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)

Calcification presents important clinical implications in cardiovascular diseases, especially in coronary arteries. Epidemiological evidence has shown the coexistence of vascular calcification with both atherosclerosis and osteoporosis, and increasing evidence has shown the role of hyperlipidemia and atherogenic phospholipids in vascular calcification. The etiology of vascular calcification is also increasingly recognized as an active process. Vascular calcification initiates with matrix vesicle formation and mineralization following a process similar to that in bone. In addition, many bone regulatory factors have been shown to be present in calcified atherosclerotic lesions. In this review, we focus on the new developments emerging during the past year in regulation of vascular calcification. Regulatory factors include matrix GLA protein, the phosphate cotransporter Pit-1, a calcium-sensing receptor related factor, osteoprotegerin, leptin, bisphosphonates and oxidized lipids. Some of these, including oxidized lipids, osteoprotegerin, and bisphosphonates, appear to regulate mineralization in both bone and vasculature and may account for the co-existence of osteoporosis and atherosclerotic calcification that is independent of age.
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PMID:Recent advances in multifactorial regulation of vascular calcification. 1156 Nov 76

High concentrations of glucose induce insulin resistance, impair insulin secretion, and affect hepatic glucose production in a manner that mirrors Type 2 diabetes, and hexosamines mimic many of these effects. This has led to the hypothesis that cells use hexosamine flux as a glucose- and satiety-sensing pathway. The hexosamine hypothesis for glucose sensing has been validated by overexpressing the rate-limiting enzyme for hexosamine synthesis, glutamine: fructose-6-phosphate amidotransferase (GFA) in several tissues including muscle, liver, fat, and beta cells. With overexpression of GFA in transgenic animals, skeletal muscle becomes insulin resistant, the liver synthesizes excess fatty acid, and the beta cell secretes excess insulin leading to hyperinsulinemia. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the "thrifty phenotype." Chronically, however, these same adaptive changes result ultimately in obesity, hyperlipidemia, beta cell failure, and Type 2 diabetes. These results suggest a mechanism by which chronic overnutrition leads to the phenotype of Type 2 diabetes.
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PMID:Hexosamines as mediators of nutrient sensing and regulation in diabetes. 1187 72

Glycogen storage disease type 1 (GSD-1), also known as von Gierke disease, is a group of autosomal recessive metabolic disorders caused by deficiencies in the activity of the glucose-6-phosphatase (G6Pase) system that consists of at least two membrane proteins, glucose-6-phosphate transporter (G6PT) and G6Pase. G6PT translocates glucose-6-phosphate (G6P) from cytoplasm to the lumen of the endoplasmic reticulum (ER) and G6Pase catalyzes the hydrolysis of G6P to produce glucose and phosphate. Therefore, G6PT and G6Pase work in concert to maintain glucose homeostasis. Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Both manifest functional G6Pase deficiency characterized by growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, and lactic acidemia. GSD-1b patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, resulting in recurrent bacterial infections as well as ulceration of the oral and intestinal mucosa. The G6Pase gene maps to chromosome 17q21 and encodes a 36-kDa glycoprotein that is anchored to the ER by 9 transmembrane helices with its active site facing the lumen. Animal models of GSD-1a have been developed and are being exploited to delineate the disease more precisely and to develop new therapies. The G6PT gene maps to chromosome 11q23 and encodes a 37-kDa protein that is anchored to the ER by 10 transmembrane helices. A functional assay for the recombinant G6PT protein has been established, which showed that G6PT functions as a G6P transporter in the absence of G6Pase. However, microsomal G6P uptake activity was markedly enhanced in the simultaneous presence of G6PT and G6Pase. The cloning of the G6PT gene now permits animal models of GSD-1b to be generated. These recent developments are increasing our understanding of the GSD-l disorders and the G6Pase system, knowledge that will facilitate the development of novel therapeutic approaches for these disorders.
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PMID:The molecular basis of type 1 glycogen storage diseases. 1189 41

Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. The two major subtypes are GSD-Ia (MIM232200), caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib (MIM232220), caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Both G6Pase and G6PT are associated with the endoplasmic reticulum (ER) membrane. G6PT translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the ER, where G6Pase hydrolyses the G6P into glucose and phosphate. Together G6Pase and G6PT maintain glucose homeostasis. G6Pase is expressed in gluconeogenic tissues, the liver, kidney, and intestine. However G6PT, which transports G6P efficiently only in the presence of G6Pase, is expressed ubiquitously. This suggests that G6PT may play other roles in tissues lacking G6Pase. Both GSD-Ia and GSD-Ib patients manifest phenotypic G6Pase deficiency, characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic academia and the current treatment is a dietary therapy. GSD-Ib patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, which is treated with granulocyte colony stimulating factor to restore myeloid function. The GSD-Ia and GSD-Ib genes have been cloned. To date, 76 G6Pase and 69 G6PT mutations have been identified in GSD-I patients. A database of the residual enzymatic activity retained by the G6Pase missense mutants is facilitating the correlation of the disease phenotype with the patients' genotype. While the molecular basis for the GSD-I disorders are now known and symptomatic therapies are available, many aspects of the diseases are still poorly understood, and there are no cures. Recently developed animal models of the disorders are now being exploited to delineate the disease more precisely and develop new, more causative therapies.
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PMID:Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. 1194 31

Understanding and modifying the causes of the high cardiovascular morbidity and mortality associated with renal disease is the greatest challenge faced by renal physicians. About one person in 20 has a serum creatinine level above normal (> or =1.5 mg/dl in males and > or =1.4 mg/dl in females), signifying mild kidney disease. People with hypertension, hyperlipidaemia, and/or diabetes (approximately 350000 people per million in the general population) have the highest risk of renal failure. Anaemia, extracellular volume expansion, increased angiotensin II and aldosterone levels, high calcium-phosphate product, inflammation, hyperhomocysteinaemia, and impaired nitric oxide synthesis all amplify the risk of cardiovascular disease in patients with renal failure. These factors may adversely affect the cardiovascular system by influencing the generation of reactive oxygen species, thus contributing to high oxidative stress. Further research into optimal follow-up of patients with mild renal insufficiency is needed. Identification of 'problematic' and/or treatment-resistant patients should be a primary goal. Greater understanding of the genetic and environmental precursors of diseases associated with renal insufficiency would also be beneficial, particularly for younger patients. Observational studies aimed at linking these risk factors to well-defined and measured renal and cardiovascular outcomes should increase knowledge of renal disease progression and cardiovascular risk in these populations.
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PMID:Cardiorenal risk as a new frontier of nephrology: research needs and areas for intervention. 1238 60

Risk factors for progression of kidney disease include hypertension, proteinuria, male sex, obesity, diabetes mellitus, hyperlipidemia, smoking, high-protein diets, phosphate retention, and metabolic acidosis. Angiotensin II production upregulates the expression of transforming growth factor-beta1, tumor necrosis factor-alpha, nuclear factor-kappaB, and several adhesion molecules and chemoattractants. In addition to angiotensin, other vasoactive compounds, such as thromboxane A(2), endothelin, and prostaglandins, are upregulated. Treatment with one of several growth factors may ameliorate the progression of kidney disease: insulin-like growth factor-1, hepatocyte growth factor, and bone morphogenetic protein-7.
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PMID:Progression of chronic renal disease. 1261 42

1. Overproduction of superoxide anions in the vascular wall contributes to endothelial dysfunction in vascular disease. A superoxide-generating reduced beta-nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major source of oxidative radicals in vascular tissues. We studied the effects of a synthetic manganese-containing superoxide dismutase (SOD) mimetic, M40403, on NADPH oxidase-dependent superoxide generation and on endothelial dysfunction. 2. In rat aortic smooth muscle cells, NADPH (100 micro M) markedly stimulated superoxide production as detected by lucigenin (5 micro M)-enhanced chemiluminescence. M40403 reduced NADPH oxidase-dependent superoxide production in a concentration-dependent manner, with IC(50) being 31.6 micro M. In contrast, native Cu/Zn SOD (up to 300 U ml(-1)) had no effect. Angiotensin II (100 nM) increased the NADPH oxidase activity by 70%, and treatment with M40403 (10 micro M) reduced this increased superoxide to the control level. 3. In aortae from apolipoprotein(E)-deficient mice (apoE(0)) with hyperlipidemia and atherosclerosis, superoxide production is largely derived from NADPH oxidase. The attenuation of endothelial nitric oxide vasodilator function parallels the increase in vascular superoxide production at different stages of the disease. Acute incubation of such aortic rings with M40403 significantly suppressed superoxide production and improved endothelium-dependent vasorelaxation to a level comparable to that in wildtype control mice. 4. In summary, the cell-permeable SOD mimetic M40403 was found to reverse endothelial dysfunction in apoE(0) aorta ex vivo by decreasing NADPH oxidase-dependent superoxide levels. The advantages of synthetic SOD mimetics over the native Cu/Zn SOD enzyme, such as greater cell permeability and stability, confer significant therapeutic potential in vascular disease.
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PMID:Superoxide dismutase mimetic M40403 improves endothelial function in apolipoprotein(E)-deficient mice. 1287 23

Essential hypertension in humans may develop through a combination of genetic and environmental factors. Diet has long been under investigation as a potential effector of blood pressure. A diet high in sucrose or fructose can give rise to hyperlipidemia, insulin resistance and hypertension. Insulin resistance, glucose intolerance and oxidative stress are common features of hypertension. If glucose metabolism through the glycolytic pathway is impaired, as in insulin resistance, there will be a build-up of glyceraldehyde, glyceraldehyde-3-phosphate and dihydroxyacetone phosphate with further metabolism to methylglyoxal, a highly reactive ketoaldehyde. Excess aldehydes can bind sulfhydryl groups of membrane proteins, altering membrane calcium channels, increasing cytosolic free calcium, peripheral vascular resistance and blood pressure. The presence of reactive aldehydes can also lead to oxidative stress. Dietary management through lower sucrose or fructose intake and increased consumption of vitamins improves glucose metabolism, lowers tissue aldehydes, increases anti-oxidant capacity and may also prevent hypertension.
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PMID:Prevention of fructose-induced hypertension by dietary vitamins. 1467 55

Hyperlipidemia is a secondary disorder associated with many metabolic disorders including hypothyroidism. The occurrence of dyslipidemia in subclinical hypothyroidism is controversial. Hyperphosphatemia may accompany the dyslipidemia in some metabolic disorders. Both hyperlipidemia and hyperphosphatemia are considered to be risk factors for the coronary heart diseases. In the present study, we investigated the occurrence of dyslipidemia and altered serum phosphate concentrations in patients with thyroid disorders. The results indicated a significantly elevated serum cholesterol and triglyceride concentrations in the hypothyroid patients. The dyslipidemia was accompanied with significantly elevated serum phosphate level. On the other hand, no significant difference was evident in the serum lipid or phosphate concentrations of subclinical hypothyroid patients compared to euthyroid subjects. A significantly reduced serum phosphate level was shown in hyperthyroid patients with unaltered serum lipid levels. Significant correlations were evident between TSH and T(4) levels as independent parameters and the serum concentrations of triglyceride, cholesterol and phosphate. The results indicate in hypothyroidism that a secondary hyperphosphatemia may aggravate myocardial and arterial abnormalities induced by the secondary hyperlipidemia, which may need correction.
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PMID:The secondary dyslipidemia and deranged serum phosphate concentration in thyroid disorders. 1501 Feb 97

Early optimalization of the treatment of patients with chronic renal insufficiency can reduce morbidity and deaths. For each patient with a raised serum creatinine concentration, the creatinine clearance should be measured or calculated. When this is abnormal, the cause thereof should be investigated. Chronic renal insufficiency is often progressive, even when the initiating factors are no longer present. Progression can be delayed by treating the high blood pressure, proteinuria and hyperlipidemia by means of a restricted protein diet and advice not to smoke. Acute deterioration of an existing chronic renal dysfunction through dehydration and underfill or through the use of certain medications or toxic substances such as radio-opaque media should be avoided. In patients with chronic renal insufficiency specific attention should be paid not only to hypertension, lipid disturbances, smoking and weight, but also to the calcium-phosphate balance, anaemia and homocysteine levels. The blood pressure, oedema and weight of patients with a clearance between 30-59 ml/min should be checked 2-3 times a year, in addition to laboratory tests for Hb, Ht, creatinine, urea, potassium, calcium, phosphate, pH, bicarbonate and lipid spectrum. It is recommended that when creatinine clearance (< 50 ml/min) falls a nephrologist should be consulted at least once with respect to the strategy to be followed. Symptoms of chronic renal insufficiency can occur when the creatinine clearance is < 30 ml/min. This relates to: sodium retention, imbalances in the calcium and phosphate levels, anaemia, uraemia, water retention, potassium retention and metabolic acidosis. Referral should take place at a creatinine clearance of < or = 30 ml/min.
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PMID:[Treatment of patients with chronic renal insufficiency; a guideline for internists]. 1511 99


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