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)

Highly-active antiretroviral therapy (HAART) has lead to a dramatic decrease in the morbidity of patients infected with the human immunodeficiency virus (HIV). However, metabolic side effects, including lipodystrophy-associated (LD-associated) dyslipidemia, have been reported in patients treated with antiretroviral therapy. This study was designed to determine whether successful HAART was responsible for a dysregulation in the homeostasis of tumor necrosis factor-alpha (TNF-alpha), a cytokine involved in lipid metabolism. Cytokine production was assessed at the single cell level by flow cytometry after a short-term stimulation of peripheral blood T cells from HIV-infected (HIV(+)) patients who were followed during 18 months of HAART. A dramatic polarization to TNF-alpha synthesis of both CD4 and CD8 T cells was observed in all patients. Because it was previously shown that TNF-alpha synthesis by T cells was highly controlled by apoptosis, concomitant synthesis of TNF-alpha and priming for apoptosis were also analyzed. The accumulation of T cells primed for TNF-alpha synthesis is related to their escape from activation-induced apoptosis, partly due to the cosynthesis of interleukin-2 (IL-2) and TNF-alpha. Interestingly, we observed that LD is associated with a more dramatic TNF-alpha dysregulation, and positive correlations were found between the absolute number of TNF-alpha CD8 T-cell precursors and lipid parameters usually altered in LD including cholesterol, triglycerides, and the atherogenic ratio apolipoprotein B (apoB)/apoA1. Observations from the study indicate that HAART dysregulates homeostasis of TNF-alpha synthesis and suggest that this proinflammatory response induced by efficient antiretroviral therapy is a risk factor of LD development in HIV(+) patients.
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PMID:Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome. 1080 87

Tumor necrosis factor alpha (TNF-alpha) is a multifunctional cytokine constitutively produced by adipose tissue that may mediate insulin resistance. Studies in Caucasian subjects have suggested that the G-308A transition in the 5' region of the TNF-alpha gene may be associated with insulin resistance and obesity. These factors have been proposed to underlie the clustering of type 2 diabetes, hypertension, and dyslipidemia found in the metabolic syndrome, the prevalence of which is reaching epidemic proportions in Hong Kong Chinese. We investigated the association of this gene polymorphism with the components of the metabolic syndrome including the lipid profile, as well as with the indices of obesity and insulin resistance as measured by the insulin-glucose product, in 440 Chinese subjects (healthy [27.5%] and overlapping groups with type 2 diabetes [54.1%], hypertension [38.8%], dyslipidemia [39.3%], or obesity [39.5%]). The frequency of the mutant A allele was 7.4% in 121 healthy controls and 9.0% in the total population. The mutation was not associated with any component of the metabolic syndrome or with the prevalence of albuminuria and retinopathy in these subjects. Furthermore, there was no difference in anthropometric measures, insulin resistance, or lipid levels between subjects with the GG genotype and those with the mutant allele. In summary, the TNF-alpha gene G-308A polymorphism is unlikely to play an important role in the development of these disorders in this population.
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PMID:Tumor necrosis factor alpha gene G-308A polymorphism in the metabolic syndrome. 1095 20

Despite the improvements in dialysis technology, the cardiovascular mortality rate is still unacceptably high among dialysis patients. It is obvious that traditional risk factors, such as hypertension, chronic heart failure (CHF), dyslipidemia and diabetes mellitus, may account for a large part of the increased cardiovascular mortality rate in these patients. However, based on recent research it could be speculated that other, non-traditional risk factors might also contribute to the high cardiovascular mortality rate in dialysis patients. Chronic inflammation, as evidenced by increased levels of pro-inflammatory cytokines and C-reactive protein (CRP), is a common feature in dialysis patients and is associated with an increased cardiovascular morbidity and mortality. Indeed, elevated levels of pro-inflammatory cytokines (such as TNF-alpha, IL-1 and IL-6) may cause malnutrition and progressive atherosclerotic cardiovascular disease by several pathogenetic mechanisms, which will be discussed in this review. Based on the strong associations observed between malnutrition, inflammation and atherosclerosis in patients with chronic renal failure (CRF) we have proposed that these features constitute a specific syndrome (MIA), which carries a high mortality rate. As elevated levels of pro-inflammatory cytokines may play a central part in the vicious circle of malnutrition, inflammation and atherosclerosis, further research is needed to investigate whether or not different anti-cytokine treatment strategies may improve survival in dialysis patients.
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PMID:Inflammatory and atherosclerotic interactions in the depleted uremic patient. 1111 78

Peroxisome proliferator-activated receptors (PPARs) are essential in glucose and lipid metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as diabetes and dyslipidemia. Conversely, antidiabetic glitazones and hypolipidemic fibrate drugs, known as PPARgamma and PPARalpha ligands, respectively, reduce the process of atherosclerotic lesion formation, which involves chronic immunoinflammatory processes. Major histocompatibility complex class II (MHC-II) molecules, expressed on the surface of specialized cells, are directly involved in the activation of T lymphocytes and in the control of the immune response. Interestingly, expression of MHC-II has recently been observed in atherosclerotic plaques, and it can be induced by the proinflammatory cytokine interferon-gamma (IFN-gamma) in vascular cells. To explore a possible role for PPAR ligands in the regulation of the immune response, we investigated whether PPAR activation affects MHC-II expression in atheroma-associated cells. In the present study, we demonstrate that PPARgamma but not PPARalpha ligands act as inhibitors of IFN-gamma-induced MHC-II expression and thus as repressors of MHC-II-mediated T-cell activation. All different types of PPARgamma ligands tested inhibit MHC-II. This effect of PPARgamma ligands is due to a specific inhibition of promoter IV of CIITA and does not concern constitutive expression of MHC-II. Thus, the beneficial effects of antidiabetic PPARgamma activators on atherosclerotic plaque development may be partly explained by their repression of MHC-II expression and subsequent inhibition of T-lymphocyte activation.
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PMID:PPARgamma but not PPARalpha ligands are potent repressors of major histocompatibility complex class II induction in atheroma-associated cells. 1186 26

The endothelium is the first line of defense for maintaining normal vascular function in the vessel wall; however, the endothelium is sensitive to metabolic stress. In patients with insulin resistance or type 2 diabetes mellitus, a set of metabolic insults--namely high plasma levels of glucose and free fatty acids, increased inflammation, dyslipidemia, and hypertension--cause endothelial dysfunction and a transition from an antiatherogenic endothelium to a proatherogenic endothelium. Disruption of endothelial function leads to activation of platelets and macrophages, increased thrombotic potential, transition of macrophages to foam cells, stimulation of cytokine secretion, and proliferation of vascular smooth muscle cells. Insulin-sensitizing agents, such as the thiazolidinediones (TZDs), improve flow-mediated vasodilation, decrease macrophage and smooth muscle cell activation, proliferation, and migration, and decrease plaque formation. The TZDs exert multifaceted effects on the vasculature by regulating the expression of transcription factors and orchestrating whole-gene programs that restore vascular physiology to the healthy state. Exercise training and increased levels of habitual physical activity have therapeutic benefit in terms of both preventing and treating insulin resistance and diabetes. However, this benefit of exercise training and increased physical activity is complicated by the fact that individuals with insulin resistance or type 2 diabetes have decreased maximal exercise capacity or maximal oxygen consumption and have slower oxygen uptake kinetics at the beginning of exercise. Both of these abnormalities contribute to the decreased levels of habitual physical activity observed in patients with diabetes. Preliminary data suggest that TZDs improve measures of cardiac function and exercise capacity, and investigators are assessing the impact of treatment with rosiglitazone on exercise capacity in an ongoing clinical trial.
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PMID:Novel actions of thiazolidinediones on vascular function and exercise capacity. 1467 69

There is increasing evidence that an ongoing cytokine-induced acute-phase response (sometimes called low-grade inflammation, but part of a widespread activation of the innate immune system) is closely involved in the pathogenesis of type 2 diabetes and associated complications such as dyslipidemia and atherosclerosis. Elevated circulating inflammatory markers such as C-reactive protein and interleukin-6 predict the development of type 2 diabetes, and several drugs with anti-inflammatory properties lower both acute-phase reactants and glycemia (aspirin and thiazolidinediones) and possibly decrease the risk of developing type 2 diabetes (statins). Among the risk factors for type 2 diabetes, which are also known to be associated with activated innate immunity, are age, inactivity, certain dietary components, smoking, psychological stress, and low birth weight. Activated immunity may be the common antecedent of both type 2 diabetes and atherosclerosis, which probably develop in parallel. Other features of type 2 diabetes, such as fatigue, sleep disturbance, and depression, are likely to be at least partly due to hypercytokinemia and activated innate immunity. Further research is needed to confirm and clarify the role of innate immunity in type 2 diabetes, particularly the extent to which inflammation in type 2 diabetes is a primary abnormality or partly secondary to hyperglycemia, obesity, atherosclerosis, or other common features of the disease.
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PMID:Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. 1498 10

The emergence of a new metabolic syndrome in patients with HIV infection, termed "HIV-associated dyslipidemic lipodystrophy" (HADL), is characterized by central fat redistribution, severe dyslipidemia, and insulin resistance and predisposes to an increased risk of cardiovascular disease. The factors promoting the development of cardiovascular disease in this condition are not well understood and may involve contributions from antiretroviral drugs and components of the HIV virus, as well as inflammatory cytokines, leading to accelerated lipolysis, dyslipidemia, lipotoxic insulin resistance, and vascular inflammation. In this article, we review HADL in terms of metabolic, molecular, and cytokine derangements leading to cardiovascular disease.
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PMID:Cardiovascular implications of HIV-associated dyslipidemic lipodystrophy. 1506 41

Obesity may be an independent risk factor for coronary artery disease and contribute to a chronic state of systemic inflammation leading to atherosclerosis and metabolic abnormalities, such as diabetes, insulin resistance, dyslipidemia and hypertension. Visceral fat, in fact, may act as an endocrine organ, synthesizing and releasing atherogenic inflammatory cytokines, whose circulating levels depend on the individual's nutritional state, and the extent and anatomical location of fat stores. Unsuspected viral infections might also be involved in enhancing autocrine/paracrine mechanisms of cytokine release from omental fat. Elevated levels of blood cytokines may interact with the neuroendocrine system, autonomic nerves and peripheral lymphatic organs. This may lead to local inflammatory reactions in many body compartments, in particular in the heart tissue, possibly affecting the process of circulatory recovery in obese subjects, and predisposing these patients to a greater risk of myocardial inflammatory disease than individuals with normal body mass index. Circulating levels of inflammatory cytokines might be considered to determine risk categories for development of cardiovascular complications in obese subjects. In addition, their reduction with pharmacological antagonists might prevent and/or control acute cardiovascular events and increase energy expenditure in obese patients, especially after surgical treatment, through reduction of cytokine inhibition of the hypothalamic-pituitary-thyroid axis.
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PMID:New paradigms in neuroendocrinology: relationships between obesity, systemic inflammation and the neuroendocrine system. 1512 16

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 is poorly understood. Here we show that overexpression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3 in liver causes insulin resistance and an increase in the key regulator of fatty acid synthesis in liver, sterol regulatory element-binding protein (SREBP)-1c. Conversely, inhibition of SOCS-1 and -3 in obese diabetic mice improves insulin sensitivity, normalizes the increased expression of SREBP-1c, and dramatically ameliorates hepatic steatosis and hypertriglyceridemia. In obese animals, increased SOCS proteins enhance SREBP-1c expression by antagonizing STAT3-mediated inhibition of SREBP-1c promoter activity. Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating insulin signaling and cytokine signaling.
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PMID:Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. 1524 Aug 80

The aim of the study was to assess the effect of two major groups of hypolipemic drugs, HMG-CoA reductase inhibitors (statins) and PPARalpha activators (fibrates), on the secretory function of T-lymphocytes in patients with primary type II dyslipidemia. Sixty-three patients with type IIa dyslipidemia were randomized to fluvastatin (40 mg daily; n = 33) or simvastatin (20mg daily; n = 30), while 68 type IIb dyslipidemic patients were treated with micronized ciprofibrate (100mg daily; n = 34) or micronized fenofibrate (200mg daily; n = 34). Lipid profile and cytokine (interferon-gamma and interleukin-2) release by phytohemagglutinin-stimulated lymphocytes were determined at the beginning of the study and after 30 and 90 days of treatment. Compared to healthy subjects (n = 59), both type IIa and IIb dyslipidemic patients exhibited higher baseline release of interferon-gamma and interleukin-2. Fluvastatin, simvastatin and, to a less extent, ciprofibrate and fenofibrate inhibited the release of both cytokines, but this effect did not correlate with their lipid-lowering potential. Hypolipemic agents also slightly reduced plasma interleukin-2 levels. Our study suggests that the beneficial effect of hypolipemic drugs involves their inhibitory action on the secretory function of T-lymphocytes. This lipid-independent action is stronger for statins than for fibrates and probably results from their "class" effect. The treatment-induced reduction in the release of both cytokines may contribute to the clinical effectiveness of statins and fibrates in the therapy of atherosclerosis and in the management of organ transplant recipients.
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PMID:The effect of statins and fibrates on interferon-gamma and interleukin-2 release in patients with primary type II dyslipidemia. 1538 Apr 56


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