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)

Premature atherosclerosis is a major cause of morbidity and mortality in end-stage renal disease patients. Dyslipidemia and increased oxidative stress contribute to premature atherogenesis in these patients. The dyslipidemia of end-stage renal disease consists of both quantitative and qualitative abnormalities in serum lipoproteins. Qualitative changes include hypertriglyceridemia (increased remnant lipoproteins), low high-density lipoprotein-cholesterol, and increased lipoprotein (a). In addition to quantitative changes, lipoproteins in end-stage renal disease undergo compositional and qualitative changes that make them pro-atherogenic, such as various modifications of apolipoprotein B, including oxidation, and modification by advanced glycation end-products. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and low-dose fibrates could be effective therapies for lipid disorders. The best evidence for increased oxidative stress in end-stage renal disease is the demonstration of increased plasma F2-isoprostanes. Confirmation of the positive findings with high-dose alpha-tocopherol in the Secondary Prevention with Antioxidants of Cardiovascular Disease in End-stage Renal Disease Study is urgently needed. Clinical trials with statins and other drugs that improve dyslipidemia also need to be undertaken. These therapies could clearly lead to a reduction in cardiovascular morbidity and mortality in these patients.
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PMID:Accelerated atherosclerosis, dyslipidemia, and oxidative stress in end-stage renal disease. 1185 5

Diabetic dyslipidemia is featured by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol levels, and elevated low-density lipoprotein (LDL) cholesterol commonly in the form of small, dense LDL particles. First-line treatment, fibrates versus statins or both, of dyslipidemia in diabetic patients has been the focus of debate. We investigated the potential hypolipidemic effects of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor with good triglyceride lowering properties, in patients with combined dyslipidemia and evidence of impaired fasting glucose or type 2 diabetes. Twenty patients were recruited for the study, and after a 60-day wash out period, baseline measurements of lipoprotein parameters, LDL particle diameter, and apolipoprotein B (apoB) degradation fragments were obtained. The group was then randomized, in a double-blinded manner, into 2 subgroups. Group A received atorvastatin (80 mg) and group B received placebo daily for 60 days. After the first treatment period, all patients were reanalyzed for the above parameters. The treatment regime then crossed over for the second treatment period in which group A received placebo and group B received atorvastatin (80 mg) daily for 60 days. All parameters were remeasured at the end of the study. Treatment with atorvastatin resulted in a statistically significant reduction in total cholesterol (41%), LDL cholesterol (55%), triglycerides (TG) (32%), and apoB (40%). Mean LDL particle diameter significantly increased from 25.29 +/- 0.24 nm (small, dense LDL subclass) to 26.51 < 0.18 nm (intermediate LDL subclass) after treatment with atorvastatin (n = 20, P <.005). At baseline, LDL particles were predominantly found in the small, dense subclass; atorvastatin treatment resulted in a shift in the profile to the larger and more buoyant LDL subclass. Atorvastatin treatment did not produce consistent changes in the appearance of apoB degradation fragments in plasma. Our results suggest that atorvastatin beneficially alters the atherogenic lipid profile in these patients and significantly decreases the density of LDL particles produced resulting in a shift from small, dense LDL to more buoyant and less atherogenic particles.
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PMID:Atorvastatin treatment beneficially alters the lipoprotein profile and increases low-density lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting glucose/type 2 diabetes. 1188 70

The composition and the transport of lipoproteins are seriously disturbed in thyroid diseases. Overt hypothyroidism is characterized by hypercholesterolaemia and a marked increase in low-density lipoproteins (LDL) and apolipoprotein B (apo A) because of a decreased fractional clearance of LDL by a reduced number of LDL receptors in the liver. The high-density lipoprotein (HDL) levels are normal or even elevated in severe hypothyroidism because of decreased activity of cholesteryl-ester transfer protein (CETP) and hepatic lipase (HL), which are enzymes regulated by thyroid hormones. The low activity of CETP, and more specifically of HL, results in reduced transport of cholesteryl esters from HDL(2) to very low-density lipoproteins (VLDL) and intermediate low-density lipoprotein (IDL), and reduced transport of HDL(2) to HDL(3). Moreover, hypothyroidism increases the oxidation of plasma cholesterol mainly because of an altered pattern of binding and to the increased levels of cholesterol, which presents a substrate for the oxidative stress. Cardiac oxygen consumption is reduced in hypothyroidism. This reduction is associated with increased peripheral resistance and reduced contractility. Hypothyroidism is often accompanied by diastolic hypertension that, in conjunction with the dyslipidemia, may promote atherosclerosis. However, thyroxine therapy, in a thyrotropin (TSH)-suppressive dose, usually leads to a considerable improvement of the lipid profile. The changes in lipoproteins are correlated with changes in free thyroxine (FT(4)) levels. Hyperthyroidism exhibits an enhanced excretion of cholesterol and an increased turnover of LDL resulting in a decrease of total and LDL cholesterol, whereas HDL are decreased or not affected. The action of thyroid hormone on Lp(a) lipoprotein is still debated, because both decrease or no changes have been reported. The discrepancies are mostly because of genetic polymorphism of apo(a) and to the differences between the various study groups. Subclinical hypothyroidism (SH) is associated with lipid disorders that are characterized by normal or slightly elevated total cholesterol levels, increased LDL, and lower HDL. Moreover, SH has been associated with endothelium dysfunction, aortic atherosclerosis, and myocardial infarction. Lipid disorders exhibit great individual variability. Nevertheless, they might be a link, although it has not been proved, between SH and atherosclerosis.
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PMID:Thyroid disease and lipids. 1203 52

Obesity is strongly associated with dyslipidemia, which may account for the associated increased risk of atherosclerosis and coronary disease. We aimed to test the hypothesis that kinetics of hepatic apolipoprotein B-100 (apoB) metabolism are disturbed in men with visceral obesity and to examine whether these kinetic defects are associated with elevated plasma concentration of apolipoprotein C-III (apoC-III). Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB kinetics were measured in 48 viscerally obese men and 10 age-matched normolipidemic lean men using an intravenous bolus injection of d(3)-leucine. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry (GCMS). Kinetic parameters were derived using a multicompartmental model (Simulation, Analysis, and Modeling Software II [SAAM-II]). Compared with controls, obese subjects had significantly elevated plasma concentrations of plasma triglycerides, cholesterol, LDL-cholesterol, VLDL-apoB, IDL-apoB, LDL-apoB, apoC-III, insulin, and lathosterol (P <.01). VLDL-apoB secretion rate was significantly higher (P =.034) in obese than control subjects; the fractional catabolic rates (FCRs) of IDL-apoB and LDL-apoB (P <.01) and percent conversion of VLDL-apoB to LDL-apoB (P <.02) were also significantly lower in obese subjects. However, the decreased VLDL-apoB FCR was not significantly different from the lean group. In the obese group, plasma concentration of apoC-III was significantly and positively associated with VLDL-apoB secretion rate and inversely with VLDL-apoB FCR and percent conversion of VLDL to LDL. In multiple regression analysis, plasma apoC-III concentration was independently and significantly correlated with the secretion rate of VLDL-apoB (regression coefficient [SE] 0.511 [0.03], P =.001) and with the percent conversion of VLDL-apoB to LDL-apoB (-0.408 [0.01], P =.004). Our findings suggest that plasma lipid and lipoprotein abnormalities in visceral obesity may be due to a combination of overproduction of VLDL-apoB particles and decreased catabolism of apoB containing particles. Elevated plasma apoC-III concentration is also a feature of dyslipidemia in obesity that contributes to the kinetic defects in apoB metabolism.
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PMID:Apolipoprotein B-100 kinetics in visceral obesity: associations with plasma apolipoprotein C-III concentration. 1214 79

Hyperandrogenemia and low levels of sex hormone binding globulin (SHBG) are frequently found in women with metabolic syndrome, which is characterized by low high-density lipoprotein cholesterol, hypertriglyceridemia, obesity, and hyperinsulinemia. The specific contribution of these various factors to coronary heart disease (CHD) is controversial. The coronary angiograms of 87 consecutive postmenopausal women were evaluated using 2 semiquantitative scoring systems to estimate the extent of focal and diffuse vessel wall alterations. Fasting sera were analyzed for levels of glucose, lipids, insulin, leptin, dehydroepiandrosterone sulfate, testosterone, and SHBG. Obesity was assessed by measuring body mass index, waist-to-hip ratio, skinfold thicknesses, and body impedance. After adjusting for age, there were significant differences in 55 women with CHD compared with 32 women without CHD: higher levels of low-density lipoprotein cholesterol (159 +/- 51 vs 132 +/- 39 mg/dl), apolipoprotein B (121 +/- 33 vs 102 +/- 29 mg/dl), triglycerides (115 vs 91 mg/dl), and basal insulin (7.5 vs 4.6 mU/L), as well as lower levels of high-density lipoprotein cholesterol (59.9 +/- 18.0 vs 69.0 +/- 17.1 mg/dl), SHBG (44.6 vs 68.1 nmol/L) and the quantitative insulin sensitivity check index (0.66 +/- 0.41 vs 0.93 +/- 0.73). Multivariate analysis by logistic regression identified age (odds ratio [OR] 1.22, 95% confidence intervals [CI] 1.09 to 1.37), smoking (OR 11.46, 95% CI 2.56 to 51.39), SHBG (OR 0.98, 95% CI 0.96 to 0.99), and apolipoprotein B (OR 1.02, 95% CI 1.01 to 1.04) as independently associated with the presence of CHD. Thus, low plasma levels of SHBG are associated with CHD in women independently of insulin, obesity markers, and dyslipidemia.
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PMID:Relation of serum levels of sex hormone binding globulin to coronary heart disease in postmenopausal women. 1216 Dec 23

Uremic patients suffer from a secondary form of complex dyslipidemia consisting of quantitative and qualitative abnormalities in serum lipoproteins resulting in altered lipoprotein composition and metabolism. The most prominent are an increase in serum triglyceride levels (due to elevated very-low-density lipoprotein remnants and intermediate-density lipoprotein) and low high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein (LDL) cholesterol is often normal, but the cholesterol may originate from the atherogenic small and dense LDL subclass. The apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide modification of the enzymatic and advanced glycation end-product, oxidation or glycosylation). Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote prolonged circulation. HDL particles are structurally altered during states of inflammation. The contribution of this complex and atherogenic form of dyslipidemia to cardiovascular disease in patients with renal disease is at present unclear. Most studies are negative in demonstrating the predictive power of serum lipids for the development of cardiovascular disease. This is most likely due to interference with deteriorating aspects of the activated acute-phase response. Since it is also still unclear whether we have therapeutics available with a sufficient impact on LDL size, remnant lipoprotein lowering and restoration of HDL function, we urgently need specific intervention trials.
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PMID:Uremia-specific alterations in lipid metabolism. 1220 90

The growing epidemic of the metabolic syndrome is now well recognized and there is widespread effort to understand the pathogenesis of this complex syndrome and its major metabolic consequences. One of the severe complications accompanying insulin resistant states is the hypertriglyceridemia that appears to occur largely due to overproduction of triglyceride-rich, apolipoprotein B (apoB) containing-lipoproteins. As a result, mechanisms regulating the overproduction of these atherogenic apoB-containing lipoproteins have been the focus of much investigation in recent years. Both in vitro as well as in vivo models of insulin resistance are currently being used to further our understanding of the mechanisms involved in the deregulation of lipid metabolism in insulin resistant states. Evidence from these animal models as well as human studies has identified hepatic very low density lipoprotein (VLDL) overproduction as a critical underlying factor in the development of hypertriglyceridemia and metabolic dyslipidemia. In recent years, a dietary animal model of insulin resistance, the fructose-fed hamster model developed in our laboratory, has proven invaluable in studies of the link between development of an insulin resistant state, derangement of hepatic lipoprotein metabolism, and overproduction of apoB-containing lipoproteins. Evidence from the fructose-fed hamster model now indicates oversecretion of both hepatically-derived apoB100-containing VLDL as well as intestinal apoB48-containing triglyceride-rich lipoproteins in insulin resistant states. A number of novel intracellular factors that may be involved in modulation of VLDL have also been identified. This review focuses on these recent developments and examines the hypothesis that a complex interaction among enhanced flux of free fatty acids from peripheral tissues to liver and intestine, chronic up-regulation of de novo lipogenesis by hyperinsulinemia, and attenuated insulin signaling in the liver and the intestine may be critical to lipoprotein overproduction accompanying insulin resistance.
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PMID:Mechanisms of metabolic dyslipidemia in insulin resistant states: deregulation of hepatic and intestinal lipoprotein secretion. 1245 12

Hypertension is often associated with insulin resistance, dyslipidemia and obesity, which indicate a prediabetic state and increased risk of cardiovascular disease. Pioglitazone treatment of patients with type 2 diabetes reduces insulin resistance and improves lipid profiles. The present double-blind placebo-controlled study is the first study to report effects of pioglitazone in non-diabetic patients with arterial hypertension. Following a one week run-in, 60 patients were randomized to receive either pioglitazone (45 mg/day) or placebo for 16 weeks. Insulin sensitivity (M-value) increased by 1.2 +/- 1.7 mg/min/kg with pioglitazone compared with 0.4 +/- 1.4 mg/min/kg (P = 0.022) with placebo. HOMA index was decreased (-22.5 +/- 45.8) by pioglitazone but not by placebo (+0.8 +/- 26.5; P < 0.001). Decreases in fasting insulin and glucose were significantly (P = 0.002 and P = 0.004, respectively) greater with pioglitazone than placebo. Body weight did not change significantly with either treatment. HDL-cholesterol was increased and apolipoprotein B was decreased to a significantly greater extent with pioglitazone. There was a significantly (P = 0.016) greater decrease from baseline in diastolic blood pressure with pioglitazone. These changes would suggest improved glucose metabolism and a possible reduction in risk of cardiovascular disease with pioglitazone treatment of non-diabetic patients with arterial hypertension.
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PMID:Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. 1246 45

Recent studies have demonstrated that the incidence of cardiovascular events occurring with renal transplantation is higher than that in the general population. Renal transplantation modifies the characteristic dyslipidemia of chronic renal failure. In this study the change in lipoprotein and lipid values of 103 transplant recipients after transplantation was investigated. The aim of our work was to examine the short-term and long-term variations in lipid metabolism. The major lipoprotein fractions (VLDL, LDL, HDL) were separated by preparative ultracentrifugation, and TG and cholesterol concentrations were determined in plasma and lipoprotein fractions. Whole plasma apolipoproteins were determined by a rate immunonephelometric technique. In the pretransplant period the patients displayed the typical picture of uremics. After transplantation the most evident alterations in the lipoprotein profile occurred in our case series after 3 mon. The major finding was a 35% reduction in plasma TG. The modifications in the TG-rich lipoproteins of our transplant recipients persisted throughout the observation period. In the initial 3-mon period, total cholesterol remained steady, whereas LDL-cholesterol and total apolipoprotein B showed a significant increase. No significant changes were found in total and transported TG and cholesterol between the 3-mon and the 6-yr values. The substantial stability of cholesterol levels after transplantation and in subsequent reports, as well as a higher incidence of cardiovascular complications, may suggest that the mechanisms responsible for vessel damage must be sought mainly in the structural and physicochemical alterations of the individual lipoprotein fractions or in other risk factors.
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PMID:Lipoprotein-apolipoprotein changes in renal transplant recipients. 1253 May 56

Newer, more effective statins are powerful agents for reducing elevated levels of low-density lipoprotein (LDL) cholesterol and thereby lowering the risk of coronary heart disease (CHD) and related adverse events. Although LDL remains the primary target of therapy for reducing CHD risk, increased interest is focusing on apolipoprotein B (apoB)-containing lipoprotein subfractions--particularly very-low-density lipoprotein (VLDL). VLDL remnants, and intermediate-density lipoproteins (IDL)--as secondary targets of therapy. Elevated apoB is known to be an important risk factor for CHD, and dysregulation of the metabolism of apoB-containing lipoproteins is involved in the progression of atherosclerosis. Statins reduce circulating concentrations of atherogenic apoB-containing lipoproteins by decreasing the production of VLDL in the liver and, thus, the production of VLDL remnants and LDL. Statins also increase the clearance of these particles through upregulation of LDL receptors in the liver. Efforts to develop statins with enhanced lipid-modifying properties are ongoing. The optimal statin would offer a high degree of inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a prolonged duration of action, hepatic selectivity for maximal upregulation of LDL receptors, and a low potential for drug-drug interactions. Recent studies have shown that rosuvastatin, a new agent in this class, demonstrates these qualities. Rosuvastatin is a highly effective inhibitor of HMG-CoA reductase, is relatively nonlipophilic, has a half-life of approximately 20 h, exhibits hepatic selectivity, has little systemic availability, and has a low potential for drug-drug interactions because of its limited degree of metabolism by the cytochrome P450 system. A recent double-blind, crossover study revealed that treatment with rosuvastatin resulted in marked reductions in apoB-containing lipoproteins in patients with type IIa or IIb dyslipidemia. By reducing the number of atherogenic lipoprotein particles, rosuvastatin decreases the atherosclerotic burden in hyperlipidemic patients at high risk for CHD and related adverse outcomes.
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PMID:New dimension of statin action on ApoB atherogenicity. 1253 16


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