Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperglycemia increases oxidative stress in various tissues and leads to diabetic cardiovascular complication. Dyslipidemia, such as an increase in oxidized low-density lipoprotein (LDL), is well recognized in diabetic patients with hyperglycemia. However, the mechanism by which hyperglycemia causes the increased LDL oxidation remains unclear. Albumin is the most abundant protein in the circulation, and can function as an antioxidant. Therefore, we examined whether glycoxidative modification inhibits the antioxidant activity of albumin to LDL oxidation and clarified the mechanism by which this modification may suppress its antioxidant activity. Human serum albumin (HSA) was incubated in phosphate-buffered saline with and without glucose at 37 degrees C for up to 8 weeks under aerobic conditions (referred to as glycoxidation (goHSA) and oxidation (oHSA), respectively). Metal chelator-treated, nonoxidative HSA (chHSA) and freshly prepared HSA (fHSA) were used as controls. N(epsilon)-(carboxymethyl)lysine (CML), a glycoxidative product, was determined by enzyme-linked immunosorbent assay. Oxidation was estimated by measuring the thiols of the HSA molecule. Copper-mediated oxidation of LDL was conducted in the presence or absence of modified HSAs at 37 degrees C for 6 days. Malondialdehyde and negative charge of LDL were measured. To clarify the mechanism of reduced antioxidant activity of HSA, we examined firstly the binding activity of modified HSAs to copper, and secondly the effects of free radical scavengers on the formation of malondialdehyde. CML was formed in goHSA in a time- and concentration-dependent manner. Both goHSA and oHSA significantly decreased the contents of free thiol groups compared to ch- and fHSAs. The antioxidant activity of goHSA to LDL oxidation was the lowest among various modified HSAs. The oHSA showed a moderate decrease in antioxidant activity. The binding activity of go- and oHSAs to copper was lower than that of ch- and fHSAs. The formation of MDA from LDL oxidation in the presence of goHSA was completely inhibited by Tiron (1,2-dihydroxy-3,5-benzenedisulfonic acid) and superoxide dismutase. In contrast, catalase and mannitol had no effect. Our results indicate that in vitro glycoxidation of HSA induced a marked loss of antioxidant activity of this molecule to copper-mediated oxidation of LDL, which may be caused by the generation of superoxide.
 ...
PMID:Contribution of superoxide to reduced antioxidant activity of glycoxidative serum albumin. 1243 98

The objective of this study is to determine the effect of dyslipidemia on the plasma protein and lipoprotein distribution of haloperidol. In doing so, total plasma cholesterol and triglyceride levels were adjusted by adding differing volumes of concentrated low-density lipoproteins and very-low-density lipoproteins to normolipidemic plasma. Following the incubation of [3H]-haloperidol plus cold haloperidol (18 microg/ml) the plasma was separated into its lipoprotein and lipoprotein deficient fractions by density gradient ultra centrifugation and [3H]-haloperidol distribution was determined. Our results revealed a significant positive correlation between total cholesterol concentration and haloperidol recovery in the low-density lipoprotein fraction (r=0.975, df=13, P<0.005). A positive correlation was also observed between total plasma triglyceride concentration and haloperidol recovery from both the very low-density lipoprotein (r=0.965, df=16, P<0.002) and low-density lipoprotein fractions (r=0.935, df=16, P<0.005). This redistribution was the result of haloperidol leaving the lipoprotein-deficient fraction were it is primarily bound to albumin and alpha(1)-acid glycoprotein. This redistribution of haloperidol may influence its clinical efficacy.
 ...
PMID:The influence of dyslipidemia on the plasma protein and lipoprotein distribution of haloperidol. 1248 Jan 20

Mice deficient in hepatocyte nuclear factor 1 alpha (HNF-1alpha) develop dwarfism, liver dysfunction, and type 2 diabetes mellitus. Liver dysfunction in HNF-1alpha-null mice includes severe hepatic glycogen accumulation and dyslipidemia. The liver dysfunction may appear as soon as 2 weeks after birth. Since the HNF-1alpha-null mice become diabetic 2 weeks after birth, the early onset of the liver dysfunction is unlikely to be due to the diabetic status of the mice. More likely, it is due directly to the deficiency of HNF-1alpha in liver. Although the HNF-1alpha-null mice have an average life span of 1 year, the severe liver phenotype has thwarted attempts to study the pathogenesis of maturity-onset diabetes of the young type 3 (MODY3) and to examine therapeutic strategies for diabetes prevention and treatment in these mice. To circumvent this problem, we have generated a new Hnf-1alpha mutant mouse line, Hnf-1alpha(kin/kin), using gene targeting to inactivate the Hnf-1alpha gene and at the same time, to incorporate the Cre-loxP DNA recombination system into the locus for later revival of the Hnf-1alpha gene in tissues by tissue-specifically expressed Cre recombinase. The Hnf-1alpha(kin/kin) mice in which the expression of HNF-1alpha was inactivated in germ line cells were indistinguishable from the HNF-1alpha-null mice with regard to both the diabetes and liver phenotypes. Intriguingly, when the inactivated Hnf-1alpha gene was revived in liver (hepatic Hnf-1alpha revived) by the Cre recombinase driven by an albumin promoter, the Hnf-1alpha(kin/kin) mice, although severely diabetic, grew normally and did not develop any of the liver dysfunctions. In addition, we showed that the expression of numerous genes in pancreas, including a marker gene for pancreas injury, was affected by liver dysfunction but not by the deficiency of HNF-1alpha in pancreas. Thus, our hepatic-Hnf-1alpha-revived mice may serve as a useful mouse model to study the human MODY3 disorder.
 ...
PMID:Liver-specific reactivation of the inactivated Hnf-1alpha gene: elimination of liver dysfunction to establish a mouse MODY3 model. 1252 98

In renal failure, parathyroid hormone (PTH) is not only involved in the genesis of disturbed calcium/phosphate metabolism and ostitis fibrosa; it is also a permissive factor in the genesis of hypertension, cardiovascular damage, and dyslipidemia. The allosteric activator of the calcium sensing receptor NPSR-568 (R-568) has been shown to reduce the serum intact PTH (iPTH) concentration in uremic rats. It was the purpose of this study in subtotally nephrectomized (SNX) rats to compare pharmacologic abrogation of secondary hyperparathyroidism by R-568 with parathyroidectomy (PTX). The effects on progression of renal failure, BP, and lipid and structural parameters of kidney and heart were studied. Four groups of male SD-rats were studied: (1) sham-operated + vehicle-treated rats (controls); (2) SNX + vehicle-treated rats (SNX); (3) parathyroidectomized SNX + vehicle-treated rats (SNX+PTX); and (4) SNX + calcimimetic R-568-treated rats (SNX+R-568). R-568 (50 micro mol/kg per d) was administered by gavage. Eight weeks after SNX, serum creatinine concentration, urinary albumin excretion, BP, and serum LDL-cholesterol concentration were significantly lower in both R-568-treated and parathyroidectomized SNX compared with vehicle-treated SNX. In addition, structural abnormalities of the kidney (glomerulosclerosis, tubulointerstitial changes) and the heart (interstitial fibrosis, capillary length density, arteriolar wall thickness) were significantly less pronounced than in vehicle-treated SNX. It is concluded that in experimental renal failure abrogation of hyperparathyroidism by administration of a calcimimetic or PTX similarly attenuates progression of renal failure. Furthermore, it interferes with the development of cardiovascular risk factors and cardiac remodeling.
 ...
PMID:Beneficial effects of calcimimetics on progression of renal failure and cardiovascular risk factors. 1266 Mar 30

Kidney transplant recipients are not only prone to dyslipidemia but also have a high risk of cardiovascular death. Impairment of the fibrinolytic system is thought to be one factor playing a role in development of thrombotic complications. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a glycoprotein, linking coagulation and fibrinolysis. The purpose of this study was to assess TAFI concentrations and activities in renal transplant recipients stratified based upon serum cholesterol values above 220 mg/dL or below 200 mg/dL. The groups did not differ regarding age, creatinine clearance, BMI, time after transplantation, albumin, fibrinogen, thrombomodulin, or PAP. Additionally, we evaluated thrombin activity (thrombin-antithrombin complex TAT, prothrombin fragments 1 + 2); TAFI activator; thrombomodulin (TM), catalyzer of TAFI activation; and the degree of plasmin generation (plasmin-antiplasmin complex PAP) using commercially available kits. In patients with hyperlipidemia significantly higher TAFI concentrations and activities may contribute to prolonged ECLT and lowered fibrinolytic activity index (FAI). Increased levels of F1 + 2 and TAT were observed in hypercholesterolemic patients, indicating enhanced thrombin generation. Elevated TAFI concentration, and activities and enhanced thrombin generation observed in hypercholesterolemic kidney transplant recipients may contribute to hypofibrinolysis and progression of atherosclerosis in this group of patients.
 ...
PMID:Thrombin-activatable fibrinolysis inhibitor in kidney transplant recipient with dyslipidemia. 1452 94

The aim of this study was to investigate the relationship between plasma viscosity and lipoprotein and apolipoprotein pattern in normo- and hypercholesterolemic patients with peripheral occlusive arterial disease (POAD). 40 patients with POAD have been selected (8 females and 32 males, mean age: 54+/-3.2 years) with clinically evident superficial femoral occlusive artery disease. They were separated into two groups as normocholesterolemic (plasma total cholesterol <200 mg/dl) and hypercholesterolemic (plasma total cholesterol >200 mg/dl). Plasma total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides, total protein, and albumin levels were determined by enzymatic methods using commercial kits. Levels of apolipoprotein AI (apo AI), and apolipoprotein B (apo B) were measured using a immunoturbidometric method. Plasma viscosity (PV) was measured by capillary viscometer. Classifying the patients with PAOD according to the cholesterol levels; hypercholesterolemic (mean total-cholesterol: 227.90+/-26.97 mg/dl) patients had significantly higher LDL-C, PV and triglyceride levels compared with nornocholesterolemic patients (p<0.001, p<0.001, p<0.001, respectively). HDL-C and apo B were significantly lower in hypercholesterolemic patients than in normocholesterolemic patients (p<0.001, p<0.001, respectively). PV was positively correlated with total cholesterol (r=0.485, p<0.05), atherogenic index (r=0.624, p<0.01), total-C/HDL-C ratio (r=0.624, p<0.05), and LDL-C/HDL-C ratio (r=0.707, p<0.001) in hypercholesterolemic patients with POAD. PV was higher in hypercholesterolemic patients with POAD than in normocholesterolemic patients with POAD. We suggest that POAD patients should be regarded as a heterogenous group with lipid and lipoprotein parameters in order to assess the microcirculation in the affected limb. In case of dyslipidemia in POAD patients an elevated plasma viscosity should be considered as coexisting risk factor.
 ...
PMID:Impaired plasma viscosity via increased cholesterol levels in peripheral occlusive arterial disease [correction of disase]. 1456 98

Type 2 diabetes mellitus is a leading cause of morbidity and mortality. Cardiovascular disease (CVD) is the most prevalent complication and primarily accounts for the excess morbidity and mortality in diabetic patients, but microvascular complications, such as kidney disease and retinopathy, are frequent and contribute to the total disease burden. Lipid abnormalities in patients with type 2 diabetes are a major problem and associated with the increased risk of CVD. The most common pattern of dyslipidemia in these patients consists of elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol. Low-density lipoprotein levels in these patients are often similar to that of the nondiabetic population, although there may be important qualitative differences in the pattern that contribute to the increased risk of CVD. Abnormal levels of urinary albumin occur in 30-40% of patients with type 2 diabetes and the presence of kidney disease enhances the mortality from CVD. Microalbuminuria, an early marker of diabetic nephropathy, is an independent risk factor for CVD. The increased levels of urinary albumin secretion may represent a more generalized vascular damage than renal microvascular injury alone. This Review focuses on the significance of diabetic dyslipidemia and microalbuminuria to CVD risk as well as to kidney complications. We also discuss the role of aggressive therapy to ameliorate vascular injury in the diabetic patient and reduce or prevent the cardiovascular and renal consequences of the disease.
 ...
PMID:Dyslipidemia in patients with type 2 diabetes. relationships between lipids, kidney disease and cardiovascular disease. 1459 67

The paradigm of obesity leading to insulin resistance and type 2 diabetes is examined in relation to dyslipidemia, which typically consists of high levels of triglycerides (TG) and low levels of high-density lipoprotein (HDL). Kinetic studies with stable isotope-labeled amino acid precursors have shown that the development of visceral obesity, as well as type 2 diabetes, leads to overproduction of the apolipoprotein B-100 and TG in very low-density lipoproteins. Elevated plasma levels or increased flux of albumin-bound free fatty acids to the liver appear to be underlying metabolic events in this process. Low levels of HDL are due to increased catabolism, which can be related to TG enrichment.
 ...
PMID:Lipoprotein metabolism in obesity and diabetes: insights from stable isotope kinetic studies in humans. 1467 71

One of the central functions of the kidney is to excrete low molecular weight, water soluble, plasma, waste products into the urine, whereas macromolecules, the size of albumin and larger, are retained. The flow of the glomerular filtrate is thought to follow an extracellular route, passing through the endothelial fenestrae, then across the glomerular basement membrane and finally through the slit diaphragm between the foot processes of podocytes. Recently it has been hypothesized that microalbuminuria leading to proteinuria and to end stage renal disease (ESRD) is mainly due to an altered glomerular fitration barrier at podocyte level. The "conditio sine qua non" for the development of diabetic ESRD is hyperglycemia. However, arterial hypertension and abnormalities of blood lipid concentrations and structure are also an important antecedent of such complication in diabetes mellitus. Interestingly it has been suggested that hyperglycemia, arterial hypertension and dyslipidemia cause disorderes of albumin excretion rate by damaging podocyte and slit diaphragm protein scaffold with over production of and extracellular release of oxygen radical species at glomerular level. The present review will briefly discuss recent reports which describe the relationship between blood glucose and lipid abnormalities and the occurrence and progression of renal damage in diabetes mellitus. More particularly we will give evidence that the risk of a rapid decline of glomerular function abruptly increases when glycated hemoglobin is steadily higher than 7.5% and postprandial blood glucose is above 200 mg/dL. Eventually we will analyze recent reports showing that treatment with statins, the inhibitors of hydroxymethylglutaryl-coenzyme A reductase, ameliorate the course of renal function in type 2 diabetic patients. It is not yet fully understood whether this effect is due to the lowering of the circulating levels of low density lipoproteins (LDL) or to an improved endothelial function or to lower patterns of LDL oxidation.
 ...
PMID:Blood glucose and lipid control as risk factors in the progression of renal damage in type 2 diabetes. 1473

Insulin resistance and type 2 diabetes are associated with elevated circulating levels of nonesterified FA (NEFA) and lipoprotein remnants. The dyslipidemia is an important contributor to the excess arterial disease associated with insulin resistance and type 2 diabetes, but the mechanisms involved are elusive. In the present study we examined the effect of NEFA on macrophages. For this purpose, we utilized human macrophages, prepared by treating THP-1 monocytes with phorbol ester. We found that albumin-bound NEFA at physiological levels increase the secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) by the THP-1 macrophages in a dose-dependent manner. The effect was registered as an increase in mRNA, and the amount of GM-CSF secreted correlated with the accumulation of TAG and DAG in the cell. The NEFA-induced rise in GM-CSF appeared to be mediated by activation of protein kinase C, probably acting on extracellular signal-regulated kinases 1 and 2 and being calcium dependent. We speculate that increased secretion of GM-CSF by resident macrophages in the intima exposed chronically to high levels of NEFA, such as those present in insulin resistance, may contribute to a proatherogenic response of arterial cells.
 ...
PMID:Fatty acids induce increased granulocyte macrophage-colony stimulating factor secretion through protein kinase C-activation in THP-1 macrophages. 1523 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>