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)

To investigate the effect of thyroid dysfunction on high-density lipoprotein (HDL) metabolism, we measured HDL subfractions, apolipoprotein A-I containing particles (LpA-I and LpA-I:A-II), and the activities of enzymes involved in the remodeling and metabolism of HDL [namely hepatic lipase (HL), lipoprotein lipase, and cholesteryl ester transfer protein (CETP)] in 18 hyperthyroid and 17 hypothyroid patients before and after treatment. HDL was subfractionated by density gradient ultracentrifugation, and LpA-I was analyzed by electroimmunodiffusion. The major changes were found in the HDL2 subfraction and in LpA-I particles. HDL2-C and LpA-I were reduced in hyperthyroidism (P < 0.01, P < 0.05, respectively) and increased in hypothyroidism (both P < 0.05) compared with their respective euthyroid matched controls. Changes in HDL2-cholesterol were reversed after treatment in both hyper- and hypothyroid patients, and LpA-I also decreased in the hypothyroid patients after treatment. HL (P < 0.05) and CETP activities (P < 0.05) were elevated in hyperthyroidism and reduced in hypothyroidism (P < 0.05, P < 0.01 respectively) and both were related to free T4 levels. The changes in HDL2-C and LpA-I correlated significantly with changes in HL after treatment but not with CETP or lipoprotein lipase. In summary, HDL metabolism was altered in thyroid dysfunction, and the effect of thyroid hormone on HDL was mediated mainly via its effect on HL activity.
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PMID:Effect of thyroid dysfunction on high-density lipoprotein subfraction metabolism: roles of hepatic lipase and cholesteryl ester transfer protein. 970 70

The peroxisome proliferator-activated receptors (PPARs) [alpha, delta (beta) and gamma] form a subfamily of the nuclear receptor gene family. All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazones are ligands for PPAR-gamma. PPAR-alpha activation mediates pleiotropic effects such as stimulation of lipid oxidation, alteration in lipoprotein metabolism and inhibition of vascular inflammation. PPAR-alpha activators increase hepatic uptake and the esterification of free fatty acids by stimulating the fatty acid transport protein and acyl-CoA synthetase expression. In skeletal muscle and heart, PPAR-alpha increases mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation through stimulating the muscle-type carnitine palmitoyltransferase-I. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha dependent stimulation of lipoprotein lipase and an inhibition of apolipoprotein C-III expressions, whereas the increase in plasma HDL cholesterol depends on an overexpression of apolipoprotein A-I and apolipoprotein A-II. PPARs are also expressed in atherosclerotic lesions. PPAR-alpha is present in endothelial and smooth muscle cells, monocytes and monocyte-derived macrophages. It inhibits inducible nitric oxide synthase in macrophages and prevents the IL-1-induced expression of IL-6 and cyclooxygenase-2, as well as thrombin-induced endothelin-1 expression, as a result of a negative transcriptional regulation of the nuclear factor-kappa B and activator protein-1 signalling pathways. PPAR activation also induces apoptosis in human monocyte-derived macrophages most likely through inhibition of nuclear factor-kappa B activity. Therefore, the pleiotropic effects of PPAR-alpha activators on the plasma lipid profile and vascular wall inflammation certainly participate in the inhibition of atherosclerosis development observed in angiographically documented intervention trials with fibrates.
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PMID:Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. 1043 61

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARalpha, the first identified PPAR family member, is principally expressed in tissues exhibiting high rates of beta-oxidation such as liver, kidney, heart and muscle. PPARgamma, on the other hand, is expressed at high levels in adipose tissue. PPARs are activated by dietary fatty acids and eicosanoids, as well as by pharmacological drugs, such as fibrates for PPARalpha and glitazones for PPARgamma. PPARalpha mediates the hypolipidemic action of fibrates in the treatment of hypertriglyceridemia and hypoalphalipoproteinemia. PPARalpha is considered a major regulator of intra- and extracellular lipid metabolism. Upon fibrate activation, PPARalpha down-regulates hepatic apolipoprotein C-III and increases lipoprotein lipase gene expression, key players in triglyceride metabolism. In addition, PPARalpha activation increases plasma HDL cholesterol via the induction of hepatic apolipoprotein A-I and apolipoprotein A-II expression in humans. Glitazones exert a hypotriglyceridemic action via PPARgamma-mediated induction of lipoprotein lipase expression in adipose tissue. PPARs play also a role in intracellular lipid metabolism by up-regulating the expression of enzymes involved in conversion of fatty acids in acyl-coenzyme A esters, fatty acid entry into mitochondria and peroxisomal and mitochondrial fatty acid catabolism. These observations have provided the molecular basis leading to a better understanding of the mechanism of action of fibrates and glitazones on lipid and lipoprotein metabolism and identify PPARs as attractive targets for the rational design of more potent lipid-lowering drugs.
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PMID:Regulation of lipid and lipoprotein metabolism by PPAR activators. 1077 55

Fibrates are old hypolipidemic drugs with pleitropic effects on lipid metabolism. Until, recently their intimate molecular mechanisms of action were mysterious. In the late 5 years, we have shown that the pharmacological effects of fibrates depend on their binding to "Peroxisome Proliferator Activated Receptor alpha" (PPAR alpha). The binding of fibrates to PPAR alpha induces the activation or the inhibition of multiple genes involved in lipid metabolism through the binding of the activated PPAR alpha to "Peroxisome Proliferator Response Element" (PPRE) located in the gene promoters. Fibrates reduce plasma triglyceride levels by altering the expression of numerous genes coding for proteins involved in fatty acid metabolism (fatty acid transport protein, acyl-CoA synthetase, etc.) and also by increasing the lipoprotein lipase synthesis and decreasing the apolipoprotein C-III synthesis. Fibrates increase HDL cholesterol levels by increasing apolipoprotein A-I and apolipoprotein A-II synthesis. Furthermore, we recently demonstrated that fibrates are potent anti-inflammatory molecules through an indirect modulation of the nuclear-factor-kappa B activity. Therefore, we suggest that fibrates inhibit atherosclerosis development not only by improving the plasma lipid profile but also by reducing inflammation in the vascular wall.
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PMID:[Molecular mechanism of action of the fibrates]. 1085 58

In addition to their central role in triglyceride storage, fat cells are a primary depot of unesterified cholesterol (FC) in the body. In comparison, peripheral cells contain very little FC. This difference in adipocytes versus peripheral tissues is inconsistent with the current theory of cholesterol homeostasis. Attempting to resolve this discrepancy, we examined intracellular storage sites of FC in murine 3T3-F442A adipocytes. Using the cholesterol-binding antibiotic, filipin, in combination with high resolution fluorescence microscopy, intense fluorescent staining characteristically decorated the periphery of triglyceride droplets (TGD) as well as the plasma membrane (PM) of fat cells. Filipin-staining was not visible inside the lipid droplets. Purification of TGD by subcellular fractionation demonstrated that the rise in total FC content of adipocytes upon differentiation was attributable to an increase in TGD-FC, which contributed up to one third of the total cellular FC. The protein component of purified TGD from cultured adipocytes as well as from murine adipocytes obtained from fresh tissues contained the lumenal endoplasmic reticulum (ER) immunoglobulin binding protein (BiP) and the integral ER membrane protein calnexin. Efflux experiments using the extracellular FC acceptors (&bgr;)-cyclodextrin or apolipoprotein A-I demonstrated that TGD-associated FC was releasable from TGD. Whereas FC efflux from adipocytes was unaffected in the presence of brefeldin A or monensin, the secretion of a control protein, lipoprotein lipase, was effectively reduced. In summary, our findings identify the TGD surface layer as primary intracellular storage site for FC within adipocytes. We suggest that the structural role of ER-resident proteins in this adipocyte TGD envelope has been previously neglected. Our findings support the suggestion that an ER-like structure, albeit of modified lipid composition, constitutes the lipid droplets' surface layer. Finally, the efflux process of FC from adipocytes upon extracellular stimulation with (beta)-cyclodextrin provides evidence for an energy-dependent intracellular trafficking route between the TGD-FC pool and the PM-FC sites which is distinct from the secretory pathway of proteins.
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PMID:Intracellular distribution and mobilization of unesterified cholesterol in adipocytes: triglyceride droplets are surrounded by cholesterol-rich ER-like surface layer structures. 1093 37

When cultured cells are exposed to plasma, the initial acceptors of unesterified cholesterol are small lipid-poor apolipoprotein A-I (apoA-I)-containing high density lipoproteins (HDLs) with pre-beta electrophoretic mobility. These are converted by lecithin:cholesterol acyltransferase into larger spheroidal cholesteryl ester-rich HDLs with alpha mobility. To study the determinants of the concentration of small pre-beta HDLs in tissue fluids, we collected prenodal peripheral lymph from 34 fasted normal men. By crossed immunoelectrophoresis, the concentration of pre-beta HDLs in lymph averaged 20% of that in plasma. On multiple regression analysis, pre-beta apoA-I concentration in lymph was directly related to pre-beta apoA-I concentration in plasma and independently to alpha apoA-I concentration in lymph. Similar results were obtained when the same apoA-I-containing particles were quantified by size exclusion chromatography. Lymph pre-beta apoA-I concentration was low in a subject with familial lecithin:cholesterol acyltransferase deficiency, despite a normal plasma pre-beta apoA-I concentration, but was normal in a subject with familial lipoprotein lipase deficiency. These results suggest that the concentration of small pre-beta HDLs in human tissue fluids is determined only in part by the transfer of pre-beta HDLs across capillary endothelium from plasma. Local production, by remodeling of spheroidal alpha HDLs in tissue fluids, may be equally important. Lipolysis of triglyceride-rich lipoproteins by lipoprotein lipase appears to have little effect.
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PMID:Concentrations of electrophoretic and size subclasses of apolipoprotein A-I-containing particles in human peripheral lymph. 1097 62

Familial combined hyperlipidemia (FCHL), the most common familial dyslipidemia, is implicated in up to 20% of cases of premature coronary heart disease. Although underlying mutations for FCHL have yet to be identified, several candidate genes/regions have been identified. A positive linkage to chromosome 1q markers has been reported, with the highest lod score of 5.93 occurring at a location between D1S104 and D1S1677. Using the same diagnostic criteria, the Family Heart Study (FHS) has defined 71 FCHL families, comprising 170 cases, for a total of 137 possible affected sibling pairs. The FCHL criteria require elevation in serum low density lipoprotein cholesterol and triglyceride levels within the family, with at least 2 affected first-degree relatives. Markers D1S104 and D1S1677 were typed, and significant allele sharing was found in FCHL sibships (multipoint lod score with use of the model from the Finnish study was 2.52, and multipoint nonparametric score was 2.48; P=0.007), replicating linkage in this chromosome 1 region. In addition, previously reported linkage of FCHL to apolipoprotein A-I/C-III/A-IV has been investigated in FHS families. FHS results revealed positive but nonsignificant allele sharing among FCHL sibships with apolipoprotein A-I/C-III/A-IV by use of marker D11S4127 (nonparametric linkage score 1.11, P=0.13). Two-locus analyses of D1S104 and D11S4127 suggested possible heterogeneity rather than epistasis, with a maximum 2-locus lod score of 3.05. A nonparametric 2-locus analysis revealed significant improvement in the 2-locus versus single-locus scores. Finally, no linkage was found with markers near the lipoprotein lipase gene region.
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PMID:Replication of linkage of familial combined hyperlipidemia to chromosome 1q with additional heterogeneous effect of apolipoprotein A-I/C-III/A-IV locus. The NHLBI Family Heart Study. 1103 Dec 15

The hypolipidemic fibric acid drugs are peroxisome proliferator-activated receptor a (PPAR alpha) ligands. PPAR alpha activated by fibric acids form heterodimers with the 9-cis retinoic acid receptor (RXR). The PPAR/RXR heterodimers bind to peroxisome proliferator response elements (PPRE), which are located in numerous gene promoters and increase the level of the expression of mRNAs encoded by PPAR alpha target genes. Fibric acids decrease triglyceride plasma levels through increases in the expression of genes involved in fatty acid-beta oxidation. Furthermore, they decrease triglycerides by increasing lipoprotein lipase gene expression and by decreasing apolipoprotein C-III gene expression. Fibric acids increase high-density lipoprotein (HDL) cholesterol partly by increasing apolipoprotein A-I and apolipoprotein A-II gene expression. Fibric acids also reduce vascular wall inflammation and the expression of genes involved in different vascular functions (ie, vasomotricity, thrombosis). Fibric acids are used to treat primary hypertriglyceridemia and mixed hyperlipidemia. Some fibric acid molecules are active in essential hypercholesterolemia. Clinical evidence shows that fibric acids reduce coronary atherosclerosis progression in dyslipidemic patients (eg, bezafibrate, gemfibrozil) and in type 2 diabetic patients (fenofibrate). Gemfibrozil decreases coronary morbidity and mortality in patients with low HDL cholesterol, normal triglycerides,and normal low-density lipoprotein (LDL) cholesterol plasma levels. Further clinical studies are necessary to investigate if fibric acids decrease cardiovascular mortality in type 2 diabetes and in primary prevention of hypertriglyceridemia and hypolipidemia.
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PMID:The role of fibric acids in atherosclerosis. 1112 53

Coronary heart disease (CHD) is a complex disease that is affected by environmental as well as genetic factors. Research is ongoing that probes the relationship of human genetic variation to disease, potentially leading to better diagnosis and therapy. Variation in factors such as low-density lipoprotein cholesterol, apolipoprotein E, high-density lipoprotein cholesterol, apolipoprotein A-I/CIII/A-IV, lipoprotein lipase, cholesteryl ester transfer protein, lipoprotein (a), and homocysteine may affect CHD risk via genetic or environmental mechanisms or their interactions.
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PMID:Genetic markers for coronary heart disease. 1144 49

In the HERITAGE Family Study, 675 sedentary, healthy, white and black men and women, aged 17 to 65 years, performed 20 weeks of supervised cycle ergometer exercise at the same relative intensity and weekly volume. As a group, subjects had normal mean baseline lipid levels for North Americans with the exception of below average high density lipoprotein cholesterol (HDL-C) levels. A significant mean increase in plasma HDL-C of 3.6 % was observed; however, there was marked variability in responsiveness to training, ranging from a mean 9.3 % decrease in Quartile 1 of HDL-C response to a mean 18 % increase in Quartile 4 (P < 0.0001 by ANOVA). Parallel changes in HDL(2)-C and HDL(3)-C, apolipoprotein A-I levels, and lipoprotein lipase activity were noted across quartiles. The change in HDL-C across quartiles was inversely related to baseline HDL-C (p < 0.0001) and to changes with training in plasma triglycerides (p = 0.0007). No significant differences in HDL-C response were observed across quartiles by sex, race, age, or increase in VO(2)max with training; however, weak positive associations were observed with age-adjusted education level and with reduction in abdominal fat and increase in VO(2)max at the ventilatory threshold following training. Multivariate regression analysis including baseline variables and training responses only accounted for 15.5 % of the variability in the HDL-C response to training. Thus, marked variability was found in the HDL-C response to the same endurance exercise training stimulus with only a modest amount of the response predictable by identified nongenetic factors.
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PMID:Variability in the response of HDL cholesterol to exercise training in the HERITAGE Family Study. 1177 59


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