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)

The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus. There is a growing body of evidence to show that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, reduce cardiovascular-related morbidity and mortality in patients with or without coronary artery disease. Recent clinical observations argue for a simple strategy of considering routine statin therapy for patients with type 2 diabetes. Furthermore, statin therapy is also found to be effective in allowing LDL-cholesterol goal achievement in hypercholesterolemic high-risk patients with the metabolic syndrome. However, the effects of statins on the pathogenesis of the metabolic syndrome remain to be elucidated. Several types of statins are commercially available now. Among them, pravastatin is unique because it is the only statin that has been shown to have protective role against the development of diabetes in a large clinical trial. Moreover, a recent clinical study revealed that pravastatin treatment improved insulin sensitivity in 25 women with the metabolic syndrome with impaired glucose intolerance. These observations let us to speculate that pravastatin is a promising strategy for the treatment of hypercholesterolemic patients with the metabolic syndrome. It may improve the insulin sensitivity in these patients and subsequently prevent the development of type 2 diabetes. In this paper, we would like to propose the possible ways of testing our hypothesis as follows. (1) Does pravastatin treatment improve insulin resistance in patients of the metabolic syndrome or in insulin resistant hypertensive or obese patients? If the answers are yes, are these beneficial effects of pravastatin superior to those of other anti-hyperlipidemic statins with equihypolipidemic properties? (2) Does pravastatin treatment actually reduce the development of diabetes in these insulin resistant patients? At that time, does pravastatin treatment increase serum levels of adiponectin, a key adipokine with insulin-sensitizing property? How about the effects of pravastatin treatment on adipokines that could elicit insulin resistance such as tumor necrosis factor-alpha? These clinical studies will provide further information whether pravastatin treatment can improve insulin resistance and subsequently reduce the development of diabetes in insulin resistant patients with the metabolic syndrome.
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PMID:Protective role of pravastatin in the pathogenesis of the metabolic syndrome. 1617 51

Endothelial dysfunction is associated with several vascular conditions as atherosclerosis, hypertension, hyperlipidemia and diabetes mellitus. In all these conditions insulin resistance (IR) is present. Cytokines are low molecular weight proteins with several endocrine and metabolic functions that participate of inflammation and immune response. Several of these cytokines are independent risk factors for cerebrovascular and coronary artery disease. The major sources of cytokines (adipokines) are the visceral and subcutaneous adipose tissues. Thus, increased adipose tissue mass is associated with alteration in adipokine production as over expression of tumor necrosis factor alpha, interleukin 6, plasminogen activator inhibitor 1, and under expression of adiponectin in adipocite tissue. The pro-inflammatory status associated with these changes provides a potential link between IR and endothelial dysfunction, the early stage in the atherosclerotic process, in obese individuals, and type 2 diabetic patients. Reduction of adipose tissue mass through weight reduction in association with exercise reduces TNF-alpha, IL-6, and PAI-1, increases adiponectin, and is associated with improved insulin sensitivity and endothelial function. This review will focus on the evidence for regulation of endothelial function by insulin and the adypokines such as adyponectin, leptin, resistin, IL-6 and TNF-alpha. Interaction between insulin signaling and adypokines will be discussed, as well as the concept that aberrant adypokine secretion in IR and/or obesity impairs endothelial function and contributes further to reduce insulin sensitivity.
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PMID:[Cytokines, endothelial dysfunction, and insulin resistance]. 1676 96

Protein-energetic malnutrition, characterized by both lean mass and fat depletion, was common in the pre-HAART era, and was associated with shortened survival and diminished quality of life. The pathogenesis of protein-energy malnutrition was multifactorial, and nutritional treatments were largely ineffective in the absence of disease stabilization. The introduction of HAART brought markedly improved outcomes, including a decrease in the incidence of malnutrition. However, other nutritional and metabolic alterations were noticed, and included changes in body shape, both lipoatrophy and lipohypertrophy, as well as changes in metabolism, notably hyperlipidemia and insulin resistance. These conditions, though sometimes occurring together, may occur independently, suggesting a complex, multifactorial cause. Several mechanisms have been hypothesized, including impairment to adipocyte differentiation and adipokine regulation, production of proinflammatory cytokines and mitochondrial toxicity. The role of the single drug class is still unclear, because both PI and NRTI have been associated with the syndrome, and the therapeutic protocols include both groups. Most of the medical therapies proposed for lipodystrophy are ineffective, and even if surgery remains an alternative, it is not associated with long lasting outcomes.
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PMID:[Effect of anti-retroviral therapy on body composition changes: a literature review]. 1679 74

A complete understanding of the molecular mechanisms leading to HIV-associated insulin resistance remains elusive. Complex interrelationships between genetic predisposition, disease-related body changes and multidrug therapy all contribute to alterations in glucose homeostasis. These abnormalities can be differentiated between acute and reversible changes directly induced by HAART medications and more chronic and less reversible changes due to the development of lipodystrophy and hyperlipidemia. Implicated pathways include changes in adipokine secretion, insulin signaling, lipid homeostasis and disease-related increases in inflammatory mediators. The insulin responsive facilitative glucose transporter GLUT4 is the first molecule to have been identified as a direct target of HIV protease inhibitors. Efforts to elucidate the mechanisms directly responsible for the evolution of insulin resistance during HIV infection and therapy will be greatly assisted by the further identification and characterization of direct molecular targets amenable to pharmacologic therapy and/or the development of newer antiretroviral agents that do not adversely affect these target proteins.
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PMID:Molecular Mechanisms for Altered Glucose Homeostasis in HIV Infection. 1718 64

Visfatin is a novel adipokine involved in the process of atherosclerosis. We assessed the effect of rosuvastatin on plasma visfatin levels in patients with primary hyperlipidemia. Eighty hyperlipidemic patients without evidence of cardiovascular disease were randomized to receive either rosuvastatin 10 mg/day or therapeutic lifestyle changes intervention. Plasma visfatin levels were determined at baseline and after 12-weeks post-randomization. Rosuvastatin induced a significant decrease in plasma visfatin levels (17.1+/-2.1 versus 15.5+/-2.0 ng/ml, P=0.03). This effect correlated with baseline visfatin levels (r=0.51, P<0.01) and was independent of any lipid-lowering actions of rosuvastatin.
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PMID:Effect of rosuvastatin treatment on plasma visfatin levels in patients with primary hyperlipidemia. 1793 20

Type I (T1) diabetes, also called insulin dependent diabetes mellitus (IDDM), is characterized by little or no insulin production and hyperglycemia. One of the less well known complications of T1-diabetes is bone loss which occurs in humans and animal models. This complication is receiving increased attention because T1-diabetics are living longer due to better therapeutics, and are faced with their existing health concerns being compounded by complications associated with aging, such as osteoporosis. Both male and female, endochondrial and intra-membranous, and axial and appendicular bones are susceptible to T1-diabetic bone loss. Exact mechanisms accounting for T1-diabetic bone loss are not known. Existing data indicate that the bone defect in T1-diabetes is anabolic rather than catabolic, suggesting that anabolic therapeutics may be more effective in preventing bone loss. Potential contributors to T1-diabetic suppression of bone formation are discussed in this review and include: increased marrow adiposity, hyperlipidemia, reduced insulin signaling, hyperglycemia, inflammation, altered adipokine and endocrine factors, increased cell death, and altered metabolism. Differences between T1-diabetic- and age-associated bone loss underlie the importance of condition specific, individualized treatments for osteoporosis. Optimizing therapies that prevent bone loss or restore bone density will allow T1-diabetic patients to live longer with strong healthy bones.
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PMID:Understanding the pathology and mechanisms of type I diabetic bone loss. 1797 93

Studies performed during the last decade indicate that adipose tissue is not only a site of triglyceride storage but also an active endocrine organ which secretes many biologically active mediators referred to as "adipokines". In contrast to many adipokines which are overproduced in obese individuals and exert deleterious effects on insulin sensitivity, lipoprotein metabolism and cardiovascular system, such as leptin, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, resistin, etc., adiponectin seems to be a unique adipokine which is produced in lower amounts in obese than in lean subjects and possesses predominantly beneficial activities, i.e. increases insulin sensitivity, stimulates fatty acid oxidation, inhibits inflammatory reaction and induces endothelium-dependent nitric oxide-mediated vasorelaxation. Adiponectin binds two receptors, AdipoR1 and AdipoR2. Adiponectin knockout mice exhibit various manifestations of the metabolic syndrome such as insulin resistance, glucose intolerance, hyperlipidemia, impaired endothelium-dependent vasorelaxation and hypertension, as well as augmented neointima formation after vascular injury. Clinical studies indicate that plasma adiponectin concentration is lower in patients with essential hypertension and ischemic heart disease. Raising endogenous adiponectin level or increasing the sensitivity to this hormone may be a promising therapeutic strategy for patients with metabolic and cardiovascular diseases. Among currently used drugs, thiazolidinediones (peroxisome proliferator activated receptor gamma agonists) are most effective in elevating adiponectin level.
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PMID:Adiponectin and its role in cardiovascular diseases. 1833 52

Glycogen storage disease type Ia (GSD Ia) is characterized by severe hypercholesterolaemia and hypertriglyceridaemia. Little is known about the aetiology of the hyperlipidaemia in GSD Ia. Adipokines play an important regulatory role in lipid metabolism. We investigated whether adipokine concentrations were correlated with the degree of hyperlipidaemia in GSD Ia patients. Six patients with GSD Ia were studied in semi-fasted conditions. Adiponectin, but not leptin, correlated (r(2) = -0.79, p = 0.02) with plasma triglyceride concentrations in the GSD Ia patients. Leptin correlated well with BMI (r(2) = 0.59, p < 0.01). However, neither body mass index (BMI) nor homeostasis model assessment (HOMA), as a marker of insulin sensitivity, correlated with triglyceride concentrations. Although a small number of patients were studied, these results indicate that adiponectin concentrations are correlated with the degree of hypertriglyceridaemia in GSD Ia. Pharmacological treatment aimed at increasing adiponectin levels might improve the metabolic status of these patients.
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PMID:Adiponectin levels correlate with the severity of hypertriglyceridaemia in glycogen storage disease Ia. 1926 15

Retinol-binding protein 4 (RBP4) is a recently identified adipokine that is elevated in the blood in several insulin-resistant states. We investigated the association between plasma RBP4 and histological and biochemical characteristics of chronic hepatitis C (CHC), as well as changes in RBP4 levels following interferon therapy. Eighty-one patients with CHC infected with genotype 1 received treatment with peginterferon plus ribavirin. Histological data were available for 41 out of 81 patients before treatment, and the degree of fibrosis, inflammation and steatosis was assessed. Plasma levels of RBP4 were determined in serial samples (before, at the end of treatment, and at 6 months post-treatment). RBP4 levels were lower in CHC patients than in control subjects (34.6 +/- 12.3 microg/mL vs 46.2 +/- 10.5 microg/mL; P <or= 0.001). Higher RBP4 levels were linked to lower alanine aminotransferase (ALT) (P < 0.01), higher cholinesterase (P < 0.01), hyperlipidaemia (P < 0.01), hyperglycaemia (P < 0.05), and higher platelet (P < 0.01) count in CHC patients. Plasma RBP4 levels tended to decrease concomitantly with the grade of histological fibrosis, activity, and steatosis. RBP4 levels at baseline were not a predictor of the response to antiviral therapy in CHC patients. After peginterferon plus ribavirin therapy, only patients who had achieved clearance of hepatitis C virus had higher post-treatment RBP4 levels. This study suggests that an association between RBP4 levels and abnormal metabolic features, and that liver function may determine RBP4 levels in CHC patents. This is further supported by the observation that RBP4 levels increased significantly after treatment only in sustained virological response (SVR) patients and reached levels comparable to those of healthy subjects.
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PMID:Patients achieving clearance of HCV with interferon therapy recover from decreased retinol-binding protein 4 levels. 1930 38

Angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) are secreted proteins that regulate triglyceride (TG) metabolism in part by inhibiting lipoprotein lipase (LPL). Recently, we showed that treatment of wild-type mice with monoclonal antibody (mAb) 14D12, specific for ANGPTL4, recapitulated the Angptl4 knock-out (-/-) mouse phenotype of reduced serum TG levels. In the present study, we mapped the region of mouse ANGPTL4 recognized by mAb 14D12 to amino acids Gln(29)-His(53), which we designate as specific epitope 1 (SE1). The 14D12 mAb prevented binding of ANGPTL4 with LPL, consistent with its ability to neutralize the LPL-inhibitory activity of ANGPTL4. Alignment of all angiopoietin family members revealed that a sequence similar to ANGPTL4 SE1 was present only in ANGPTL3, corresponding to amino acids Glu(32)-His(55). We produced a mouse mAb against this SE1-like region in ANGPTL3. This mAb, designated 5.50.3, inhibited the binding of ANGPTL3 to LPL and neutralized ANGPTL3-mediated inhibition of LPL activity in vitro. Treatment of wild-type as well as hyperlipidemic mice with mAb 5.50.3 resulted in reduced serum TG levels, recapitulating the lipid phenotype found in Angptl3(-/-) mice. These results show that the SE1 region of ANGPTL3 and ANGPTL4 functions as a domain important for binding LPL and inhibiting its activity in vitro and in vivo. Moreover, these results demonstrate that therapeutic antibodies that neutralize ANGPTL4 and ANGPTL3 may be useful for treatment of some forms of hyperlipidemia.
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PMID:Identification of a new functional domain in angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) involved in binding and inhibition of lipoprotein lipase (LPL). 1931 55


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