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:C0020473 (hyperlipidemia)
15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genes influence quantitative variations in plasma lipoprotein concentrations. For example, intake of dietary saturated fat and cholesterol raises the average serum cholesterol concentration, leading to a higher risk of coronary artery disease in populations. However, not all individuals within the population are susceptible: genetic factors appear to render individuals either "dietary responsive" or "dietary nonresponsive." In this review, we focus on current knowledge about the influence of genetic polymorphisms in certain genes on the lipoprotein response to dietary fat and cholesterol. Our preliminary studies in the Dietary Intervention Study in Children suggest a significant dose-response relation between the decrease in LDL cholesterol from baseline to 36 mo of follow-up in both the intervention group (who consumed a low-fat, low-cholesterol diet) and the usual care group (who consumed a regular diet) and the presence of the APOA1*A allele at the M1 site and the + site at the M2 site of the gene encoding apolipoprotein (apo) A-I. The DNA polymorphisms on the genes encoding apo A-IV, apo B, apo C-III, apo E, lipoprotein lipase, cholesteryl ester transfer protein, lecithin:cholesterol acyltransferase (phosphatidylcholine-sterol O:-acyltransferase), and LDL receptor were found by others to be associated with the plasma lipoprotein response to dietary intervention. Possible mechanisms involved in these effects are discussed and certain discrepancies in the literature about some genetic effects on responsiveness are analyzed. An improved understanding of the influence of specific genes on lipoprotein responsiveness to dietary fat and cholesterol may allow us to identify and counsel certain individuals to avoid high-fat diets so that they may reduce their risk of developing hyperlipidemia and coronary artery disease.
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PMID:Influence of genetic polymorphisms on responsiveness to dietary fat and cholesterol. 1106 69

Qualitative and quantitative anomalies of low-density lipoproteins (LDL) play a key role in the pathophysiology of atherosclerosis. Such anomalies are characteristics of the atherogenic dyslipidemias which occur most frequently, i.e. primary hypercholesterolemia of phenotype IIA (including familial hypercholesterolemia), combined hyperlipidemias (Type IIB) and hypertriglyceridemia (Type IV). An elevated concentration of circulating LDL occurs either as a result of hepatic overproduction of VLDL particles, the major precursors of LDL, or as a result of delayed catabolism, as occurs when there is a deficit of cellular LDL receptors (e.g. familial hypercholesterolemia), or as a combination of both. The major qualitative anomaly of LDL which results in elevated atherogenicity involves a predominance of small dense LDL, as seen in patients with premature coronary heart disease and equally in combined hyperlipidemia and in hypertriglyceridemia. The mechanism of the formation of these particles is complex and involves the concerted intravascular action of cholesteryl ester transfer protein (CETP), lipoprotein lipase (LPL) and hepatic lipase (HL) on triglyceride-rich precursors of dense LDL Lipid-lowering agents, such as fibrates and statins, act to reduce the atherogenicity of dense LDL by distinct mechanisms, which lead to normalisation of circulating LDL levels and/or to targeted reduction in dense particles of elevated atherogenicity. Indeed, such pharmacological probes have facilitated new insight into the molecular and cellular mechanisms which underlie each of the major forms of atherogenic dyslipidemia.
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PMID:[Role of anomalies of low density lipoproteins (LDL) in atherogenicity]. 1147 67

To study possible mechanisms for the suggested protective effect of hormone-replacement therapy (HRT) with respect to cardiovascular disease we investigated lipoprotein parameters, mass and activity of lipoprotein-metabolizing enzymes, magnitude of postprandial lipemia, and vascular endothelial function in 13 postmenopausal women. All patients were examined before and 3 months after implementation of HRT with estrogen alone (group A, n = 6) or estrogen plus gestagen (group B, n = 7). HRT (groups A and B) resulted in enhanced total transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to apolipoprotein B (apoB)-containing lipoproteins (56% +/- 11.45% v 50.82% +/- 13.68%, P <.05) and increased apoA-I plasma concentration (171 +/- 30 v 147 +/- 22 mg/dL, P <.05). Fasting triglycerides (TG) were increased (134 +/- 40 v 115 +/- 39 mg/dL, P <.05). In group A patients the magnitude of postprandial lipemia increased significantly (1,737 +/- 756 v 1,475 +/- 930 mg TG/dL plasma/8 h, P <.05) without any change in lipoprotein lipase (LPL) activity, but with a concomitant decrease in low-density lipoprotein (LDL) size. In both groups flow-mediated dilation (FMD) reflecting vascular endothelial function was not influenced, suggesting that HRT may not directly affect vascular function but rather alters lipoprotein metabolism. The increase of apoA-I was not accompanied by an equivalent rise of HDL cholesterol. Based on the present data this finding can be readily explained by an increase in CE transfer from HDL to TG-rich lipoproteins, which is not due to increased cholesteryl ester transfer protein (CETP) plasma levels, but rather reflects an increase in fasting and postprandial TG. In conclusion, the net effect of accelerated CE transfer due to HRT depends on the balance of proatherogenic aspects, like the generation of small dense LDL, and antiatherogenic aspects, like the stimulation of reverse cholesterol transport.
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PMID:Enhancement of cholesteryl ester transfer in plasma by hormone-replacement therapy. 1197 92

This article reviews the literature from 1986 to early 2001 relating to apoB100 and apoB48 kinetics in humans using amino acid precursors labeled with stable isotopes. The following subjects are reviewed: (1) methodology; (2) normal individuals and the effects of aging; (3) diet; (4) hereditary dyslipidemias: familial hypercholesterolemia, familial combined hyperlipidemia, cholesteryl ester storage disease, cholesteryl ester transfer protein deficiency, lipoprotein lipase deficiency, familial hypobetalipoproteinemia, and truncated forms of apoB; (5) hormonal perturbations: estrogen, insulin, diabetes, obesity, and growth hormone; (6) the nephrotic syndrome; and (7) the effects of the statin class of drugs. Because of the advances which have been made in mass spectrometry techniques, the advantages of using non-radioactive tracers in humans have made stable isotope kinetic studies the present day standard in this area of research.
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PMID:Apolipoprotein B metabolism in humans: studies with stable isotope-labeled amino acid precursors. 1199 42

Both hyperglycemia and hyperlipidemia have been postulated to increase atherosclerosis in patients with diabetes mellitus. To study the effects of diabetes on lipoprotein profiles and atherosclerosis in a rodent model, we crossed mice that express human apolipoprotein B (HuB), mice that have a heterozygous deletion of lipoprotein lipase (LPL1), and transgenic mice expressing human cholesteryl ester transfer protein (CETP). Lipoprotein profiles due to each genetic modification were assessed while mice were consuming a Western type diet. Fast-protein liquid chromatography analysis of plasma samples showed that HuB/LPL1 mice had increased VLDL triglyceride, and HuB/LPL1/CETP mice had decreased HDL and increased VLDL and IDL/LDL. All strains of mice were made diabetic using streptozotocin (STZ); diabetes did not alter lipid profiles or atherosclerosis in HuB or HuB/LPL1/CETP mice. In contrast, STZ-treated HuB/LPL1 mice were more diabetic, severely hyperlipidemic due to increased cholesterol and triglyceride in VLDL and IDL/LDL, and had more atherosclerosis.
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PMID:Lipoprotein lipase deficiency and CETP in streptozotocin-treated apoB-expressing mice. 1203 61

BACKGROUND: The purpose of the investigation presented here was to study the effects of insulin therapy in type 2 diabetes mellitus (type 2 DM) not only on glycemic control but also on other components of the metabolic syndrome, including lipid metabolism, blood pressure, and body weight. METHODS: Twelve patients with type 2 DM were studied before and after replacement of sulphonylurea treatment with insulin for 4 months. RESULTS: Insulin therapy resulted in a significant decrease in fasting glucose levels by 26%; glycated hemoglobin decreased by 17% and fructosamine values by 19%. With insulin treatment, fasting plasma triglyceride levels decreased by 28% and total HDL cholesterol and HDL(3) cholesterol increased by 17 and 11%, respectively. Low-density lipoprotein (LDL) cholesterol showed no significant change. The magnitude of postprandial lipemia after ingestion of a standard fatty meal decreased by 38%. Insulin treatment was also accompanied by a 21% increase in lipoprotein lipase (LPL) activity in postheparin plasma and by a 20% increase in cholesteryl ester transfer protein (CETP) activity. Hepatic lipase activity was not changed significantly with insulin. Mean BMI decreased from 28.5+/-4.2 to 28.0+/-3.1 kg/m(2) (P=0.02), which is in keeping with the finding that peripheral insulin levels did not increase and which can be explained by the fact that the insulin regimen was combined with dietary counseling. Accordingly, blood pressure showed no significant change. CONCLUSION: Our study demonstrates that judicious replacement of sulfonylurea treatment with insulin therapy, together with dietary counseling, can result in a simultaneous improvement in the major stigmata of the metabolic syndrome, i.e. a significant improvement in glycemic control and lipid metabolism without unfavorable effects on body weight and blood pressure.
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PMID:Insulin improves fasting and postprandial lipemia in type 2 diabetes. 1206 22

Postprandial triglyceride-rich lipoproteins (TRL) exert proatherogenic effects at the arterial wall, including lipid deposition. Following consumption of a mixed meal (1200 kcal), plasma-mediated cellular free cholesterol (FC) efflux, lecithin:cholesterol acyltransferase (LCAT), and cholesteryl ester transfer protein (CETP) activities were determined in subjects (n = 12) displaying type IIB hyperlipidemia and compared with those in a normolipidemic control group (n = 14). The relative capacity of plasma to induce FC efflux from Fu5AH cells via the SR-BI receptor was significantly increased 4 h postprandially (+23%; P < 0.005) in the type IIB group, whereas it remained unchanged for postprandial plasma from normolipidemic subjects. LCAT activity was significantly elevated 2 h postprandially in both the IIB and control groups, (+46% and +36%, respectively; P < 0.005 vs. respective baseline value). In type IIB subjects, total cholesteryl ester (CE) mass transfer from HDL to total TRL [chylomicrons (CMs) + VLDL-1 + VLDL-2 + IDL] increased progressively from 15 +/- 2 micro g CE/h/ml at baseline to 28 +/- 2 micro g CE transferred/h/ml (+87%; P = 0.0004) at 4 h postprandially. CE transfer to CMs and VLDL-1 was preferentially stimulated (2.6-fold and 2.3-fold respectively) at 4 h in IIB subjects and occurred concomitantly with elevation in mass and particle number of both CMs (2.3-fold) and VLDL-1 (1.3-fold). Furthermore, in type IIB subjects, CETP-mediated total CE flux over the 8 h postprandial period from HDL to potentially atherogenic TRL was significantly enhanced, and notably to VLDL-1 (32-fold elevation; P < 0.005), relative to control subjects. Such CE transfer flux was reflected in a significant postprandial increase in CE-TG ratio in both CMs and VLDL-1 in type IIB plasmas. In conclusion, HDL-CE is preferentially targeted to VLDL-1 via the action of CETP during alimentary lipemia, thereby favoring formation and accumulation of atherogenic CE-rich remnant particles.
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PMID:Cholesteryl ester flux from HDL to VLDL-1 is preferentially enhanced in type IIB hyperlipidemia in the postprandial state. 1236 49

Asian Indians who have settled overseas and those in urban India have increased risk of coronary events. Reasons for this increased risk are thought to be genetic but are yet unclear. Advances in molecular cardiology have revealed a number of single nucleotide polymorphisms associated with atherosclerosis. In this review, gene polymorphisms that have been associated with coronary diseases among Indians are discussed. Topics include the genes involved in hyperlipidemia, hypertension, and homocysteine. Mutations in the low-density lipoprotein receptor (LDLR) gene resulting in familial hypercholesterolemia have strong association with premature atherosclerosis. Common polymorphism of the apolipoproteins (apo) B-100 and E genes have been associated with variation in lipid and lipoprotein levels. Recently identified polymorphisms in the apoC3 (T-455C, C-482T), and cholesteryl ester transfer protein (CETP) (B1/B2 allele) genes are associated with increased triglycerides and reduced high-density lipoprotein (HDL)-levels, a feature now also common among Asian Indians. Angiotensin-converting enzyme-deletion (DD) polymorphism has been shown to influence beta-blocker therapy in heart failure. Mutations in methylenetetrahydrofolate reductase (C667T), cystathionine beta-synthase (T833C), and methionine synthase (A2756G) genes cause hyperhomocysteinemia, an independent risk factor for atherothrombosis. As the genetics of atherosclerosis continues to evolve, these factors along with the newer emerging factors may become a part of the routine assessment, aiding prediction of future coronary events.
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PMID:Gene polymorphism and coronary risk factors in Indian population. 1247 35

The field of new lipid-lowering drug research is very active, with researchers, looking to make the currently available drugs more powerful and safer, and to develop new classes of drugs. Among the statins, development has gone the farthest for rosuvastatin and pitavastatin. Colesevelam is a new bile acid sequestrant with a better digestive tolerance. Among the new classes of drugs, the most promising molecules are the cholesterol absorption inhibitors--with ezetimibe as the first in line--and the PPAR-alpha and PPAR-gamma activators. Among the other classes, the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, and ileal bile acid transporter inhibitors, have to be mentioned. In most of the cases, those new compounds are being developed mainly as a combined treatment with statins. However, these combination therapies differ depending on the lipid abnormalities of the patient. The statin-ezitimibe and the statin-bile acid sequestrant combinations have been the most studied treatments in pure hypercholesterolaemia. On another hand, the statin-PPAR-alpha and -gamma activator combination were the first to be developed for patients with combined hyperlipidaemia or type 2 diabetes mellitus. However, the clinical benefit of ACAT or CETP inhibitors remains to be determined and the development of MTP inhibitors has been restricted so far, because of problems of digestive intolerance and hepatic steatosis. Finally, the discovery of new specific lipoprotein receptors, such as the ABCA1 and SRB1 receptors, means that we can work towards developing new potential targets for pharmacological intervention.
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PMID:[New antilipemics: prospects]. 1282 7

A remarkable reduction of plasma concentrations of high-density lipoproteins (HDL), especially of the HDL(2) subfraction, is one of the typical lipoprotein alterations found in patients with familial combined hyperlipidemia (FCHL). Fourteen FCHL patients received 4 capsules daily of Omacor (an omega-3 polyunsaturated fatty acid [omega3 FA] concentrate providing 1.88 g of eicosapentaenoic acid [EPA] and 1.48 g of docosahexaenoic acid [DHA] per day; Pronova Biocare, Oslo, Norway) or placebo for 8 weeks in a randomized, double-blind, crossover study. Plasma triglycerides were 44% lower, and LDL cholesterol and apoliporpotein (apo)B were 25% and 7% higher after Omacor than placebo. HDL cholesterol was higher (+8%) after Omacor than placebo, but this difference did not achieve statistical significance. Omacor caused a selective increase of the more buoyant HDL(2) subfraction; plasma HDL(2) cholesterol and total mass increased by 40% and 26%, respectively, whereas HDL(3) cholesterol and total mass decreased by 4% and 6%. Both HDL(2) and HDL(3) were enriched in cholesteryl esters and depleted of triglycerides after Omacor. No changes were observed in the plasma concentration of major HDL apolipoproteins, LpA-I and LpA-I:A-II particles, lecithin:cholesterol acyltransferase (LCAT), and cholesteryl ester transfer protein (CETP). The plasma concentration of the HDL-bound antioxidant enzyme paraoxonase increased by 10% after Omacor. Omacor may be helpful in correcting multiple lipoprotein abnormalities and reducing cardiovascular risk in FCHL patients.
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PMID:An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia. 1476 65


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