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: UMLS:C0242339 (dyslipidemia)
13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fifteen polymorphisms in six lipid transport genes were studied in a German population for relationships with dyslipidemia and coronary artery disease (CAD), to investigate a possible genetic basis for the marked differences in mortality rates from coronary heart disease within Europe. In other populations these polymorphisms have all been associated with CAD or with phenotypes known to predispose to CAD. The apoAI PstI polymorphism (P<0.005) and the lipoprotein lipase Ser(447)-Ter mutation (P<0.005) were associated with plasma triglyceride concentrations. Additionally, the apoAI PstI polymorphism (P<0.05), the apoB XbaI polymorphism (P<0.05) and apoE phenotypes (P<0.05) were associated with plasma cholesterol concentrations. However, none of the allele frequencies of the polymorphisms studied were related to the presence, or absence, of coronary artery disease. Associations between five polymorphisms representing four lipid transport gene loci and dyslipidemia were demonstrated in this German population. It is possible that predisposition to dyslipidemia in Germany involves a particular selection of polymorphic loci, which are different from those identified in other European countries.
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PMID:Coronary artery disease and dyslipidemia within Europe: genetic variants in lipid transport gene loci in German subjects with premature coronary artery disease. 1204 83

Neuropeptide Y (NPY) appears to play a critical role in the integration of appetite and energy expenditure through NPY Y1 and Y5 receptor subtypes. Moreover, the NPY Y1 receptor is highly expressed on human adipocytes, where it inhibits lipolysis. The genes encoding these receptors are transcribed co-ordinately in opposite directions from a common promoter in a region of chromosome 4 that has been previously linked to triglyceride and small low-density lipoprotein (LDL) particle concentration. Therefore, the purpose of this investigation was to examine the relationship between polymorphisms in the genes encoding NPY Y1 and Y5 and the development of obesity and dyslipidemia. We screened the promoter and coding regions and identified four polymorphic variants. One of these, a cytosine to thymine (C-->T) substitution in the untranslated region between the genes for NPY Y1 and Y5 (allele frequency 0.11), was significantly associated with both lower fasting triglyceride level (152 vs 125 mg/dl), and higher high-density lipoprotein (HDL) concentrations (49 vs 45 mg/dl) (p < 0.01) in 306 obese subjects. Given the stimulatory effect of NPY on adipocyte lipoprotein lipase (LPL) activity, and the lack of association of other polymorphisms with serum lipid levels, we hypothesize that this is a gain-in-function polymorphism.
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PMID:Novel neuropeptide Y1 and Y5 receptor gene variants: associations with serum triglyceride and high-density lipoprotein cholesterol levels. 1222 Apr 33

The three major components of dyslipidemia associated with the metabolic syndrome are increased fasting and postprandial triglyceride-rich lipoproteins (TRLs), decreased high-density lipoprotein (HDL), and increased small, dense low-density lipoprotein (LDL) particles. Insulin resistance and compensatory hyperinsulinemia lead to overproduction of very low-density lipoprotein particles. A relative deficiency of lipoprotein lipase, an insulin-sensitive enzyme, is partly responsible for the decreased clearance of fasting and postprandial TRLs, and the decreased production of HDL particles. The resulting increased concentration of cholesteryl ester-rich fasting and postprandial TRLs is the central lipoprotein abnormality of the metabolic syndrome. The increase of small, dense LDL particles, and decrease of large, buoyant HDL particles are consequential events. All these lipoprotein defects contribute largely to the increased cardiovascular disease risk in individuals with insulin resistance. Peroxisome proliferator-activated receptor (PPAR)a, PPARg, and PPARd agonists seem to improve dyslipidemia of the metabolic syndrome by regulating the expression of important genes involved in the deranged lipoprotein metabolism associated with insulin resistance.
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PMID:Dyslipidemia of the metabolic syndrome. 1237 72

Adipocytes have traditionally been considered to be the primary site for whole body energy storage mainly in the form of triglycerides and fatty acids. This occurs through the ability of insulin to markedly stimulate both glucose uptake and lipogenesis. Conventional wisdom held that defects in fuel partitioning into adipocytes either because of increased adipose tissue mass and/or increased lipolysis and circulating free fatty acids resulted in dyslipidemia, obesity, insulin resistance and perhaps diabetes. However, it has become increasingly apparent that loss of adipose tissue (lipodystrophies) in both animal models and humans also leads to metabolic disorders that result in severe states of insulin resistance and potential diabetes. These apparently opposite functions can be resolved by the establishment of adipocytes not only as a fuel storage depot but also as a critical endocrine organ that secretes a variety of signaling molecules into the circulation. Although the molecular function of these adipocyte-derived signals are poorly understood, they play a central role in the maintenance of energy homeostasis by regulating insulin secretion, insulin action, glucose and lipid metabolism, energy balance, host defense and reproduction. The diversity of these secretory factors include enzymes (lipoprotein lipase (LPL) and adipsin), growth factors [vascular endothelial growth factor (VEGF)], cytokines (tumor necrosis factor-alpha, interleukin 6) and several other hormones involved in fatty acid and glucose metabolism (leptin, Acrp30, resistin and acylation stimulation protein). Despite the large number of molecules secreted by adipocytes, our understanding of the pathways and mechanisms controlling intracellular trafficking and exocytosis in adipocytes is poorly understood. In this article, we will review the current knowledge of the trafficking and secretion processes that take place in adipocytes, focusing our attention on two of the best characterized adipokine molecules (leptin and adiponectin) and on one of the most intensively studied regulated membrane proteins, the GLUT4 glucose transporter.
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PMID:An adipocentric view of signaling and intracellular trafficking. 1239 77

Traditional risk factors for coronary artery disease (CAD) predict about 50% of the risk of developing CAD. The Adult Treatment Panel (ATP) III has defined emerging risk factors for CAD, including small, dense low-density lipoprotein (LDL). Small, dense LDL is often accompanied by increased triglycerides (TGs) and low high-density lipoprotein (HDL). An increased number of small, dense LDL particles is often missed when the LDL cholesterol level is normal or borderline elevated. Small, dense LDL particles are present in families with premature CAD and hyperapobetalipoproteinemia, familial combined hyperlipidemia, LDL subclass pattern B, familial dyslipidemic hypertension, and syndrome X. The metabolic syndrome, as defined by ATP III, incorporates a number of the components of these syndromes, including insulin resistance and intra-abdominal fat. Subclinical inflammation and elevated procoagulants also appear to be part of this atherogenic syndrome. Overproduction of very low-density lipoproteins (VLDLs) by the liver and increased secretion of large, apolipoprotein (apo) B-100-containing VLDL is the primary metabolic characteristic of most of these patients. The TG in VLDL is hydrolyzed by lipoprotein lipase (LPL) which produces intermediate-density lipoprotein. The TG in intermediate-density lipoprotein is hydrolyzed further, resulting in the generation of LDL. The cholesterol esters in LDL are exchanged for TG in VLDL by the cholesterol ester tranfer proteins, followed by hydrolysis of TG in LDL by hepatic lipase which produces small, dense LDL. Cholesterol ester transfer protein mediates a similar lipid exchange between VLDL and HDL, producing a cholesterol ester-poor HDL. In adipocytes, reduced fatty acid trapping and retention by adipose tissue may result from a primary defect in the incorporation of free fatty acids into TGs. Alternatively, insulin resistance may promote reduced retention of free fatty acids by adipocytes. Both these abnormalities lead to increased levels of free fatty acids in plasma, increased flux of free fatty acids back to the liver, enhanced production of TGs, decreased proteolysis of apo B-100, and increased VLDL production. Decreased removal of postprandial TGs often accompanies these metabolic abnormalities. Genes regulating the expression of the major players in this metabolic cascade, such as LPL, cholesterol ester transfer protein, and hepatic lipase, can modulate the expression of small, dense LDL but these are not the major defects. New candidates for major gene effects have been identified on chromosome 1. Regardless of their fundamental causes, small, dense LDL (compared with normal LDL) particles have a prolonged residence time in plasma, are more susceptible to oxidation because of decreased interaction with the LDL receptor, and enter the arterial wall more easily, where they are retained more readily. Small, dense LDL promotes endothelial dysfunction and enhanced production of procoagulants by endothelial cells. Both in animal models of atherosclerosis and in most human epidemiologic studies and clinical trials, small, dense LDL (particularly when present in increased numbers) appears more atherogenic than normal LDL. Treatment of patients with small, dense LDL particles (particularly when accompanied by low HDL and hypertriglyceridemia) often requires the use of combined lipid-altering drugs to decrease the number of particles and to convert them to larger, more buoyant LDL. The next critical step in further reduction of CAD will be the correct diagnosis and treatment of patients with small, dense LDL and the dyslipidemia that accompanies it.
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PMID:Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity. 1241 79

Obestity is associated with a range of metabolic abnormalities including fasting and postprandial dyslipidemia, both of which may contribute to increased atherosclerotic risk. Male obese subjects have a decreased level of low-density lipoprotein (LDL) receptor binding in mononuclear cells, the level of which reflects binding in the liver, compared with lean controls. In this study, we investigated whether the implementation of a weight loss regimen in viscerally obese subjects improves LDL receptor binding level. We examined apolipoprotein B(48) (apo B(48)) and retinyl palmitate (RP) metabolism following an oral fat challenge to determine whether weight loss improves postprandial dyslipidemia in viscerally obese subjects. Male obese, mildly dyslipidemic, and insulin-resistant subjects were randomly assigned to either a weight loss (n = 12) or control weight maintenance (n = 10) group. In response to weight loss of 10 kg, insulin sensitivity improved as evidenced by decreased fasting insulin and homeostatic model assessment (HOMA) score. In addition, LDL receptor binding in mononuclear cells increased significantly by 27.5% and LDL-cholesterol was significantly reduced. However, despite the increased LDL receptor levels, fasting apo B(48) levels did not fall. Postprandially, the area under the curve (AUC) for RP was significantly reduced after weight loss, but the incremental and total AUCs for apo B(48) were not altered. Apo B(48) is an unequivocal marker of chylomicron particle number; hence, the reduction in RP metabolism achieved with weight reduction may reflect decreased lipid incorporation into nascent chylomicrons or improved hydrolysis of triglyceride-rich chylomicrons resulting from a decreased competition with hepatic lipoproteins for lipoprotein lipase. Our findings suggest that the improvement in LDL receptor binding following weight reduction of 10 kg in insulin-resistant male obese subjects is insufficient to reduce the elevated chylomicron remnant levels.
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PMID:Effect of weight loss on postprandial lipemia and low-density lipoprotein receptor binding in overweight men. 1260 21

Fenofibrate is the ligand for PPARalpha subtype that mediates the action of its agonists' in lipid metabolism. How fibrate exerts hypolipidemic effect? The mechanism is studied in a newly developed high-fat fructose enriched diet induced dyslipidemia-diabetic hamster model. Fenofibrate lowered the basal plasma lipids like TC, TG, PL, FFA, glycerol, VLDL, and LDL, but HDL was increased. The activity of lipoprotein lipase in liver, adipose tissue, and small intestine was upregulated. However, that of triglyceride lipase was downregulated in liver. It has also improved the insulin secretion and plasma glucose lowering, caused by impairment in insulin secretion due to high-fat load. The drug was found effective in reducing body weight and diet due to rise in leptin level. Fenofibrate also enhanced the fecal excretion of total lipids, cholic acid, and deoxycholic acid probably by the activation of 7alpha cholesterol hydroxylase enzyme. Thus, causing broad-spectrum lipid lowering along with inhibition of hepatic lipid biosynthesis and maintaining lipid-glucose homeostasis.
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PMID:Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model. 1274 61

Essential hypertension (EH) is a common late-onset disease that exhibits complex genetic heterogeneity. Human lipoprotein lipase (LPL) is a rate-limiting enzyme that regulates the catabolism of triglycerides (TG) and chylomicrons (CM). Since dyslipidemia is a common finding in hypertensive patients, the LPL gene is a logical candidate gene that could contribute to the development of hypertension. Using linkage analysis in 148 Chinese hypertensive families, we identified a region of linkage with systolic blood pressure (SBP) and diastolic blood pressure (DBP) that consisted of a 10.6-cM interval defined by markers D8S1145, D8S261, and D8S282 on chromosome 8, which maps between 31 to 41.6 cM from the 8p-telomere contained LPL gene, with statistically significant p values for the marker D8S261 (p = 0.0021 for SBP, and p = 0.0395 for DBP). In the qualitative-trait linkage analysis, evidence for linkage between the marker D8S1145 and EH was found (p = 0.0286). The transmission/disequilibrium test (TDT/S-TDT) also supported a significant linkage-disequilibrium of the allele 3 of D8S261 with EH (chi2 = 8.643, p < 0.01). Furthermore, the marker neurofilament light polypeptide (NEFL) (11 cM centromeric to the LPL gene) appeared to be in linkage with SBP and DBP (p = 0.0329 for SBP; p = 0.0319 for DBP). Additionally, two flanking markers for LPL, D8S511 (9.5 cM telomeric to the LPL gene) and D8S560 (3.2 cM centromeric to the LPL gene), also showed significant linkage with EH (p = 0.0036 for D8S511; p = 0.0115 for D8S560). Previous knowledge about the physiological involvement of LPL in blood pressure regulation and the present findings of variation near the LPL gene support the proposition that a region near the LPL gene or the LPL gene itself might contribute to the individual blood pressure variation in Chinese.
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PMID:Variation near the region of the lipoprotein lipase gene and hypertension or blood pressure levels in Chinese. 1286 2

Apolipoprotein E2, which has an R158 for C substitution, has reduced affinity for the LDL receptor and is associated with type III hyperlipoproteinemia in humans. Consistent with these observations, we have found that following adenovirus-mediated gene transfer, full-length apoE2 aggravates the hypercholesterolemia and induces hypertriglyceridemia in E-deficient mice and induces combined hyperlipidemia in C57BL/6 mice. Unexpectedly, the truncated apoE2-202 form that has an R158 for C substitution when expressed at levels similar to those of the full-length apoE2 normalized the cholesterol levels of E-deficient mice without induction of hypertriglyceridemia. The apoE2 truncation increased the affinity of POPC-apoE particles for the LDL receptor, and the full-length apoE2 had a dominant effect in VLDL triglyceride secretion. Hyperlipidemia in normal C57BL/6 mice was prevented by coinfection with equal doses of each, the apoE2 and the apoE2-202-expressing adenoviruses, indicating that truncated apoE forms have a dominant effect in remnant clearance. Hypertriglyceridemia was completely corrected by coinfection of mice with an adenovirus-expressing wild-type lipoprotein lipase, whereas an inactive lipoprotein lipase had a smaller effect. The findings suggest that the apoE2-induced dyslipidemia is not merely the result of substitution of R158 for C but results from increased secretion of a triglyceride-enriched VLDL that cannot undergo lipolysis, inhibition of LpL activity, and impaired clearance of chylomicron remnants. Infection of E(-)(/)(-)xLDLr(-)(/)(-) double-deficient mice with apoE2-202 did not affect the plasma cholesterol levels, and also did not induce hypertriglyceridemia. In contrast, apoE2 exacerbated the hypercholesterolemia and induced hypertriglyceridemia, suggesting that the LDL receptor is the predominant receptor in remnant clearance.
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PMID:Molecular mechanisms of type III hyperlipoproteinemia: The contribution of the carboxy-terminal domain of ApoE can account for the dyslipidemia that is associated with the E2/E2 phenotype. 1292 33

Dyslipidaemia, hallmarked by low HDL cholesterol and high plasma triglycerides, is a feature of insulin resistance and type 2 diabetes mellitus. These lipoprotein abnormalities represent major cardiovascular risk factors in these conditions. Among other factors, lipoprotein lipase (LPL), hepatic lipase (HL), lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) play an important role in an abnormal HDL metabolism in insulin resistance and type 2 diabetes mellitus. LPL hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. In insulin resistant states, a decreased post-heparin plasma LPL activity contributes to a low HDL cholesterol, whereas an increased activity of HL reduces HDL particle size by hydrolysing its triglycerides and phospholipids. High HL activity coincides with low HDL cholesterol. The esterification of free cholesterol by LCAT increases HDL particle size. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins. This cholesteryl ester transfer process results in lower HDL cholesterol and indirectly decreases HDL size. Plasma cholesterol esterification is unaltered or increased, whereas cholesteryl ester transfer is enhanced in type 2 diabetes mellitus, abnormalities which are probably related to the degree of hypertriglyceridaemia. It is plausible that a low LPL activity contributes to premature atherosclerosis as observed in insulin resistance and type 2 diabetes mellitus, but the effects of high HL activity and altered plasma cholesterol esterification on atherosclerosis development are uncertain. Since the cholesteryl ester transfer process between lipoproteins provides a metabolic intermediate between low HDL cholesterol and high plasma triglycerides, hypertriglyceridaemia-associated accelerated transfer of cholesteryl ester out of HDL may be pathogenetically involved in the development of cardiovascular disease in insulin resistance and type 2 diabetes mellitus.
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PMID:Role of lipases, lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in abnormal high density lipoprotein metabolism in insulin resistance and type 2 diabetes mellitus. 1465 31


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