UMLS:C0242339 - FACTA Search

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)

High levels of the triacylglycerol-rich lipoproteins, very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) have been identified as independent risk factors for coronary heart disease, and inflammation is thought to contribute to atherosclerosis and its complications. To understand how dyslipidemia promotes inflammation, we have characterised the effects of VLDL treatment on production of tumor necrosis factor-alpha (TNF) by human monocyte-derived macrophages. VLDL strongly potentiated lipopolysaccharide (LPS)-induced expression of TNF mRNA and secretion of TNF protein. VLDL activated mitogen-activated protein kinase-ERK kinase 1/2 (MEK1/2), and potentiated LPS-induced MEK1/2 activation. The MEK1/2 inhibitor U0126 strongly diminished TNF expression, indicating that MEK1/2 plays a central role in the regulation of TNF expression. VLDL did not activate transcription factors NF-kappaB and PPAR-gamma, but it activated AP-1 at least as potently as LPS, and potentiated LPS-induced activation of AP-1. The inhibitor U0126 completely prevented this potentiation. Inhibition of AP-1 by decoy oligonucleotides abolished potentiation of TNF secretion by VLDL. In conclusion, VLDL treatment potentiates TNF expression in macrophages by activation of MEK1/2 and AP-1. These findings suggest that triacylglycerol-rich lipoproteins are involved in inflammatory processes associated with atherosclerosis.
...
PMID:Very low density lipoprotein potentiates tumor necrosis factor-alpha expression in macrophages. 1577 38

Cardiovascular disease (CVD) is responsible for 35-50% of rheumatoid arthritis (RA) deaths, whereas, in the general UK adult population, coronary heart disease is responsible for 1/4 deaths in males and 1/5 deaths in female. This increased risk may be attributable to RA-specific risk factors such as hyperhomocysteinemia, disease-related dyslipidemia or vascular inflammation, or to morbidity related to medications and high levels of tumor necrosis factor-alpha (TNF-alpha). The possible roles of TNF-alpha in the development of atherosclerosis include the recruitment of inflammatory cells to the site of injury or the promotion of adverse vascular smooth muscle cell remodelling. TNF-alpha may also act as a proinflammatory factor in plaque rupture. Anticytokine therapy could prove beneficial in the treatment of patients with heart failure. While early studies supported this hypothesis, anti-TNF strategies have not demonstrated salutary benefits in large multicenter randomized and placebo-controlled clinical trials in patients with symptomatic heart failure. There is a variety of possible explanations for the failure of anti-TNF therapy: (1) TNF antagonism has untoward effects in the setting of heart failure; (2) the biological agents used in the trials were intrinsically toxic; (3) sex and race may have important implications in the outcome after anticytokine therapy; (4) the TNF-alpha protein contains a polymorphism, and, in fact, genoma plays a role in modifying the pharmacologic response to anticytokines; (5) anti-TNF-alpha approaches could have had pharmacodynamic interactions with other heart failure medications; and (6) the patients in these trials may have been inappropriately selected. These disappointing results may determine controversial attitude in the long-term treatment with anti-TNF agents in RA or Crohn's disease. The effects of TNF-alpha blockers on incident cases of congestive heart failure (CHF) in RA are controversial. The available published data suggest the following: (a) RA patients with history of CHF and a concomitant indication for the use of TNF-alpha blockers do not need a baseline cardiac evaluation to screen for heart failure; (b) patients with well-compensated mild CHF New York Heart Association (NYHA) classes I and II and a concomitant indication for the use of TNF-alpha blockers should be evaluated at baseline and then be closely monitored for any clinical signs of worsening heart failure; and (c) patients with (NYHA) class III or IV heart failure should not be treated with TNF-alpha blockers in any case.
...
PMID:TNF-alpha, rheumatoid arthritis, and heart failure: a rheumatological dilemma. 1582 1

Both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as well as peroxisome proliferator-activated receptor (PPAR)alpha activators (fibrates) proved to be effective in the primary and secondary prevention of cardiovascular diseases. The benefits of hypolipemic therapy in cardiovascular diseases cannot be explained only by the lipid-lowering potential of these agents. The aim of this study was to clarify the effect of hypolipemic agents on proinflammatory cytokine release from human monocytes in relationship with their action on plasma levels of sensitive systemic marker of low-grade vascular inflammation. Plasma lipid and high-sensitivity C-reactive protein (hsCRP) levels, and the release of tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta from monocytes were assessed at baseline and 30 and 90 days following randomization of IIa dyslipidemic patients into fluvastatin or simvastatin groups and randomization of type IIb dyslipidemic patients to the micronized form of either ciprofibrate or fenofibrate. Lipopolysaccharide-stimulated monocytes from dyslipidemic patients released significantly more TNFalpha (types IIa and IIb dyslipidemias) and interleukin-1beta (type IIa dyslipidemia) in comparison with monocytes in 59 age-, sex-, and weight-matched control subjects. Their baseline hsCRP levels were also higher. Both statins and fibrates reduced the release of TNFalpha and interleukin-1beta, and lowered plasma hsCRP levels. The effects of hypolipemic agents on cytokine release and plasma hsCRP were unrelated to their lipid-lowering action. Our results have demonstrated that type IIa and IIb dyslipidemic patients exhibit the abnormal pattern of TNFalpha and interleukin-1beta production by activated monocytes. Both HMG-CoA reductase inhibitors and PPARalpha activators normalize monocytic secretion of these cytokines, and this action may partially contribute to the systemic antiinflammatory effect of hypolipemic agents. The statin- and fibrate-induced suppression of proinflammatory cytokine release from monocytes seems to play a role in their beneficial effect on the incidence of cardiovascular events.
...
PMID:Monocyte release of tumor necrosis factor-alpha and interleukin-1beta in primary type IIa and IIb dyslipidemic patients treated with statins or fibrates. 1611 45

The increased risk of premature cardiovascular disease (CVD) in rheumatoid arthritis (RA) patients may depend on traditional risk factors but may also be attributable to RA-specific risk factors such as disease-related dyslipidemia, or cytokines such as tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is a proinflammatory cytokine that can produce widespread deleterious effects when expressed in large amounts. It is produced in the heart by both cardiac myocytes and resident macrophages under conditions of cardiac stress, and is thought to be responsible for many of the untoward manifestations of cardiac disease. TNF-alpha may play a role in the triggering and perpetuation of atherosclerosis. Treatment with biologic agents directed against TNF-alpha has significant clinical benefits in inflammatory diseases such as RA and may be able to reduce cardiovascular risk. The disappointing results of the recent studies to antagonize TNF-alpha in CVD may have various explanations. However, the effects of TNF-alpha blockers on incident cases of congestive heart failure (CHF) in RA remains controversial. Due to the lack of evidence of a beneficial effect of anti-TNF-alpha agents in treatment of CHF, they should not be used to treat patients with New York Heart Association (NYHA) class III or IV heart failure.
...
PMID:Tumor necrosis factor-alpha, biologic agents and cardiovascular risk. 1621 87

Insulin resistance, obesity, diabetes, dyslipidemia and nonalcoholic fatty liver are components of the metabolic syndrome, a disease complex that is increasing at epidemic rates in westernized countries. Although proinflammatory cytokines have been suggested to contribute to the development of these disorders, the molecular mechanism of the development of this syndrome is poorly understood. In this study, we show that expression of suppressor of cytokine signaling SOCS-1 and SOCS-3 is increased in livers of obese insulin-resistant animals, and that adenoviral-mediated overexpression of SOCS-1 or SOCS-3 in liver causes insulin resistance through down-regulation of tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. Moreover, the increased SOCS-1 and SOCS-3 also cause a prominent up-regulation of the key regulator of fatty acid synthesis in liver, sterol regulatory element binding protein (SREBP)-1. Conversely, inhibition of SOCS-1 and SOCS-3 in livers of obese diabetic db/db mice by antisense treatment modestly improves insulin sensitivity, but completely normalizes the increased expression of SREBP-1. The latter leads to dramatic amelioration of hepatic steatosis and hypertriglyceridemia. Promoter activity analysis reveals that expression of SOCS-1 or SOCS-3 with SOCS-3 being more potent enhances SREBP-1c expression, while it is inhibited by expression of STAT3. This STAT3-mediated inhibition of SREBP-1c expression is antagonized by co-expression of SOCS proteins. Moreover, db/db mice display decreased STAT3 phosphorylation in liver that is normalized by antisense treatment of SOCS proteins. These data suggest that obese subjects in the persistent inflammatory states, such as elevated circulating tumor necrosis factor-alpha, may have down-regulated STAT3-mediated signaling by increased SOCS proteins, leading to up-regulation of SREBP-1c expression and increased fatty acid synthesis in liver. Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating cytokine signaling and insulin signaling.
...
PMID:Role of suppressors of cytokine signaling SOCS-1 and SOCS-3 in hepatic steatosis and the metabolic syndrome. 1622 15

Weight gain is associated with the use of many psychotropic medications, including antidepressants, mood stabilizers, antipsychotic drugs, and may have serious long term consequences: it can increase health risks, specifically from overweight (BMI = 25-29.9 kg/m2) to obesity (BMI > or =30 kg/m2), according to Body Mass Index (BMI), and the morbidity associated therewith in a substantial part of patients (hypertension, coronary heart desease, ischemic stroke, impaired glucose tolerance, diabetes mellitus, dyslipidemia, respiratory problems, osteoarthritis, cancer); according to patients, psychosocial consequences such as a sense of demoralization, physical discomfort and being the target of substantial social stigma are so intolerable that they may discontinue the treatment even if it is effective. The paper reviews actual epidemiological data concerning drug induced weight gain and associated health problems in psychiatric patients : there is a high risk of overweight, obesity, impaired glucose tolerance, diabetes mellitus, premature death, in patients with schizophrenia or bipolar disorder; and the effects of specific drugs on body weight: Tricyclic Antidepressants (TCA) induced weight gain correlated positively with dosage and duration of treatment, more pronounced with amitriptyline ; Selective Serotonin Reuptake Inhibitors (SSRI) decrease transiently bodyweight during the first few weeks of treatment and may then increase bodyweight; weight gain appears to be most prominent with some mood stabilizers (lithium, valproate); atypical antipsychotics tend to cause more weight gain than conventional ones and weight gain, diabetes, dyslipidemia, seem to be most severe with clozapine and olanzapine. Conceming the underlying mechanisms of drug induced weight gain, medications might interfere with central nervous functions regulating energy balance; patients report about: increase of appetite for sweet and fatty foods or "food craving" (antidepressants, mood stabilizers, antipsychotic drugs) and weight gain despite reduced appetite which can be explained by an altered resting metabolic rate (TCA, SSRI, Monoaminoxidase Inhibitors MAO I). According to current concepts, appetite and feeding are regulated by a complex of neurotransmitters, neuromodulators, cytokines and hormones interacting with the hypothalamus, including the leptin and the tumor necrosis factor system. The pharmacologic mechanisms underlying weight gain are presently poorly understood: maybe the different activities at some receptor systems may induce it, but also genetic predisposition. Understanding of the metabolic consequences of psychotropic drugs (weight gain, diabetes, dyslipidemia) is essential: the insulin-like effect of lithium is known; treatment with antipsychotic medications increases the risk of impaired glucose tolerance and diabetes mellitus. Several management options of weight gain are available from choosing or switching to another drug, dietary advices, increasing physical activities, behavioural treatment, but the best approach seems to attempt to prevent the weight gain : patients beginning maintenance therapy should be informed of that risk, and nutritional assessment and counselling should be a routine part of treatment management, associated with monitoring of weight, BMI, blood pressure, biological parameters (baseline and three months monitoring of fasting glucose level, fasting cholesterol and triglyceride levels, glycosylated haemoglobin). Psychiatrics must pay attention to concomitant medications and individual factors underlying overweight and obesity. Weight gain has been described since the discovery and the use of the firstpsychotropic drugs, but seems to intensify with especially some of the second generation antipsychotic medications ; understanding of the side effects of psychotropic drugs, including their metabolic consequences (weight gain, diabetes, dyslipidemia) is essential for the psychiatrics to avoid on the one hand a risk of lack of compliance, a discontinuation of the pharmacological medication and also a risk of relapse and rehospitalization, and on the other hand to avoid acute life threatening events (diabetic ketoacidocetosis and non ketotic hyperosmolar coma, long term risk complications of diabetes and overweight).
...
PMID:[Psychotropic drugs induced weight gain: a review of the literature concerning epidemiological data, mechanisms and management]. 1638 18

Fenofibrate, a selective (1)PPAR-alpha activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-alpha reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-alpha activators may be useful in the treatment of syndrome X.
...
PMID:Peroxisome proliferator-activated receptor-alpha selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. 1647 80

Vascular dysfunction, low-grade inflammation, insulin resistance, and impaired fibrinolysis have each been reported to be present in type 2 diabetes, but their relationships, and the role of obesity, have not been investigated. We measured insulin sensitivity (euglycemic clamp), forearm blood flow responses to graded local acetylcholine (Ach) and sodium nitroprusside (SNP) infusions, plasma concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, von Willebrand factor (vWF), plasminogen activator inhibitor (PAI)-1, tissue plasminogen activator (tPA), and high-sensitivity C-reactive protein (hs-CRP) in 81 diabetic patients. When patients were stratified by insulin resistance, more severe insulin resistance was associated (P < 0.05) with overweight, central fat distribution, hypertension, and dyslipidemia (with similar sex distribution, age, fasting plasma glucose, and HbA1c). With regard to vascular function, both endothelium-dependent (Ach) (-22, -40, and -52%; P < 0.0001) and -independent (SNP) (-3, -7, and -27%; P < 0.02) vasodilatation were progressively reduced across insulin resistance tertiles. In multivariate analysis, inflammatory markers (IL-6, hs-CRP, and TNF-alpha) were independently associated with insulin resistance and fasting glycemia, fibrinolytic markers PAI-1 and tPA with insulin resistance and central fat distribution, and vascular indexes (vWF, Ach, and SNP vasodilation) with insulin resistance and obesity or cytokines (TNF-alpha or IL-6). In type 2 diabetes, insulin resistance is associated with vascular dysfunction/damage, impaired fibrinolysis, and low-grade inflammation independently of obesity and poor glycemic control.
...
PMID:Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes. 1656 39

Normal metabolic balance is maintained by a complex homeostatic system involving multiple tissues and organs. Acquired or inherited defects associated to environmental factors in any part of this system can lead to metabolic disorders such as the syndrome X which is presently a frequent syndrome in industrialized countries. It is characterized by a cluster of risk factors of atherosclerosis including insulin resistance, hyperinsulinemia, impaired glucose tolerance or type 2 diabetes, hypertension, dyslipidemia, and coagulation abnormalities. Its pathophysiology is likely to involve insulin resistance at the level of both skeletal muscle and visceral adipose tissue and altered fluxes of metabolic substrates between these tissues that in turn impair liver metabolism. Therapeutic intervention favours at present diet and exercise prescriptions. In addition, if necessary, specific treatment of the metabolic disorders is required. In the treatment of insulin resistance, new promising drugs are likely to be used in the next future. In this regard, adipose tissue, once thought to function primarily as a passive depot for the storage of excess lipid, is now understood to play a much more active role in metabolic regulation, secreting a variety of metabolic hormones and actively functioning to prevent deleterious lipid accumulation in other tissues and to modulate the insulin resistance. Here, we review new advances in our understanding of mechanisms leading to insulin resistance and type 2 diabetes from the perspective of the role and interactions of recently identified adipocyte-specific chemical messengers, the adipocytokines, such as adiponectin, tumor necrosis factor-alpha, interleukin 6, and resistin.
...
PMID:[Adipocytokins, obesity and development of type 2 diabetes]. 1659 99

Polycystic ovary syndrome (PCOS) is a diagnosis made between late adolescence and the menopause in 5-10% of women. PCOS is a heterogeneous disorder of unknown etiology characterized by hyperandrogenic chronic anovulation. This syndrome consists of a diverse constellation of signs and symptoms, such as hirsutism, acne, acanthosis nigricans, obesity, menstrual irregularities, anovulation, and/or infertility. Features of the metabolic syndrome, including obesity, insulin resistance, and dyslipidemia, are common in this patient population. Recent insights into the pathophysiology of PCOS have shown insulin resistance and hyperinsulinemia to play a substantial role. Insulin resistance is increasingly recognized as a chronic, low-level, inflammatory state. Recent studies show that serum levels of inflammatory mediators, such as tumor necrosis factor-alpha and interleukin-6, are increased in the insulin-resistant conditions of obesity and PCOS. The optimal modality for long-term treatment should have positive effects on androgen synthesis, sex hormone-binding globulin production, the lipid profile, insulin sensitivity, inflammatory mediators, and clinical symptoms including acne, hirsutism, and irregular menstrual cycles. Treatment with insulin-sensitizing agents is a relatively new therapeutic strategy in women with PCOS. Current research has shown that the use of diabetes mellitus management practices aimed at reducing insulin resistance and hyperinsulinemia (such as weight reduction and the administration of oral antidiabetic drugs) can not only reverse testosterone and luteinizing hormone abnormalities and restore menstrual cycles, but can also improve glucose, insulin, proinflammatory cytokine, and lipid profiles.Clinical treatment with troglitazone, a member of the thiazolidinedione family, for the management of PCOS complications such as insulin resistance, hyperandrogenism, and anovulation was found to have beneficial effects; however, it was taken off the market over concerns of hepatotoxicity. Although troglitazone is no longer available in the US, numerous clinical trials have established the role of thiazolidinediones in the treatment of women with PCOS. Clinical data emerging regarding the utility of two of the newer, safer thiazolidinediones, pioglitazone and rosiglitazone, for this patient population, consistently demonstrate effective improvements of endocrine and ovulatory performance in women with PCOS. The benefit and importance of lifestyle modification and weight reduction, when it can be achieved, is still an important component in the long-term treatment of PCOS. Pharmacologic reduction in insulin levels using thiazolidinediones appears to offer another therapeutic modality for PCOS, which may ameliorate the progress of both hyperinsulinemia and hyperandrogenism. However, additional studies of patients so treated are necessary before these agents can be considered first-line treatment for PCOS. Convincing data from randomized controlled trials with sufficient power to detect both the benefits and risks of long-term treatment with thiazolidinediones in women with PCOS remain to be obtained.
...
PMID:Thiazolidinediones for the therapeutic management of polycystic ovary syndrome : impact on metabolic and reproductive abnormalities. 1667 59

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