Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis with myocardial infarction, stroke, and peripheral cellular disease still maintains its position at the top of morbidity and mortality statistics in industrialized nations. Established risk factors widely accepted are smoking, arterial hypertension, diabetes mellitus, and central obesity. Furthermore, there is a strong correlation between hyperlipidemia and atherosclerosis. The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) (Lpa) levels, and coronary heart disease (CHD) refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL) apheresis is the therapeutic option. Today, there are four different LDL apheresis systems available: immunoadsorption, heparin-induced extracorporeal LDL/fibrinogen precipitation, dextran sulfate LDL adsorption and LDL hemoperfusion. Regarding the different LDL apheresis systems used, there is no significant difference with respect to the clinical outcome or concerning total cholesterol, LDL, high-density lipoprotein (HDL), or triglyceride concentrations. With respect to elevated Lpa levels, however, the immunoadsorption method seems to be the most effective. In 45 patients (25 women, 20 men) suffering from familial hypercholesterolemia resistant to diet and lipid lowering drugs, low-density lipoprotein (LDL) apheresis was performed over 95.6 +/- 44.7 months. Four different systems (Liposorber, 32 of 45, Kaneka, Osaka, Japan; Therasorb, 6 of 45, Baxter, Munich, Germany; Lipopak, 2 of 45, Pocard, Moscow, Russia; and Dali, 5 of 45, Fresenius, St. Wendel, Germany) were used. With all methods, average reductions of 57% for total cholesterol, 55.9% for LDL, 75.8% for lipoprotein a (Lpa), and 45.9% for triglycerides, and an average increase of 14.3% for HDL were reached. Severe side-effects such as shock or allergic reactions were very rare (0.3%) in all methods. In the course of treatment, an improvement in general well-being and increased performance were experienced by 44 of 45 patients. The present data demonstrate that treatment with LDL apheresis of patients suffering from familial hypercholesterolemia resistant to maximum conservative therapy is very effective and safe even in long-term application.
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PMID:Low-density lipoprotein apheresis: an overview. 1288 19

Cholesterol elimination from the body involves reverse cholesterol transport from peripheral tissues in which the elimination of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol by the liver and subsequent biliary excretion as free cholesterol and bile acids are important. In situations of peripheral fat and cholesterol accumulation, such as obesity, these pathways may be overloaded, contributing to increased cholesterol deposition. Leptin has an important role in obesity, suppressing food intake and increasing energy expenditure. This hormone, which is absent in genetically obese ob/ob mice, is also thought to be involved in the coordination of lipid excretion pathways, although available data are somewhat inconsistent. We therefore studied the expression of the hepatic HDL receptor, scavenger receptor class B type I (SR-BI), and the LDL receptor as well as the rate-limiting enzyme in bile acid synthesis, cholesterol 7alpha-hydroxylase (Cyp7a1), in leptin-deficient ob/ob mice and their wild-type controls. In ob/ob mice, protein levels of both LDL receptor and SR-BI were reduced, whereas LDL receptor mRNA levels were increased and those of SR-BI were reduced, regardless of challenge with a 2% cholesterol diet. In ob/ob mice, the enzymatic activity and mRNA for Cyp7a1 were reduced, and the increase in response to dietary cholesterol was blunted. Upon short-term (2 days) treatment with leptin, a dose-dependent increase was seen in the SR-BI protein and mRNA, whereas the Cyp7a1 protein and mRNA were reduced. Our findings indicate that leptin is an important regulator of hepatic SR-BI expression and, thus, HDL cholesterol levels, whereas it does not stimulate Cyp7a1 and bile acid synthesis.
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PMID:Leptin induces the hepatic high density lipoprotein receptor scavenger receptor B type I (SR-BI) but not cholesterol 7alpha-hydroxylase (Cyp7a1) in leptin-deficient (ob/ob) mice. 1291 27

Current lipid-altering agents that lower low density lipoprotein cholesterol (LDL-C) primarily through increased hepatic LDL receptor activity include statins, bile acid sequestrants/resins and cholesterol absorption inhibitors such as ezetimibe, plant stanols/sterols, polyphenols, as well as nutraceuticals such as oat bran, psyllium and soy proteins; those currently in development include newer statins, phytostanol analogues, squalene synthase inhibitors, bile acid transport inhibitors and SREBP cleavage-activating protein (SCAP) activating ligands. Other current agents that affect lipid metabolism include nicotinic acid (niacin), acipimox, high-dose fish oils, antioxidants and policosanol, whilst those in development include microsomal triglyceride transfer protein (MTP) inhibitors, acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitors, gemcabene, lifibrol, pantothenic acid analogues, nicotinic acid-receptor agonists, anti-inflammatory agents (such as Lp-PLA(2) antagonists and AGI1067) and functional oils. Current agents that affect nuclear receptors include PPAR-alpha and -gamma agonists, while in development are newer PPAR-alpha, -gamma and -delta agonists, as well as dual PPAR-alpha/gamma and 'pan' PPAR-alpha/gamma/delta agonists. Liver X receptor (LXR), farnesoid X receptor (FXR) and sterol-regulatory element binding protein (SREBP) are also nuclear receptor targets of investigational agents. Agents in development also may affect high density lipoprotein cholesterol (HDL-C) blood levels or flux and include cholesteryl ester transfer protein (CETP) inhibitors (such as torcetrapib), CETP vaccines, various HDL 'therapies' and upregulators of ATP-binding cassette transporter (ABC) A1, lecithin cholesterol acyltransferase (LCAT) and scavenger receptor class B Type 1 (SRB1), as well as synthetic apolipoprotein (Apo)E-related peptides. Fixed-dose combination lipid-altering drugs are currently available such as extended-release niacin/lovastatin, whilst atorvastatin/amlodipine, ezetimibe/simvastatin, atorvastatin/CETP inhibitor, statin/PPAR agonist, extended-release niacin/simvastatin and pravastatin/aspirin are under development. Finally, current and future lipid-altering drugs may include anti-obesity agents which could favourably affect lipid levels.
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PMID:Pharmacotherapy for dyslipidaemia--current therapies and future agents. 1459 46

Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of the triglyceride-rich lipoproteins and plays a critical role in lipoprotein and free fatty acid metabolism. Genetic manipulation of LPL may be beneficial in the treatment of hypertriglyceridemias, but it is unknown whether increased LPL activity may be effective in lowering plasma cholesterol and improving insulin resistance in familial hypercholesterolemic patients. To test the hypothesis that stimulation of LPL expression may be used as an adjunctive therapy for treatment of homozygous familial hypercholesterolemia, we have generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits that overexpress the human LPL transgene and compared their plasma lipid levels, glucose metabolism, and body fat accumulation with those of non-Tg WHHL rabbits. Overexpression of LPL dramatically ameliorated hypertriglyceridemia in Tg WHHL rabbits. Furthermore, increased LPL activity in male Tg WHHL rabbits also corrected hypercholesterolemia (544 +/- 52 in non-Tg versus 227 +/- 29 mg/dl in Tg, p < 0.01) and reduced body fat accumulation by 61% (323 +/- 27 in non-Tg versus 125 +/- 21ginTg, p < 0.01), suggesting that LPL plays an important role in mediating plasma cholesterol homeostasis and adipose accumulation. In addition, overexpression of LPL significantly suppressed high fat diet-induced obesity and insulin resistance in Tg WHHL rabbits. These results imply that systemic elevation of LPL expression may be potentially useful for the treatment of hyperlipidemias, obesity, and insulin resistance.
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PMID:Overexpression of lipoprotein lipase in transgenic Watanabe heritable hyperlipidemic rabbits improves hyperlipidemia and obesity. 1466 May 66

Accelerated atherosclerosis is a major cause of morbidity and death in insulin-resistant states such as obesity and the metabolic syndrome, but the underlying mechanisms are poorly understood. We show that macrophages from obese (ob/ob) mice have increased binding and uptake of oxidized LDL, in part due to a post-transcriptional increase in CD36 protein. Macrophages from ob/ob mice are also insulin resistant, as shown by reduced expression and signaling of insulin receptors. Three lines of evidence indicate that the increase in CD36 is caused by defective insulin signaling: (a) Treatment of wild-type macrophages with LY294002, an inhibitor of insulin signaling via PI3K, results in an increase in CD36; (b) insulin receptor knockout macrophages show a post-transcriptional increase in CD36 protein; and (c) administration of thiazolidinediones to intact ob/ob mice and ob/ob, LDL receptor-deficient mice results in a reversal of macrophage insulin receptor defects and decreases CD36 protein. The last finding contrasts with the increase in CD36 that results from treatment of macrophages with these drugs ex vivo. The results suggest that defective macrophage insulin signaling predisposes to foam cell formation and atherosclerosis in insulin-resistant states and that this is reversed in vivo by treatment with PPAR-gamma activators.
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PMID:Increased CD36 protein as a response to defective insulin signaling in macrophages. 1499 Oct 75

Type 2 diabetes mellitus (DM) and the metabolic syndrome, both characterized by insulin resistance, are associated with an accelerated form of atherosclerotic vascular disease and poor outcomes following vascular interventions. These vascular effects are thought to stem from a heightened inflammatory environment and reduced bioavailability of nitric oxide (NO). To better understand this process, we characterized the vascular injury response in the obese Zucker rat by examining the expression of adhesion molecules, the recruitment of inflammatory cells, and the development of intimal hyperplasia. We also evaluated the ability of exogenous NO to inhibit the sequela of vascular injury in the metabolic syndrome. Obese and lean Zucker rats underwent carotid artery balloon injury. ICAM-1 and P-selectin expression were increased following injury in the obese animals compared with the lean rats. The obese rats also responded with increased macrophage infiltration of the vascular wall as well as increased neointima formation compared with their lean counterparts (intima/media = 0.91 vs. 0.52, P = 0.001). After adenovirus-mediated inducible NO synthase (iNOS) gene transfer, ICAM-1, P-selectin, inflammatory cell influx, and oxidized low-density lipoprotein (LDL) receptor expression were all markedly reduced versus injury alone. iNOS gene transfer also significantly inhibited proliferative activity (54% and 73%; P < 0.05) and neointima formation (53% and 67%; P < 0.05) in lean and obese animals, respectively. The vascular injury response in the face of obesity and the metabolic syndrome is associated with increased adhesion molecule expression, inflammatory cell infiltration, oxidized LDL receptor expression, and proliferation. iNOS gene transfer is able to effectively inhibit this heightened injury response and reduce neointima formation in this proinflammatory environment.
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PMID:Nitric oxide modulates vascular inflammation and intimal hyperplasia in insulin resistance and the metabolic syndrome. 1573 83

In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARgamma dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARgamma ligand treatment in vivo. Serum oxLDL levels are decreased in both lean and obese diabetic animals treated with TZDs. These data identify OLR1 as a novel PPARgamma target gene in adipocytes. While the physiological role of adipose tissue in cholesterol and oxLDL metabolism remains to be established, the induction of OLR1 is a potential means by which PPARgamma ligands regulate lipid metabolism and insulin sensitivity in adipocytes.
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PMID:PPARgamma regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1. 1600 65

Noninvasive assessment of vascular dysfunction in the pediatric population has taken advantage of the development of high-resolution ultrasound techniques. The most frequently used methods are the quantification of flow-mediated endothelium-dependent dilation of the brachial artery and measurement of the intima-media thickening of the carotid artery. Both reduced flow-mediated dilation and increased intima-media thickness have been proven to correlate with late cardiovascular events and/or mortality in adults. As these noninvasive methods can easily be applied in children, there have been recent investigations in high-risk pediatric patients harboring classical cardiovascular risk factors. Endothelial dysfunction and increased thickness of the intima media are currently observed in children with familial hypercholesterolemia, obesity, and type 1 diabetes mellitus. The association of early vascular dysfunction with a known risk factor is an important issue as these anomalies precede the formation of atherosclerotic plaques. Therefore, they may help in stratification of the risk for cardiovascular event and to better tailor therapeutic interventions in at risk children. Finally, these methods have been applied in specific pediatric populations, such as children with end-stage renal disease, chronic parenteral nutrition, HIV infection, and coarctation of the aorta. In these conditions, endothelial dysfunction and vascular remodeling are also present early in life and these data raise new possibilities in the understanding of the pathogenesis of atherosclerosis in these populations.
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PMID:Noninvasive assessment of arterial stiffness and risk of atherosclerotic events in children. 1605 29

The early lesions of atherosclerosis begin in childhood, and are related to antecedent cardiovascular disease risk factors. Environmental and genetic factors such as diet, obesity, exercise, and certain inherited dyslipidemias influence the progression of such lesions. The identification of youth at risk for atherosclerosis includes an integrated assessment of these predisposing factors. Treatment starts with a diet low in total and saturated fat and cholesterol, the use of water-soluble fiber and plant sterols, weight control, and exercise. Drug therapy, for example, with inhibitors of hydroxymethylglutaryl CoA reductase, bile acid sequestrants, and cholesterol absorption inhibitors, can be considered in those with a positive family history of premature coronary artery disease and a low-density lipoprotein cholesterol above 160 mg/dL, after dietary and hygienic measures. Candidates for drug therapy often include those with familial hypercholesterolemia, familial combined hyperlipidemia, the metabolic syndrome, polycystic ovarian syndrome, type I diabetes, and the nephrotic syndrome. We review the safety and efficacy of dietary and drug therapy, and propose an updated diagnostic and therapeutic algorithm that includes the metabolic syndrome. The early identification and treatment of youth with dyslipidemias is likely to retard the atherosclerotic process.
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PMID:Treatment of dyslipidemia in children and adolescents. 1625 15

Small, dense HDL particles have been associated with factors known to increase the risk of cardiovascular disease, such as obesity, hypertriglyceridemia, small dense LDL particles, decreased HDL-cholesterol levels and increased apoA-I fractional catabolic rate from plasma. In order to assess the potential contribution of HDL particle size to atherosclerosis in heterozygous familial hypercholesterolemia (FH), we examined the electrophoretic characteristics of HDL particles in a large cohort of well defined FH heterozygotes and controls. A total of 259 FH heterozygotes and 208 controls participated in the study. FH subjects were carriers of one of the nine French Canadian mutations in the LDL receptor gene. All subjects were apoE3 homozygotes. HDL particles were characterized by non-denaturing polyacrylamide gradient gel electrophoresis following a 6-week lipid-lowering drug-free baseline period. The integrated HDL size was significantly smaller in the FH group compared to controls (FH=87.3+/-5.2 Angstroms versus controls=91.6+/-4.9 Angstroms, P<0.0001). In each groups, men had smaller HDL particles than women. Multiple regression linear analyses showed that the FH/Control status accounted for 20.3% of the variance in the integrated HDL size. These results suggest that the FH/control status was independently associated with variations in HDL particle size and that these variations could contribute to the development of premature atherosclerosis in these patients.
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PMID:Association of heterozygous familial hypercholesterolemia with smaller HDL particle size. 1654 93


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