbits.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue↗
PubMed1991

The binding of human lipoprotein lipase treated VLDL by the human hepatoma cell line HepG2.

It has been suggested that besides the LDL-receptor, hepatocytes possess an apo E or remnant receptor. To evaluate which hepatic lipoprotein receptor is involved in VLDL remnant catabolism, we studied the binding of VLDL remnants to HepG2 cells. Native VLDL was obtained from type IIb hyperlipidemic patients and treated with bovine milk lipoprotein lipase (LPL). This LPL-treated VLDL (LPL-VLDL) was used as representative for VLDL remnants. Our results show that LPL-VLDL binds with high affinity to HepG2 cells. Competition experiments showed that the binding of 125I-labelled LPL-VLDL is inhibited to about 30% of the control value by the simultaneous addition of an excess of either unlabelled LDL or LPL-VLDL. Preincubation of HepG2 cells with LDL resulted in a reduction of the binding of LDL and LPL-VLDL to 34 and 55% of the control value, whereas preincubation of the cells with heavy HDL (density between 1.16 and 1.21 g/ml) stimulated the binding of LDL and LPL-VLDL to about 230% of the control value. Preincubation of the cells with insulin (250 nM/l) also stimulated the binding of both LDL and LPL-VLDL (175 and 143% of the control value, respectively). We conclude that LPL-VLDL binds to the LDL-receptor of HepG2 cells and that no evidence has been obtained for the presence on HepG2 cells of an additional receptor that is involved in the binding of VLDL remnants.

Binding, Competitive↗
PubMedDate not supplied

Activation of lipoprotein lipase and inhibition of B16 melanoma-induced cachexia in mice by ponalrestat, an aldose reductase inhibitor.

Lipoprotein lipase (LPL) is a key regulatory enzyme responsible for the hydrolysis of triglyceride (TG)-rich lipoproteins. The reduction in LPL activity is observed in tumor bearing animals and cancer patients with cachectic symptoms, suggesting an involvement of LPL in inducing cancer cachexia. During a screening program for anti-cachectic agents we found that ponalrestat, an aldose reductase inhibitor, activates LPL activity. Ponalrestat increased the activity of LPL in adipose tissue in mice. The effect of ponalrestat on B16 melanoma-induced cachectic symptoms was next investigated in mice. The decrease in the weight of epididymal fat, carcass and whole body lipid was observed in mice following intraperitoneal inoculation of B16, compared to mice without the tumor inoculation. Treatment with ponalrestat resulted in the attenuation of the decrease in the tissue weight. The increase in the levels of TG and non-esterified fatty acid, and a decrease in the level of glucose in the blood, which was induced by the presence of tumor, were also restored to those of normal mice following ponalrestat treatment. The reduction in locomotor activity in tumor bearing mice was partially restored by the treatment with ponalrestat. Overall, this study demonstrated that ponalrestat, an aldose reductase inhibitor, possesses potent LPL activating activity and that the cachexia induced by B16 melanoma was alleviated by treatment with 'ponalrestat, suggesting that ponalrestat, a LPL activating agent, has a therapeutic potential for the treatment of cancer cachexia.

3T3 Cells↗
PubMed1999

GH but not IGF-I or insulin increases lipoprotein lipase activity in muscle tissues of hypophysectomised rats.

Changes in GH secretion are associated with changes in serum lipoproteins, utilisation of fuels and body composition. Since lipoprotein lipase (LPL) is a key enzyme in the regulation of lipid and lipoprotein metabolism, changes in LPL activity may contribute to these effects of GH. The present study was undertaken to investigate the role of GH and the GH-dependent growth factor, IGF-I, in the regulation of LPL in heart, skeletal muscle and adipose tissue. Female rats were hypophysectomised at 50 days of age. One week later, hormonal therapy was commenced. All hypophysectomised rats received l-thyroxine and cortisol. Adipose tissue, the heart, soleus and gastrocnemius muscles were excised after 1 week of hormonal therapy. The effect of insulin injections on adipose tissue and heart LPL activity was also studied. In separate experiments, LPL activity in post-heparin plasma was measured. Hypophysectomy had no effect on adipose tissue LPL activity, whereas activity was reduced in heart, soleus and gastrocnemius muscle tissues. GH treatment had no significant effect on LPL activity in adipose tissue or soleus muscle, but increased the LPL activity in heart and gastrocnemius muscle. GH treatment increased post-heparin plasma LPL activity. Recombinant human IGF-I treatment (1.25 mg/kg per day) markedly reduced LPL activity in adipose tissue, but had no effect in muscle tissues. The effect of IGF-I treatment on adipose tissue LPL was not reflected by a decrease in post-heparin plasma LPL activity. Daily injections of insulin for 7 days increased LPL activity in adipose tissue but had no effect on heart LPL activity. In adipose tissue, LPL mRNA levels tended to decrease as a result of IGF-I treatment. In the muscle tissues, no significant effects of hypophysectomy, GH or IGF-I treatment on LPL mRNA levels were observed.%It is concluded that GH increases heart and skeletal muscle tissue LPL activity, which probably contributes to an increased post-heparin plasma LPL activity. The effect of GH on muscle LPL activity is probably not mediated by IGF-I or insulin. Insulin and IGF-I have opposite effects on LPL activity in adipose tissue.

Adipose Tissue↗
PubMed1997

Lipoprotein lipase correlates positively and hepatic lipase inversely with calcific atherosclerosis in homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (FH) is a rare genetic disorder that leads to premature atherosclerosis due to a defective LDL receptor. There is, however, a large degree of phenotypic heterogeneity at the level of atherosclerosis even in patients with identical mutations of the LDL receptor protein. Lipoprotein lipase (LPL) and hepatic lipase (HL) are crucial enzymes in lipoprotein metabolism, and both have been proposed as having proatherogenic as well as antiatherogenic effects. To evaluate a potential role for these enzymes in the severity of atherosclerosis, we correlated postheparin LPL mass and activity as well as HL activity with the volume of total calcific atherosclerosis (heart and thoracic aorta), coronary artery calcific atherosclerosis, and Achilles tendon width as measured by computed tomography in 15 FH homozygotes. LPL dimer and total mass were positively correlated with all three parameters (r = .65 to .87, P < .01) as was LPL activity (r = .52 to .63, P < .05). HL activity was negatively correlated with total and coronary artery calcified lesion volume (r = -.55 to .57, P < .05). In a multiple regression model of the coronary artery lesion volume, LPL dimer mass and HL activity together accounted for 84% of the variability (r = .92, P < .0001). In a multiple regression model of the total calcified lesion volume, HL activity, total cholesterol, age, and LPL dimer mass together accounted for 85% of the variability (r = .92, P = .0005). These data demonstrate a significant correlation of LPL mass and activity with the extent of calcific atherosclerosis in homozygous FH. It is not clear whether LPL is the cause or consequence of the observed correlation, but if the association between LPL and coronary artery lesions is also present in patients with other genetic dyslipoproteinemias, LPL could constitute a new risk factor for cardiovascular disease.

Achilles Tendon↗
PubMed1997

Common variation in the lipoprotein lipase gene: effects on plasma lipids and risk of atherosclerosis.

The importance of the enzyme lipoprotein lipase (LPL) in the development of dyslipidaemia and atherosclerosis is increasingly recognised. Variations in the LPL gene which are common in the general population have been shown to be associated with alterations in plasma lipids. D9N and N291S both occur at carrier frequencies of up to about 5% and have been associated with increased plasma triacylglycerol and decreased high density lipoprotein cholesterol concentrations, effects which seem to be magnified in more obese individuals. S447X carrier frequency is approximately 20%, but unlike carriers of N9 or S291, X447 carriers appear to have a more favourable lipid profile. A transition within the LPL promoter at position-93 may lead to increased LPL activity and have a beneficial effect on plasma lipids. Greater knowledge of the underlying mechanisms of these variations within the LPL gene may be of considerable importance in understanding genetic predisposition to atherosclerosis and heart disease.

Arteriosclerosis↗
PubMed1994

Stimulatory release of lipoprotein lipase activity with activation of protein tyrosine kinase produced by low molecular weight dextran sulfate in Ehrlich ascites tumor cells.

Lipoprotein lipase (LPL), which is responsible for the hydrolysis of lipoprotein triacylglyceride, has been examined in Ehrlich ascites tumor cells. Low molecular weight dextran sulfate (DXS, M.W. 3.2 kDa) stimulates the release of the enzyme activity from the tumor cells into the incubation medium in a time-dependent manner. The stimulatory effect of DXS was markedly decreased by incubation with protein tyrosine kinase (TK) inhibitors, such as ST 638, biochanin A and amiloride. The activity of the partially purified TK preparation from the tumor cells was found to be increased following incubation with DXS in a manner which was both time- and dose-dependent. These results suggest that the stimulatory release of LPL activity by DXS is associated with the activation of TK in the tumor cells.

Animals↗
PubMed1996

Lipoprotein lipase degradation by adipocytes: receptor-associated protein (RAP)-sensitive and proteoglycan-mediated pathways.

Lipoprotein lipase (LPL), the major enzyme responsible for the hydrolysis of triglycerides, is primarily synthesized by adipocytes and myocytes. In addition to synthesis, degradation of cell surface-associated LPL is thought to be important in regulating production of the enzyme. We studied LPL metabolism in the LPL synthesizing adipocyte cell line BFC-1 beta and assessed the contributions of cell surface heparan sulfate proteoglycans (HSPG), low density lipoprotein receptor related protein (LRP), and glycosylphosphatidylinositol (GPI)-linked proteins to LPL uptake and degradation by these cells. Adipocytes degraded 10-12% of total cell surface I-labeled LPL in 2 h and 23-28% in 4 h. In 1 h, 30-54% of the degradation was inhibited by the 39 kDa receptor associated protein (RAP), an inhibitor of ligand binding to LRP. At 4 h, only 19-23% of the LPL degradation was RAP inhibitable. This suggested that two pathways with different kinetics were important for LPL degradation. Heparinase/heparitinase treatment of cells showed that most LPL degradation required the presence of HSPG. Treatment with phosphatidylinositol-specific phospholipase C (PIPLC) inhibited 125I-labeled LPL degradation by 13%. However, neither RAP nor PIPLC treatment of adipocytes significantly increased the amount of endogenously produced LPL activity in the media. To determine whether direct uptake of LPL bound to HSPG could account for the non-RAP sensitive LPL uptake and degradation, proteoglycan metabolism was assessed by labeling cells with 35SO4. Of the total pericellular proteoglycans, 14% were PIPLC releasable; surprisingly, 30% were dissociated from the cells with heparin. The amount of labeled pericellular proteoglycans decreased 26% in 2 h and 50% in 8 h, rapid enough to account for at least half of the degradation of cell surface LPL. We conclude that adipocytes degrade a fraction of the cell surface LPL, and that this process is mediated by both proteoglycans and RAP-sensitive receptors.

Adipose Tissue↗