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)

Cardiovascular diseases are the leading causes of mortality among patients with end-stage renal disease (ESRD), with arterial disease and left ventricular hypertrophy being the two principal factors of the high mortality rate in this population. In addition to traditional risk factors (age, gender, diabetes, hypertension, lifestyle, hyperlipidemia, smoking, hyperhomocystinemia), inflammation, oxidative stress and disorders of mineral metabolism may contribute to cardiovascular risk in patients with uremic syndrome. High serum phosphate may influence vascular calcifications directly and indirectly, by worsening secondary hyperparathyroidism. Several treatment options are available for the treatment of hyperphosphatemia and secondary hyperparathyroidism in patients with ESRD. The treatment approach includes a diet low in phosphorus, with less than 1 g/kg/day of protein. Vitamin D supplementation is an important part of treatment. Phosphate binding agents are in most of the patients necessary in addition to diet. Aluminum hydroxide has been widely used for many years. It is very potent, but also very toxic, with severe encephalopathy as the most dangerous side effect. Calcium salts are less potent, and were considered safe for use in patients on dialysis. However, improvement in the understanding of vascular calcifications has demonstrated that calcium overload significantly contributes to widespread atherosclerosis in patients with ESRD. Sevelamer-hydrochloride is a novel non-aluminum, non-calcium containing phosphate binder, which is capable of reducing the levels of phosphorus as well as of low-density lipoprotein cholesterol, and increasing high-density lipoprotein cholesterol.
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PMID:[Hyperphosphatemia and cardiovascular risk in patients on dialysis]. 1550 84

Cardiac disease is the leading cause of death in patients having end-stage renal disease (ESRD). Patients with ESRD have a higher risk for developing coronary artery disease (CAD) than one would estimate from the presence of traditional risk factors such as hypertension, diabetes, hyperlipidemia, and cigarette smoking. Patients with milder forms of renal dysfunction who do not require dialysis also appear to have an increased risk for CAD. ESRD is associated with anemia, hyperhomocystinemia, increased calcium-phosphate product, hypoalbuminemia, increased troponin, increased markers of inflammation, increased oxidant stress, and decreased nitric oxide activity, factors that could contribute to increased CAD risk. Patients with ESRD require aggressive management of traditional risk factors for CAD, which include hypertension, hyperlipidemia, hyperhomocystinemia, and hypercoagulability. Milder forms of renal dysfunction could also be predictors of occult CAD and should be screened for in assessing cardiac risk in asymptomatic individuals.
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PMID:Chronic renal dysfunction as an independent risk factor for the development of cardiovascular disease. 1570 61

The main pathological findings in atherosclerosis include abnormal reactions of neutrophils, lymphocytes and monocytes/macrophages, vascular smooth muscle cells and vascular endothelial cells, and the accumulation of cholesterol ester in the arterial wall. Therefore, investigating the effects of these abnormal reactions on the arterial wall may improve understanding of the mechanisms underlying atherosclerosis. Three types of peroxisome proliferator-activated receptors (PPARs): PPARalpha, PPARbeta/delta, and PPARgamma are expressed in endothelial cells. In endothelial cells, the ligands/activators for PPARalpha and PPARgamma increase Cu2+, Zn2+ -superoxide dismutase. In addition, the phorbol myristate acetate (PMA)-stimulated 22 kDa-subunit (p22phox) protein levels and 47 kDa-subunit (p47phox) protein levels in NADPH (superoxide generating enzyme nicotinamide adenine dinucleotide phosphate (reduced form)) oxidase were decreased by treatment with PPARalpha and PPARgamma ligands/activators. Recently, we showed that the CLOCK: BMAL1 heterodimer regulates the PPARalpha gene via promoter of PPARalpha. Moreover, we report a patient with severe hypertriglyceridemia associated with anemia and hypoalbuminemia, in which the former may have caused the latter two conditions. This is the first reported case of abrupt onset of severe hypertriglyceridemia resulting in suppression of bone marrow and liver function. Here, based on recent studies including our own, we describe the relationships between risk factors for atherosclerosis, especially hyperlipidemia and PPARs and the molecular mechanisms that govern lipid metabolism in the arteries.
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PMID:[Hyperlipidemia and peroxisome proliferator-activated receptor (PPAR)--regulation of the PPARalpha gene by CLOCK: BMAL1]. 1582 32

The polyol isomalt (Palatinit) is a well established sugar replacer. The impact of regular isomalt consumption on metabolism and parameters of gut function in nineteen healthy volunteers was examined in a randomised, double-blind, cross-over trial with two 4-week test periods. Volunteers received 30 g isomalt or 30 g sucrose daily as part of a controlled diet. In addition to clinical standard diagnostics, biomarkers and parameters currently discussed as risk factors for CHD, diabetes or obesity were analysed. Urine and stool Ca and phosphate excretions were measured. In addition, mean transit time, defecation frequency, stool consistency and weight were determined. Consumption of test products was affirmed by the urinary excretion of mannitol. Blood lipids were comparable in both phases, especially in volunteers with hyperlipidaemia, apart from lower apo A-1 (P=0.03) for all subjects. Remnant-like particles, oxidised LDL, NEFA, fructosamine and leptin were comparable and not influenced by isomalt. Ca and phosphate homeostasis was not affected. Stool frequency was moderately increased in the isomalt phase (P=0.006) without changes in stool consistency and stool water. This suggests that isomalt is well tolerated and that consumption of isomalt does not impair metabolic function or induce hypercalciuria. In addition, the study data indicate that isomalt could be useful in improving bowel function.
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PMID:Effects of isomalt consumption on gastrointestinal and metabolic parameters in healthy volunteers. 1619 83

Vascular calcification is often encountered in advanced atherosclerotic lesions and is a common consequence of aging. Calcification of the coronary arteries has been positively correlated with coronary atherosclerotic plaque burden, increased risk of myocardial infarction, and plaque instability. Chronic kidney disease (CKD) patients have two to five times more coronary artery calcification than healthy age-matched individuals. Vascular calcification is a strong prognostic marker of cardiovascular disease mortality in CKD patients. Vascular calcification has long been considered to be a passive, degenerative, and end-stage process of atherosclerosis and inflammation. However, recent evidence indicates that bone matrix proteins such as osteopontin, matrix Gla protein (MGP), and osteocalcin are expressed in calcified atherosclerotic lesions, and that calcium-regulating hormones such as vitamin D3 and parathyroid hormone-related protein regulate vascular calcification in in vitro vascular calcification models based on cultured aortic smooth muscle cells. These findings suggest that vascular calcification is an actively regulated process similar to osteogenesis, and that bone-associated proteins may be involved in the development of vascular calcification. The pathogenesis of vascular calcification in CKD is not well understood and is almost multifactorial. In CKD patients, several studies have found associations of both traditional risk factors, such as hypertension, hyperlipidemia, and diabetes, and uremic-specific risk factors with vascular calcification. Most patients with progressive CKD develop hyperphosphatemia. An elevated phosphate level is an important risk factor for the development of calcification and cardiovascular mortality in CKD patients. Thus, it is hypothesized that an important regulator of vascular calcification is the level of inorganic phosphate. In order to test this hypothesis, we characterized the response of human smooth muscle cell (HSMC) cultures to inorganic phosphate levels. Our findings indicate that inorganic phosphate directly regulates HSMC calcification through a sodium-dependent phosphate transporter mechanism. After treatment with elevated phosphate, there is a loss of smooth muscle lineage markers, such as alpha-actin and SM-22alpha, and a simultaneous gain of osteogenic markers such as cbfa-1 and osteocalcin. Elevated phosphate may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification, and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. Furthermore, putative calcification inhibitory molecules have been identified using mouse mutational analyses, including MGP, beta-glucosidase, fetuin-A, and osteoprotegerin. Mutant mice deficient in these molecules present with enhanced cardiovascular calcification, demonstrating that specific molecules are normally important in suppressing vascular calcification. These findings suggest that the balance of inducers, such as phosphate, and inhibitors, such as MGP, fetuin-A, and others, are likely to control whether or not calcification occurs under pathological conditions.
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PMID:Vascular calcification in chronic kidney disease. 1650 29

Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. As an oxidant, pathological levels of NO inhibit nearly all enzyme-catalyzed reactions through protein oxidation. However, as a signaling molecule, physiological levels of NO stimulate glucose uptake as well as glucose and fatty acid oxidation in skeletal muscle, heart, liver and adipose tissue; inhibit the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhance lipolysis in adipocytes. Thus, an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. The putative underlying mechanisms may involve multiple cyclic guanosine-3',5'-monophosphate-dependent pathways. First, NO stimulates the phosphorylation of adenosine-3',5'-monophosphate-activated protein kinase, resulting in (1) a decreased level of malonyl-CoA via inhibition of acetyl-CoA carboxylase and activation of malonyl-CoA decarboxylase and (2) a decreased expression of genes related to lipogenesis and gluconeogenesis (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c and phosphoenolpyruvate carboxykinase). Second, NO increases the phosphorylation of hormone-sensitive lipase and perilipins, leading to the translocation of the lipase to the neutral lipid droplets and, hence, the stimulation of lipolysis. Third, NO activates expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, thereby enhancing mitochondrial biogenesis and oxidative phosphorylation. Fourth, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake and product removal via the circulation. Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance.
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PMID:Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. 1652 13

Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are widely used for the treatment of hyperlipidemia, and recent studies and animal data suggest that statins promote osteogenesis and increase bone strength. However, little is known about the effects of statins delivered by sustained delivery system to a target site of a defect and segmental bone fractures on certain biochemical markers including reproductive hormones. The purpose of this study was to develop a targeted statin delivery system using Tricalcium Phosphate Lysine (TCPL) for defect and segmental femoral injuries and evaluate the effects on alkaline phosphatase, total protein, malinodialdehyde, glutathione, total cholesterol, testosterone, luteinizing hormone, statins, and follicle-stimulating hormone. Because of the influence oral intake of statins might have on certain body organs, we also examine the histomorphology of the vital and reproductive organs of the animals receiving statins for a period of 30 days and 12 weeks post surgery. Simvastatin used in this study significantly increased fracture healing and without significant influence on the body weights and the weights and morphology of the vital and reproductive organs. There was a significant reduction in the cholesterol levels on the 3rd week in both phases of the study and at the conclusion of the study the difference in the cholesterol levels was no more significant in both phases. Other biochemical markers including plasma LH, FSH and testosterone levels were not affected by active treatment with simvastatin. In conclusion, short and long-term simvastatin treatment delivered at a fracture target site did not influence vital and reproductive organs, the systemic levels of the biochemical markers studied, but was able to effectively stimulate bone formation in simple and complicated segmental fractures.
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PMID:Effects of sustained release of statin by means of tricalcium phosphate lysine delivery system in defect and segmental femoral injuries on certain biochemical markers in vivo. 1681 97

Fatty liver is commonly associated with insulin resistance and type 2 diabetes, but it is unclear whether triacylglycerol accumulation or an excess flux of lipid intermediates in the pathway of triacyglycerol synthesis are sufficient to cause insulin resistance in the absence of genetic or diet-induced obesity. To determine whether increased glycerolipid flux can, by itself, cause hepatic insulin resistance, we used an adenoviral construct to overexpress glycerol-sn-3-phosphate acyltransferase-1 (Ad-GPAT1), the committed step in de novo triacylglycerol synthesis. After 5-7 days, food intake, body weight, and fat pad weight did not differ between Ad-GPAT1 and Ad-enhanced green fluorescent protein control rats, but the chow-fed Ad-GPAT1 rats developed fatty liver, hyperlipidemia, and insulin resistance. Liver was the predominant site of insulin resistance; Ad-GPAT1 rats had 2.5-fold higher hepatic glucose output than controls during a hyperinsulinemic-euglycemic clamp. Hepatic diacylglycerol and lysophosphatidate were elevated in Ad-GPAT1 rats, suggesting a role for these lipid metabolites in the development of hepatic insulin resistance, and hepatic protein kinase Cepsilon was activated, providing a potential mechanism for insulin resistance. Ad-GPAT1-treated rats had 50% lower hepatic NF-kappaB activity and no difference in expression of tumor necrosis factor-alpha and interleukin-beta, consistent with hepatic insulin resistance in the absence of increased hepatic inflammation. Glycogen synthesis and uptake of 2-deoxyglucose were reduced in skeletal muscle, suggesting mild peripheral insulin resistance associated with a higher content of skeletal muscle triacylglycerol. These results indicate that increased flux through the pathway of hepatic de novo triacylglycerol synthesis can cause hepatic and systemic insulin resistance in the absence of obesity or a lipogenic diet.
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PMID:Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance. 1738 95

D-Glucose-6-phosphatase is a key regulator of endogenous glucose production, and its inhibition may improve glucose control in type 2 diabetes. Herein, 2'-O-(2-methoxy)ethyl-modified phosphorothioate antisense oligonucleotides (ASOs) specific to the glucose 6-phosphate transporter-1 (G6PT1) enabled reduction of hepatic D-Glu-6-phosphatase activity in diabetic ob/ob mice. Treatment with G6PT1 ASOs decreased G6PT1 expression, reduced G6PT1 activity, blunted glucagon-stimulated glucose production, and lowered plasma glucose concentration in a dose-dependent manner. In contrast to G6PT1 knock-out mice and patients with glycogen storage disease, excess hepatic and renal glycogen accumulation, hyperlipidemia, neutropenia, and elevations in plasma lactate and uric acid did not occur. In addition, hypoglycemia was not observed in animals during extended periods of fasting, and the ability of G6PT1 ASO-treated mice to recover from an exogenous insulin challenge was not impaired. Together, these results demonstrate that effective glucose lowering by G6PT1 inhibitors can be achieved without adversely affecting carbohydrate and lipid metabolism.
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PMID:Specific reduction of hepatic glucose 6-phosphate transporter-1 ameliorates diabetes while avoiding complications of glycogen storage disease. 1747 31

Obstructive sleep apnea (OSA), a condition leading to intermittent hypoxia (IH) during sleep, has been associated with dyslipidemia, atherosclerosis, and increased cardiovascular mortality. We previously showed in C57BL/6J mice that IH causes hypercholesterolemia and upregulation of sterol regulatory element binding protein (SREBP)-1, a transcription factor of lipid biosynthesis in the liver. The goal of the present study was to provide mechanistic evidence that IH causes hypercholesterolemia via the SREBP-1 pathway. We utilized mice with a conditional knockout of SREBP cleavage-activating protein (SCAP) in the liver (L-Scap- mice), which exhibit low levels of an active nuclear isoform of SREBP-1 (nSREBP-1). We exposed L-Scap- mice and wild-type (WT) littermates to IH or intermittent air control for 5 days. IH was induced during the 12-h light phase by decreasing Fi(O(2)) from 20.9% to 5% for a period of 30 s with rapid reoxygenation to 20.9% through the subsequent 30 s. In WT mice, IH increased fasting levels of serum total and HDL cholesterol, serum triglycerides, serum and liver phospholipids, mRNA levels of SREBP-1 and mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT), and protein levels of SCAP, nSREBP-1, and mtGPAT in the liver. In L-Scap- mice, IH did not have any effect on serum and liver lipids, and expression of lipid metabolic genes was not altered. We conclude that hyperlipidemia in response to IH is mediated via the SREBP-1 pathway. Our data suggest that the SREBP-1 pathway could be used as a therapeutic target in patients with both OSA and hyperlipidemia.
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PMID:Effect of deficiency in SREBP cleavage-activating protein on lipid metabolism during intermittent hypoxia. 1766 24


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