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PubMed1994

Growth hormone but not gonadal steroids influence lipoprotein lipase and hepatic lipase activity in hypophysectomized rats.

Lipoprotein lipase and hepatic lipase are involved in the degradation and cellular uptake of lipids in peripheral tissues and the liver. These enzymes seem to be influenced by gonadal steroids in the rat as well as in man. Since gonadal steroids have been shown to influence the secretory pattern of GH and since the effect of gonadal steroids on several metabolic functions may be dependent upon their effects on GH secretion, the present study was undertaken to investigate the developmental regulation of heparin-releasable lipoprotein lipase and hepatic lipase activities in female and male rats, and to study the effects of gonadal steroids and different modes of GH administration to hypophysectomized rats on these enzyme activities. Female and male Sprague-Dawley rats from 20 to 65 days of age were studied. Hypophysectomy was performed at 50 days of age and these rats were given replacement therapy with thyroxine and cortisone. Groups of hypophysectomized rats were treated with either oestradiol valerate (0.1 mg/kg per day) or testosterone enanthate (1 mg/kg per day). Bovine GH (1 mg/kg per day) was given to groups of hypophysectomized rats either by two daily subcutaneous injections or by continuous infusion using osmotic minipumps. Hormone treatment was given for 1 week. Lipoprotein lipase and hepatic lipase activities were measured in heparinized plasma. There was no difference in lipoprotein lipase activity between male and female rats at 20 to 45 days of age. Lipoprotein lipase activity decreased between 45 and 65 days of age in male rats but not in females and, at 65 days of age, lipoprotein lipase activity was higher in females compared with males.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

[The application of end user computing (EUC) for detection of lipoprotein lipase gene abnormality].

Lipoprotein lipase (LPL) is an enzyme digesting lipoprotein triglyceride (TG) in peripheral blood vessels. Most patients with LPL deficiency show very high plasma TG and low HDL-C. To establish an effective computer-based screening system to identify individuals with genetic LPL disorders, we selected 50 subjects whose plasma TG was over 350mg/dl and HDL-C was lower than 35mg/dl from patients at Hamamatsu University Hospital. We applied End User Computing (EUC) of our laboratory system to select high risk subjects with LPL gene abnormalities. Polymerase chain reaction (PCR) products from LPL gene exons 2-9 were screened by single-strand conformation polymorphism (SSCP), direct DNA sequence analysis and restriction fragment length polymorphism (RFLP). We found a novel missense mutation (1223C-->G, S323C) in LPL gene exon 7 from three subjects. By PCR-mediated site-directed mutagenesis and restriction digestion, the three subjects were found to be heterozygous. In addition, we identified two other common mutations in Japanese employing the RFLP method. One was the 1595C-->G (S447X) in exon 9 from six subjects, two homozygous and four heterozygous individuals. The other was a mutation of intron 3 (C-->T transition) from four heterozygous subjects. Using EUC screening method, we detected genetic LPL abnormalities more easily. The frequency of the LPL gene mutation in the 50 high-risk subjects was 26%, and was estimated to be one out of 2,000 patients at our clinic. Using the EUC system to screen for LPL mutations was established to be an effective computer-based screening system to identify individuals with genetic abnormalities.

Adult↗
PubMed1996

Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene.

BACKGROUND: Patients with lipoprotein lipase deficiency usually present with chylomicronemia in childhood. The syndrome has been considered nonatherogenic primarily because of the low levels of low-density lipoprotein (LDL) cholesterol. We prospectively evaluated patients with lipoprotein lipase deficiency for atherosclerosis. METHODS: Evidence of carotid, peripheral, and coronary atherosclerosis was sought in four patients (two men and two women) with the phenotype of familial chylomicronemia by clinical examination over a period of 14 to 30 years and by Doppler ultrasonography, B-mode ultrasonography [corrected], and exercise-tolerance testing after the age of 40. Angiography was performed when indicated. Lipoprotein lipase deficiency was assessed in vivo and in vitro by functional assays and DNA-sequence analysis. RESULTS: All four patients had a profound functional deficiency of lipoprotein lipase with a reduced enzymatic mass due to missense mutations on both alleles of the lipoprotein lipase gene. In all four patients, peripheral or coronary atherosclerosis (or both) was observed before the age of 55. Despite following a low-fat diet in which fat composed 10 to 15 percent of the daily caloric intake, the patients had hypertriglyceridemia (mean [+/- SD] triglyceride level, 2621 +/- 1112 mg per deciliter [29.59 +/- 12.55 mmol per liter]), low plasma levels of high-density lipoprotein cholesterol (17 +/- 7 mg per deciliter [0.43 +/- 0.18 mmol per liter]), and very low levels of LDL cholesterol (28 +/- 16 mg per deciliter [0.72 +/- 0.41 mmol per liter]). Three patients had one risk factor for atherosclerosis, whereas in one male patient, heavy smoking and diabetes were associated with an accelerated course of the disease. CONCLUSIONS: Premature atherosclerosis can occur in patients with familiar chylomicronemia as a result of mutations in the lipoprotein lipase gene. Defective lipolysis may increase susceptibility to atherosclerosis in humans.

Aged↗
PubMed1993

Lipoprotein lipase enhances the interaction of low density lipoproteins with artery-derived extracellular matrix proteoglycans.

The association of plasma low density lipoproteins (LDL) with arterial proteoglycans (PG) is of key importance in LDL retention and modification in the artery wall. Lipoprotein lipase (LpL), the rate-limiting enzyme for hydrolysis of lipoprotein triglyceride, is known to bind both LDL and arterial PG. In the presence of LpL, cellular internalization and degradation of LDL is enhanced by a pathway initiated by interaction of LDL with a cell surface heparan sulfate proteoglycan. To determine whether LpL enhances the binding of LDL to arterial chondroitin sulfate (CS)PG and dermatan sulfate (DS)PG, the major extracellular PG of the artery wall, a microtiter plate assay was used to study LpL-PG-LDL interactions. Binding of LDL to both CSPG and DSPG was increased in the presence of LpL but differential effects were seen for the two PG. LpL enhanced the binding of LDL to CSPG a maximum of 20% and to DSPG a maximum of 40%. Heparin displacement of PG binding suggested a greater binding strength for DSPG-LpL-LDL with 0.25 micrograms heparin required to displace 50% of DSPG compared to 0.01 micrograms to displace 50% of CSPG. The greater enhancement of DSPG-LDL interaction by LpL is of particular interest since increases in DSPG correlate with the accumulation of aortic cholesterol. These data suggest that lipoprotein lipase may enhance the interaction of plasma low density lipoprotein with arterial chondroitin sulfate proteoglycan and dermatan sulfate proteoglycan and thus facilitate low density lipoprotein retention in the artery wall.

Animals↗
PubMed2006

Combined analysis of six lipoprotein lipase genetic variants on triglycerides, high-density lipoprotein, and ischemic heart disease: cross-sectional, prospective, and case-control studies from the Copenhagen City Heart Study.

CONTEXT: Genetic variants in lipoprotein lipase may affect triglycerides, high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD). OBJECTIVE: The objective of this study was to investigate the influence of T(-93)G, G(-53)C, Asp9Asn, Gly188Glu, Asn291Ser, and Ser447Ter lipoprotein lipase genotypes on triglycerides, HDL, and IHD. DESIGN: The cross-sectional study involved 9004 adults. The prospective study consisted of 8817 adults developing 1001 IHD events over 23 yr. The case-control study involved 7818 non-IHD individuals vs. cohorts of 915 and 1062 IHD patients, respectively. SETTING: The study was performed in the Danish general population (the Copenhagen City Heart Study). PARTICIPANTS: IHD was angina pectoris or myocardial infarction. MAIN OUTCOME MEASURES: Triglycerides, HDL, and IHD were the main outcome measures. RESULTS: Cross-sectionally, triglycerides varied by genotype with 1.27 mmol/liter in women and 1.22 mmol/liter in men. HDL cholesterol varied by genotype with 0.49 mmol/liter in women and 0.60 mmol/liter in men. Prospectively, 9Asn (with -93G) heterozygotes and homozygotes combined vs. noncarriers had a hazard ratio for IHD of 1.6 [95% confidence interval (CI), 1.2-2.3]; 291Ser and 447Ter did not change IHD risk. In the case-control study, combining the cohorts of IHD patients, 9Asn (with -93G) heterozygotes and homozygotes combined vs. noncarriers had an odds ratio for IHD of 1.5 (CI, 1.2-2.1). 291Ser and 447Ter did not change IHD risk. Stratified for apolipoprotein E genotype, the odds ratios for IHD in 9Asn (with -93G) heterozygotes and homozygotes combined vs. noncarriers were 2.6 (CI, 1.2-5.5) among epsilon32 individuals and 2.4 (CI, 1.4-4.1) among epsilon43 individuals. CONCLUSIONS: Genetic variation in lipoprotein lipase is associated with differences in plasma triglycerides greater than 1 mmol/liter and differences in HDL cholesterol greater than 0.5 mmol/liter. A 1.6-fold risk of IHD in 9Asn (with -93G) heterozygotes and homozygotes combined is influenced by apolipoprotein E genotype.

Adult↗
PubMed1976

Purification of rat adipose tissue lipoprotein lipase by affinity chromatography.

Lipoprotein lipase (EC 3.1.1.3) from rat adipose tissue was purified by affinity chromatography with heparin-Sepharose. Elution was carried out with buffered solutions of increasing NaCl molarity. Proteins without affinity for heparin were eluted with 0.5 M NaCl, while lipoprotein lipase activity was eluted as two peaks with 1.16 M NaCl (In earlier work on human adipose tissue (Etienne et al. (1974) C.R. Acad. Sc. Paris 279, 1487-1490) two fractions with lipoprotein lipase activity were also obtained). Phospholipase activity was detected in the fraction eluted with buffered 0.5 M NaCl and containing proteins without affinity for heparin. On feeding the fasting rats with fresh cream or glucose two peaks were also obtained, but the first peak had clearly increased while the second one had remained virtually unchanged.

Adipose Tissue↗
PubMed1983

Changes with starvation in the rat of the lipoprotein lipase activity and hydrolysis of triacylglycerols from triacylglycerol-rich lipoproteins in adipose tissue preparations.

Lipoprotein lipase activity was higher in fat-pad pieces than in isolated adipocytes from the same fed rats, whereas hydrolysis of triacylglycerols from triacylglycerol-rich lipoproteins was similar in the two preparations when incubated either in basal conditions or in the presence of heparin. In both preparations there was a similar release of lipoprotein lipase activity into the medium during basal incubation, enhanced by the presence of heparin. In fat-pad pieces, but not in isolated adipocytes, incubation with heparin produced a decrease in the lipoprotein lipase activity measured in the tissue preparation. In fat-pad pieces from 24 h-starved rats, lipoprotein lipase activity was the same as in isolated adipocytes from the same animals and incubation with heparin did not affect the appearance of lipoprotein lipase in the medium or the utilization of triacylglycerols from triacylglycerol-rich lipoproteins. These results support the following conclusions. (1) The effectiveness of lipoprotein lipase in adipose tissue preparations in vitro depends more on its availability to the substrate than on its total activity. (2) Heparin acts on adipose tissue preparations from fed animals both by enhancing the release of pre-existing extracellular enzyme (which is absent in isolated adipocytes) and by enhancing the transfer outside the cells of the intracellular (and mainly undetectable) enzyme that is activated in the secretion process. (3) In adipose tissue from starved animals there is not only a decrease in the active extracellular form of lipoprotein lipase activity but also a reduction in the intracellular (and mainly undetectable) pool of the enzyme.

Adipose Tissue↗
PubMed1981

Secretion of lipoprotein lipase by macrophages in culture.

Cultured macrophages were shown to synthesize and constitutively secrete a triglyceride lipase identified as lipoprotein lipase on the basis of the following criteria: 1) it required apolipoprotein C-II for optimal activity; 2) it exhibited maximal activity at pH 8.2; 3) it was inhibited by 1 M NaCl; 4) it bound tightly to a heparin-Sepharose affinity gel and was eluted with buffer containing 1.5 M NaCl; and 5) the quantity of enzyme released from macrophages was enhanced by heparin. Cycloheximide treatment of macrophage cultures blocked the spontaneous secretion of lipoprotein lipase. Macrophage secretion of lipoprotein lipase may be relevant to the role of this cell in atherogenesis.

Animals↗
PubMed2002

The translational regulation of lipoprotein lipase by epinephrine involves an RNA binding complex including the catalytic subunit of protein kinase A.

The balance of lipid flux in adipocytes is controlled by the opposing actions of lipolysis and lipogenesis, which are controlled primarily by hormone-sensitive lipase and lipoprotein lipase (LPL), respectively. Catecholamines stimulate adipocyte lipolysis through reversible phosphorylation of hormone-sensitive lipase, and simultaneously inhibit LPL activity. However, LPL regulation is complex and previous studies have described translational regulation of LPL in response to catecholamines because of an RNA-binding protein that interacts with the 3'-untranslated region of LPL mRNA. In this study, we identified several protein components of an LPL RNA binding complex. Using an LPL RNA affinity column, we identified two of the RNA-binding proteins as the catalytic (C) subunit of cAMP-dependent protein kinase (PKA), and A kinase anchoring protein (AKAP) 121/149, one of the PKA anchoring proteins, which has known RNA binding activity. To determine whether the C subunit was involved in LPL translation inhibition, the C subunit was depleted from the cytoplasmic extract of epinephrine-stimulated adipocytes by immunoprecipitation. This resulted in the loss of LPL translation inhibition activity of the extract, along with decreased RNA binding activity in a gel shift assay. To demonstrate the importance of the AKAPs, inhibition of PKA-AKAP binding with a peptide competitor (HT31) prevented epinephrine-mediated inhibition of LPL translation. C subunit kinase activity was necessary for LPL RNA binding and translation inhibition, suggesting that the phosphorylation of AKAP121/149 or other proteins was an important part of RNA binding complex formation. The hormonal activation of PKA results in the reversible phosphorylation of hormone-sensitive lipase, which is the primary mediator of adipocyte lipolysis. These studies demonstrate a dual role for PKA to simultaneously inhibit LPL-mediated lipogenesis through inhibition of LPL translation.

3' Untranslated Regions↗
PubMed1982

Stabilization of lipoprotein lipase by endothelial cells.

Lipoprotein lipase, purified from bovine milk, lost 90% of its activity when incubated in Hanks' balanced salt solution for 5 min at 37 degrees C. Bovine pulmonary artery endothelial cells, maintained in culture, markedly stabilized this enzyme. The stabilizing factor of endothelial cells was non-dialyzable, resistant to heating at 100 degrees C and to changes in pH, and unaffected by treatments of cells with proteolytic enzymes or with heparinase (Flavobacterium heparinum enzyme). However, the stabilizing effect on lipoprotein lipase was reduced by 60-70% by the extraction of cells with chloroform/methanol (2:1). The lipid extract of the cells stabilized the enzyme, suggesting that lipid component(s) of the endothelial cells account for their stabilizing effect. Since the endothelial cell is thought to be the site of action of lipoprotein lipase, stabilization of the enzyme by this cell may play a role in its preservation and function in vivo.

Animals↗
PubMed1996

Dimeric lipoprotein lipase is bound to triglyceride-rich plasma lipoproteins.

Lipoprotein lipase hydrolyzes the triglyceride-rich core of chylomicrons and very low density lipoproteins. It is also a ligand, in vitro, for binding of lipoproteins to the low density lipoprotein receptor-related protein and may play a central role in the receptor-mediated removal of triglyceride-rich lipoproteins. The aim of the present study was to determine to which lipoprotein subclass the enzyme is bound in preheparin plasma and when released into plasma by heparin injection. Tetrahydrolipstatin, a potent inhibitor of serine lipases, was used to block lipolytic activity, thereby preventing changes in plasma lipoproteins due to ex vivo lipolysis. To analyze the distribution pattern of lipoprotein lipase dimers among lipoprotein classes, a specific ELISA was used and gel filtration was performed in pre- and postheparin plasma from five subjects with triglyceride ranging from 69 to 522 mg/dl. When lipolytic activity was not inhibited, lipoprotein lipase dimers eluted in association with low and high density lipoproteins, reproducing results previously obtained by several groups of investigators. However, in pre- and postheparin samples treated with tetrahydrolipstatin, most of the dimeric enzyme was found associated with very low density lipoprotein particles. In conclusion in pre- and postheparin samples most of the lipoprotein lipase dimers are associated with very low density lipoproteins when ex vivo lipolytic activity is inhibited, which supports the hypothesis that, in vivo, lipoprotein lipase may affect the receptor-mediated removal of these particles. Moreover, it suggests that the association between lipoprotein lipase and cholesterol-rich lipoproteins might be an ex vivo phenomenon due to lack of inhibition of lipolytic activity.

Adult↗
PubMed2003

Lipoprotein lipase and atherosclerosis.

Lipoprotein lipase (LPL) is a key enzyme in catabolism of plasma lipoprotein triglycerides (TGs), and in that capacity has a salutary influence on plasma HDL, and thus appears to be antiatherogenic. However, the non-catalytic functions of LPL, such as lipoprotein bridging and selective uptake of lipoprotein cholesteryl ester, are regarded as proatherogenic. The balance between the pro and antiatherogenic attributes of LPL is evaluated on the basis of recent evidence derived from transgenic animals and from studies of common LPL mutations in man. This review also includes recently accrued information on the role of nuclear receptors and their ligands and agonists in regulation of LPL in various organs. The studies reviewed are not only of academic interest, but may also have practical applications in development of agents that may regulate LPL activity in humans.

Animals↗
PubMed1989

Two different mechanisms are involved in nutritional regulation of lipoprotein lipase in guinea-pig adipose tissue.

Lipoprotein lipase activity in adipose tissue responds rapidly to changes in the physiological state. To study what mechanisms are involved in the regulation, guinea pigs were fasted and the decrease in adipose-tissue lipoprotein lipase activity was compared with the decreases in mRNA and lipase synthesis. The mRNA pattern (three species) did not change. There was a close parallelism between the abundance of lipase mRNA and relative lipase synthesis (immunoprecipitable 35S-labelled lipoprotein lipase as fraction of total [35S]protein after pulse-labelling with [35S]methionine). Total protein synthesis decreased on fasting, compounding the decrease in relative lipase synthesis. Lipoprotein lipase mRNA changed similarly in fat-pads and in isolated adipocytes, whereas lipase activity changed more in the pads, indicating disproportionally large changes in extracellularly located lipase. In old guinea pigs the decreases in lipoprotein lipase activity and lipase synthesis were comparable, but in young animals the change in lipase activity was substantially larger than the change in lipase synthesis. Refeeding of fasted young guinea pigs with glucose resulted in a rapid increase in lipoprotein lipase activity, but there was only a small change in lipase mRNA. Old animals responded slowly to refeeding. The results indicate that in older animals the major mechanism for regulation of adipose lipoprotein lipase activity is a relatively slow change in lipase mRNA, whereas in younger animals an additional, more rapid, regulation is exerted on the transport and turnover of the enzyme.

Adipose Tissue↗
PubMed1994

The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP.

Lipoprotein lipase (LPL) binds with high affinity to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and promotes binding, uptake, and degradation of normal triglyceride-rich lipoproteins in a process mediated by LRP (Chappell, D. A., Fry, G. L., Naknitx, M.A., Muhonen, L. E., Pladet, M. W., Iverius, P-H., and Strickland, D. K. (1993) J. Biol. Chem. 268, 14168-14175). To localize the portion of LPL that is responsible for interacting with LRP, fragments of LPL were expressed in bacteria. A fragment of human LPL containing the COOH-terminal domain (residues 313-448, designated LPLC) which lacks the catalytic site was able to bind to LRP. Purified LRP bound specifically to microtiter wells coated with LPL or LPLC with KD values of 2.8 and 5 nM, respectively. The effects of several mutations of LPLC were tested. Mutation of Lys407 to Ala reduced the affinity of LPLC for LRP by approximately 10-fold. Like native LPL, LPLC prevented the binding of activated alpha 2-macroglobulin and the 39-kDa receptor-associated protein to LRP and inhibited the internalization and degradation of activated alpha 2-macroglobulin and receptor-associated protein in cultured fibroblasts. LPLC also bound to 125I-labeled human normal triglyceride-rich lipoproteins and promoted their binding to purified LRP and to cultured cells. Mutation of Trp393 and Trp394 to Ala completely abolished the ability of LPLC to bind to lipoproteins, but had little effect on its interaction with LRP. These data indicate that the COOH-terminal domain of LPL may function both in binding lipoproteins and mediating their interaction with LRP.

Amino Acid Sequence↗