Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.34 (lipoprotein lipase)
7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The binding of an amphipathic alpha-helical peptide to small unilamellar lipid vesicles has been examined using chemical derivitization and mass spectrometry. The peptide is derived from the sequence of human apolipoprotein C-II (apoC-II), the protein activator of lipoprotein lipase (LpL). ApoC-II(19-39) forms approximately 60% alpha-helix upon binding to model egg yolk phosphatidylcholine small unilamellar vesicles. Measurement of the affinity of the peptide for lipid by spectrophotometric methods is complicated by the contribution of scattered light to optical signals. Instead, we characterize the binding event using the differential labeling of lysine residues by the lipid- and aqueous-phase cross-linkers, disuccinimidyl suberate (DSS) and bis(sulfosuccinimidyl) suberate (BS(3)), respectively. In aqueous solution, the three lysine residues of the peptide are accessible to both cross-linkers. In the presence of lipid, the C-terminal lysine residue becomes inaccessible to the lipid-phase cross-linker DSS, but remains accessible to the aqueous-phase cross-linker, BS(3). We use mass spectrometry to characterize this binding event and to derive a dissociation constant for the interaction (K(d) = 5 microM). We also provide evidence for the formation of dimeric cross-linked peptide when high densities of peptide are bound to the lipid surface.
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PMID:Mass spectrometry to characterize the binding of a peptide to a lipid surface. 1054 5

Type I hyperlipoproteinemia (type I HLP) is a rare disorder of lipid metabolism characterized by fasting chylomicronemia and reduced postheparin plasma lipoprotein lipase (LPL) activity. Most cases of type I HLP are due to genetic defects in the LPL gene or in its activator, the apolipoprotein CII gene. Several cases of acquired type I HLP have also been described in the course of autoimmune diseases due to the presence of circulating inhibitors of LPL. Here we report a case of type I HLP due to a transient defect of LPL activity during puberty associated with chronic idiopathic urticaria (CIU). The absence of any circulating LPL inhibitor in plasma during the disease was demonstrated. The LPL genotype showed that the patient was heterozygous for the D9N variant. This mutation, previously described, can explain only minor defects in the LPL activity. The presence of HLP just after the onset of CIU, and the elevation of the LPL activity with remission of the HLP when the patient recovered from CIU, indicate that type I HLP was caused by CIU. In summary, we report a new etiology for type I HLP - a transient decrease in LPL activity associated with CIU and with absence of circulating inhibitors. This is the first description of this association, which suggests a new mechanism for type I HLP.
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PMID:Acquired lipoprotein lipase deficiency associated with chronic urticaria. A new etiology for type I hyperlipoproteinemia. 1057 67

Apolipoprotein C-II (apoC-II) is an exchangeable plasma apolipoprotein and an endogenous activator of lipoprotein lipase (LpL). Genetic deficiencies of apoC-II and overexpression of apoC-II in transgenic mice are both associated with severe hyperlipidemia, indicating a complex role for apoC-II in the regulation of blood lipid levels. ApoC-II exerts no effect on the activity of LpL for soluble substrates, suggesting that activation occurs via the formation of a lipid-bound complex. We have synthesized a peptide corresponding to amino acid residues 39-62 of mature human apoC-II. This peptide does not bind to model lipid surfaces but retains the ability to activate LpL. Conjugation of the fluorophore 7-nitrobenz-2-oxa-1,3-diazole (NBD) to the N-terminal alpha-amino group of apoC-II39-62 facilitated determination of the affinity of the peptide for LpL using fluorescence anisotropy measurements. The dissociation constant describing this interaction was 0.23 microM, and was unchanged when LpL was lipid-bound. Competitive binding studies showed that apoC-II39-62 and full-length apoC-II exhibited the same affinity for LpL in aqueous solution, whereas the affinity for full-length apoC-II was increased at least 1 order of magnitude in the presence of lipid. We suggest that while the binding of apoC-II to the lipid surface promotes the formation of a high-affinity complex of apoC-II and LpL, activation occurs via direct helix-helix interactions between apoC-II39-62 and the loop covering the active site of LpL.
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PMID:Apolipoprotein C-II39-62 activates lipoprotein lipase by direct lipid-independent binding. 1072 38

Studies in humans on the in vivo metabolism of apolipoprotein (apo) Cs have been hampered by the highly complex nature of lipoprotein metabolism, which can be influenced by multiple genetic and environmental factors. In order to gain new insights into the function of the individual apoCs in lipoprotein metabolism, several laboratories have created mouse models lacking or overexpressing the respective APOC genes through the technologies of gene targeting and transgenesis. Until now, the only well-established in vivo metabolic function of apoC-I has been its inhibitory action on the uptake of very low-density lipoprotein (VLDL) via hepatic receptors, particularly the low-density lipoprotein (LDL) receptor-related protein. Consequently, the presence of apoC-I on the lipoprotein particle may prolong its residence time in the circulation and subsequently facilitate its conversion to LDL. ApoC-II, on the other hand, is a major activator of lipoprotein lipase, which is required for an efficient processing of triglyceride-rich lipoproteins in the circulation. However, an excess of apoC-II on the lipoprotein particle has been suggested to inhibit the lipoprotein-lipase-mediated hydrolysis of triglycerides. From studies with APOC3 transgenic and ApoC3-knockout mice, it appears that apoC-III inhibits the lipolysis of triglyceride-rich lipoproteins by hampering the interaction of these lipoproteins with the heparan sulfate proteoglycan-lipoprotein lipase complex. Subsequently, the poorly lipolyzed apoC-III-containing lipoprotein particles may accumulate in plasma because of their lower binding affinity towards hepatic receptors due to a change in lipid composition, particle size or the presence of apoC-III on the particle itself. From these data it can thus be concluded that all C apolipoproteins specifically modulate the metabolism of triglyceride-rich lipoproteins, which may contribute to the development of hyperlipidemia and other lipoprotein abnormalities in humans.
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PMID:Insights into apolipoprotein C metabolism from transgenic and gene-targeted mice. 1093 55

Apolipoprotein C-II (apoC-II), which is known to activate lipoprotein lipase (LPL), was identified by ordered differential display (ODD)-polymerase chain reaction (PCR) as a cDNA fragment exhibiting a distinct increase in expression during 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced differentiation of promonocytic U937 cells into monocytes and macrophages. The amount of apoC-II mRNA expression detectable in U937 cells significantly increased and reached a maximum 24-48 h after treatment with 32 nM TPA. apoC-II mRNA was also detected in monocytic THP-1 cells but was not detected in promyelocytic HL-60 cells. In healthy human tissues, the most significant expression of apoC-II mRNA was in the liver. Although apoC-II mRNA expression was markedly up-regulated during the induced differentiation of HL-60 cells into monocytes and macrophages with 32 nM TPA, such expression was not induced during the differentiation of HL-60 cells into granulocytes with 1.25% dimethyl sulfoxide. These results suggest that human apoC-II expression is induced at the transcription level during myelomonocytic differentiation and may confer an important role to macrophages involved in normal lipid metabolism and atherosclerosis.
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PMID:Expression of the apolipoprotein C-II gene during myelomonocytic differentiation of human leukemic cells. 1131 Aug 52

Previously we found lipase activity with characteristics similar to lipoprotein lipase (LPL) in tissues from rainbow trout [Biochim. Biophys. Acta 1255 (1995) 205], whereas no equivalent to the related hepatic lipase could be found. An equivalent to apolipoprotein CII was also identified and characterized [Gene 254 (2000) 189]. We present here the full nucleotide sequence for LPL from rainbow trout (Oncorhynchus mykiss) and have investigated some properties of the enzyme. In contrast to what has been found in mammals, LPL mRNA was expressed in livers of adult trout. This indicates that trout LPL carries out functions that hepatic lipase has evolved to take over in mammals. Trout LPL was unstable at 37 degrees C compared with bovine and human LPL. Two sequence differences that may relate to the instability are that trout LPL lacks the disulfide bridge in the C-terminal domain and lacks Pro(258). This residue is conserved in LPL from all mammals and has been shown to be critical for enzyme stability at 37 degrees C. On chromatography on heparin-Sepharose trout and chicken LPL eluted at higher salt concentration than bovine (or other mammalian) LPL. The C-terminal end of LPL has been implied in heparin binding and the higher heparin affinity of the trout and chicken enzymes may be because they have 17 and 15 extra amino acid residues at the C-terminal end, of which three residues are positively charged.
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PMID:Lipoprotein lipase from rainbow trout differs in several respects from the enzyme in mammals. 1211 16

An infant presented with massive hyperchylomicronemia and a severe encephalopathy. MRI showed marked lipid deposition throughout the brain. Despite the normalization of the biochemistry, there was little clinical improvement, and at 18 months of age she has severe developmental delay, a strikingly abnormal MRI. Apolipoprotein C-II, the lipoprotein on chylomicrons responsible for the activation of lipoprotein lipase, was not detectable in blood. Analysis of the APO C-II gene revealed a novel homozygous point mutation, 1118C-->A. Subsequently, another sibling has been born with the same homozygous mutation and similar biochemistry but, perhaps because of early treatment, a normal neurological outcome.
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PMID:Apolipoprotein C-II deficiency presenting as a lipid encephalopathy in infancy. 1278 30

In this study, the effects of in vivo administration of 3-thia fatty acids (FAs) on lipid metabolism in muscle and liver of Atlantic salmon were investigated. Prior to analysis, the fish were kept in tanks supplied with 5 degrees C seawater for 20 weeks. The fish were fed fish meal and fish oil (FO)-based diets supplemented with either nothing (FO), or 0.3% and 0.6% of the 3-thia FAs dodecylthioacetic acid (DTA) and tetradecylthioacetic acid (TTA) respectively. The fish grew from an initial weight of 110 g to 220 g in the FO group and to approximately 160 g in the 3-thia FA groups. There was a significant higher mortality (66%) in fish fed 0.6% TTA than in fish fed the 0.3% DTA (15%) and FO diets (15%). None of the 3-thia FA diets affected the lipid content of the salmon muscle. The liver index, however, was significantly higher and the total liver fat content lower in the TTA group than in the FO group. Both DTA and TTA were incorporated into the lipid fraction of muscle and liver (0.4% to 0.9%). There were no major differences in the total FA composition of liver and muscle between the dietary groups; except for a small increase of n-3 polyunsaturated FAs (PUFAs) in liver of the DTA group. The mRNA expression of peroxisome proliferator-activated receptor (PPAR) alpha, apolipoprotein AI (ApoAI), apolipoprotein CII (ApoCII) and low-density lipoprotein receptor (LDL-R) was down-regulated in liver of the salmon fed 0.3% DTA. PPARalpha and ApoAI transcripts were also reduced in liver of salmon fed 0.6% TTA. Additionally, the hepatic lipoprotein lipase (LPL) mRNA level was 3.8 fold increased in TTA fish relative to the FO group. In muscle there were no significant changes in gene expression pattern of any of the genes investigated. This is the first report on the effects of 3-thia FAs on gene expression in Atlantic salmon.
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PMID:Effects of 3-thia fatty acids on expression of some lipid related genes in Atlantic salmon (Salmo salar L.). 1697 Nov 50

A sex difference in surfactant lipids is associated with a higher incidence of respiratory distress syndrome for males in cases of preterm birth. In animal models, the sex difference in surfactant lipids was shown to be androgen receptor-dependent. This report examines expression of apolipoprotein (apo)A-I, apoA-II, apoC-II, apoE, apoH, and lipoprotein lipase (LPL) by quantitative real-time PCR in pools of male and female fetal lung tissues from various mouse litters from gestation day (GD) 15.5 to 18.5, and in various adult tissues. Although the expression profiles of ApoA-I, ApoA-II, ApoC-II, and ApoH are complex, these genes are co-regulated and they all present a sex difference (P=0.0896, 0.0896, 0.0195, and 0.0607 respectively) with higher expression for females for several litters. Pulmonary expression of apoA-I, apoA-II, and apoH were specific to the developing lung. ApoE and LPL mRNAs showed a significant increase from GD 17.5 to 18.5. An increase in apoA-I-, apoA-II-, apoC-II-, and apoH-mRNA accumulation was observed from GD 16.5 to 17.5 in correlation with the emergence of mature type II pneumonocytes. These four apolipoprotein genes are co-regulated with type 2 and 5 17beta-hydroxysteroid dehydrogenases, which are respectively involved in inactivation and synthesis of androgens. Finally, apoC-II was detected by immunohistochemistry in epithelial cells of the distal epithelium. Positive signals looking like secretory granules were located near the basal membrane. Our results are compatible with a role for apolipoproteins in lipid metabolism and transport in the developing lung in association with the sex difference in surfactant lipid synthesis.
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PMID:Apolipoprotein A-I, A-II, C-II, and H expression in the developing lung and sex difference in surfactant lipids. 1910 36

End-stage renal disease (ESRD) is associated with accelerated atherosclerosis and premature death from cardiovascular disease. These events are driven by oxidative stress inflammation and lipid disorders. ESRD-induced lipid abnormalities primarily stem from dysregulation of high-density lipoprotein (HDL), triglyceride-rich lipoprotein metabolism, and oxidative modification of lipoproteins. In this context, production and plasma concentration of Apo-I and Apo-II are reduced, HDL maturation is impaired, HDL composition is altered, HDL antioxidant and anti-inflammatory functions are depressed, clearance of triglyceride-rich lipoproteins and their atherogenic remnants is impaired, their composition is altered, and their plasma concentration is elevated in ESRD. The associated defect in HDL maturation is largely caused by acquired lecithin-cholesterol acyltransferase deficiency while its triglyceride enrichment is due to hepatic lipase deficiency. Hypertriglyceridemia, abnormal composition, and impaired clearance of triglyceride-rich lipoproteins and their remnants are mediated by down-regulation of lipoprotein lipase, hepatic lipase, very low-density lipoprotein (VLDL) receptor, and LDL receptor-related protein, relative reduction in ApoC-II/ApoC-III ratio, up-regulation of acyl-CoA cholesterol acyltransferase, and elevated plasma level of cholesterol ester-poor prebeta HDL. Impaired clearance and accumulation of oxidation-prone VLDL and chylomicron remnants and abnormal LDL composition in the face of oxidative stress and inflammation favors their uptake by macrophages and resident cells in the artery wall. The effect of heightened influx of lipids is compounded by impaired HDL-mediated reverse cholesterol transport leading to foam cell formation which is the central event in atherosclerosis plaque formation and subsequent plaque rupture, thrombosis, and tissue damage.
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PMID:Causes of dysregulation of lipid metabolism in chronic renal failure. 2001 35


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