Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For the care of an expanding segment of the US population with multiple coronary risk factors, combination lipid-altering therapy is emerging as a treatment imperative. The most recent National Cholesterol Education Program's consensus guidelines emphasize long-term global coronary heart disease (CHD) risk status, designate patients with CHD risk equivalents (eg, diabetes, peripheral arterial disease, 20% or more 10-year absolute CHD risk) for aggressive lipid-altering therapy, and deem the metabolic syndrome (eg, obesity, insulin resistance, hypertension, elevated triglycerides, low levels of high-density lipoprotein cholesterol, small dense low-density lipoprotein particles) as a secondary target for intervention. With the advancing age of the US population and the high prevalence of diabetes, the metabolic syndrome, and CHD, increasing numbers of patients will require a more balanced metabolic attack attainable only through combination lipid-altering regimens. Many of these patients, as well as persons at heightened risk for cardiovascular disease because of a range of heritable conditions (eg, familial hypercholesterolemia, familial combined hyperlipidemia), will undoubtedly require binary or ternary regimens involving statins in concert with niacin, fibric-acid derivatives, or bile acid resins. Such approaches enable the clinician to exploit the complementary effects of these agents, allowing them to be administered at low, optimally tolerable doses that are consistent with superior efficacy and a lower risk of adverse events as compared with escalating doses of monotherapy.
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PMID:Combination lipid-altering therapy: an emerging treatment paradigm for the 21st century. 1148 48

Traditional risk factors for coronary artery disease (CAD) predict about 50% of the risk of developing CAD. The Adult Treatment Panel (ATP) III has defined emerging risk factors for CAD, including small, dense low-density lipoprotein (LDL). Small, dense LDL is often accompanied by increased triglycerides (TGs) and low high-density lipoprotein (HDL). An increased number of small, dense LDL particles is often missed when the LDL cholesterol level is normal or borderline elevated. Small, dense LDL particles are present in families with premature CAD and hyperapobetalipoproteinemia, familial combined hyperlipidemia, LDL subclass pattern B, familial dyslipidemic hypertension, and syndrome X. The metabolic syndrome, as defined by ATP III, incorporates a number of the components of these syndromes, including insulin resistance and intra-abdominal fat. Subclinical inflammation and elevated procoagulants also appear to be part of this atherogenic syndrome. Overproduction of very low-density lipoproteins (VLDLs) by the liver and increased secretion of large, apolipoprotein (apo) B-100-containing VLDL is the primary metabolic characteristic of most of these patients. The TG in VLDL is hydrolyzed by lipoprotein lipase (LPL) which produces intermediate-density lipoprotein. The TG in intermediate-density lipoprotein is hydrolyzed further, resulting in the generation of LDL. The cholesterol esters in LDL are exchanged for TG in VLDL by the cholesterol ester tranfer proteins, followed by hydrolysis of TG in LDL by hepatic lipase which produces small, dense LDL. Cholesterol ester transfer protein mediates a similar lipid exchange between VLDL and HDL, producing a cholesterol ester-poor HDL. In adipocytes, reduced fatty acid trapping and retention by adipose tissue may result from a primary defect in the incorporation of free fatty acids into TGs. Alternatively, insulin resistance may promote reduced retention of free fatty acids by adipocytes. Both these abnormalities lead to increased levels of free fatty acids in plasma, increased flux of free fatty acids back to the liver, enhanced production of TGs, decreased proteolysis of apo B-100, and increased VLDL production. Decreased removal of postprandial TGs often accompanies these metabolic abnormalities. Genes regulating the expression of the major players in this metabolic cascade, such as LPL, cholesterol ester transfer protein, and hepatic lipase, can modulate the expression of small, dense LDL but these are not the major defects. New candidates for major gene effects have been identified on chromosome 1. Regardless of their fundamental causes, small, dense LDL (compared with normal LDL) particles have a prolonged residence time in plasma, are more susceptible to oxidation because of decreased interaction with the LDL receptor, and enter the arterial wall more easily, where they are retained more readily. Small, dense LDL promotes endothelial dysfunction and enhanced production of procoagulants by endothelial cells. Both in animal models of atherosclerosis and in most human epidemiologic studies and clinical trials, small, dense LDL (particularly when present in increased numbers) appears more atherogenic than normal LDL. Treatment of patients with small, dense LDL particles (particularly when accompanied by low HDL and hypertriglyceridemia) often requires the use of combined lipid-altering drugs to decrease the number of particles and to convert them to larger, more buoyant LDL. The next critical step in further reduction of CAD will be the correct diagnosis and treatment of patients with small, dense LDL and the dyslipidemia that accompanies it.
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PMID:Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity. 1241 79

The recent focus on emerging cardiovascular risk factors, such as C-reactive protein, homocysteine, and small, dense low-density lipoprotein (LDL), may give the false impression that the current approach to the assessment of cardiovascular disease risk fails to identify a large section of the high-risk population. On the contrary, the new guidelines of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) propose classifying an enormous number of individuals, including people with any form of atherosclerotic disease, diabetes, and a combination of major risk factors, into the category of high risk (>20% likelihood of a major coronary event or stroke in 10 years). Considering the widespread prevalence of the metabolic syndrome-a high-risk condition characterized by mild hypertension, mild dyslipidemia, hyperglycemia, and visceral obesity-we may be faced with the challenge of implementing aggressive risk reduction therapies in as much as 30% of the adult US population. From the point of view of risk assessment, a practical approach is to follow the NCEP guidelines (ie, place patients with diabetes and those with atherosclerotic complications in the highest risk category), apply the Framingham calculation to determine risk in people with common risk factors, and initiate early intervention in people who have familial hypercholesterolemia (LDL cholesterol >200 mg/dL) or a family history of early cardiovascular disease. The emerging risk factors may be useful for further stratifying risk in individuals with intermediate risk and the presence of risk factors not included in the Framingham calculation.
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PMID:A practical approach to risk assessment to prevent coronary artery disease and its complications. 1286 51

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

The very low-density lipoprotein (VLDL) receptor is a member of the low-density lipoprotein (LDL) receptor family. In vitro and in vivo studies have shown that VLDL receptor binds triglyceride (TG)-rich lipoproteins but not LDL, and functions as a peripheral remnant lipoprotein receptor. VLDL receptor is expressed abundantly in fatty acid-active tissues (heart, skeletal muscle and fat), the brain and macrophages. It is likely that VLDL receptor functions in concert with lipoprotein lipase (LPL), which hydrolyses TG in VLDL and chylomicron. In contrast to the LDL receptor, VLDL receptor binds apolipoprotein (apo) E2/2 VLDL particles as well as apoE3/3 VLDL, and the expression is not down-regulated by intracellular lipoproteins. Recently, various functions of the VLDL receptor have been reported in lipoprotein metabolism, metabolic syndrome/atherosclerosis, cardiac fatty acid metabolism, neuronal migration and angiogenesis/tumor growth. Gene therapy of VLDL receptor into the liver showed a benefit effect for lipoprotein metabolism in both LDL receptor knockout and apoE mutant mice. Beyond its function as a peripheral lipoprotein receptor, possibilities of its physiological function have been extended to include signal transduction, angiogenesis and tumor growth.
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PMID:The very low-density lipoprotein (VLDL) receptor: characterization and functions as a peripheral lipoprotein receptor. 1535 79

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

LDL receptor (LDLR)-null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome, have vascular calcification (VC) worsened by chronic kidney disease (CKD) and ameliorated by bone morphogenetic protein-7 (BMP-7), an efficacious agent in treating animal models of renal osteodystrophy. Here, LDLR-/- high-fat-fed mice without CKD were shown to have significant reductions in bone formation rates, associated with increased VC and hyperphosphatemia. Superimposing CKD resulted in a low turnover osteodystrophy, whereas VC worsened and hyperphosphatemia persisted. BMP-7 treatment corrected the hyperphosphatemia, corrected the osteodystrophy, and prevented VC, compatible with skeletal phosphate deposition leading to reduced plasma phosphate and removal of a major stimulus to VC. A pathologic link between abnormal bone mineralization and VC through the serum phosphorus was supported by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in this model of the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to low bone turnover rates, producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through deposition of phosphate and increased bone formation.
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PMID:Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome. 1574 94

SREBP family have been recently established as bHLH type transcription factors governing lipid synthesis. While SREBP-2 regulates expression of genes involved in cholesterol biosynthesis and LDL receptor, SREBP-1c controls fatty acid synthesis. Cellular cholesterol is regulated by feedback system where SCAP/Insig system regulates cleavage of SREBP-2 for its activation depending upon cellular cholesterol demand. Meanwhile, SREBP-1c is nutritionally regulated, excess energy intake could activate hepatic SREBP-1c expression leading to formation of remnant lipoproteins and hepatic insulin resistance through suppression of IRS-2 expression. Hepatic SREBP-1c could be deeply involved in metabolic syndrome. Thus, SREBP-1c could be a therapeutic target to treat metabolic syndrome. Polyunsaturated fatty acids suppress SREBP-1c and suppress lipogenesis.
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PMID:[Lipid synthetic transcription factor, SREBP]. 1588 Nov 88

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

Gender and dietary fatty acids are involved in the regulation of lipid metabolism, disturbances of which can lead to pathologies such as metabolic syndrome or CVD. Possible interactions between these factors were investigated in male and female hamsters fed diets rich in either saturated fatty acids ( "butter" diet) or in alpha-linolenic acid ( "linseed oil" diet). Gender effect predominated over the diet effect on cholesterol (CH) metabolism; compared to males, females exhibited lower concentrations of plasma total CH (-20 %, P<0.001), LDL-CH (-40 %, P<0.001) and HDL-CH (-16 %, P<0.001), together with higher LDL receptor (+40 %) and lower HDL receptor (-60 %) hepatic content. Triacylglycerol (TG) metabolism was affected by diet above all: compared to animals fed the "butter" diet, those fed the "linseed oil" diet exhibited lower plasma (-23 %, P=0.046) and liver TG (-20 %, P=0.026) concentration which may result from both an increased beta-oxidation (P<0.001), without any change in PPARalpha mRNA, and a decreased hepatic lipogenesis (P=0.023), without increased sterol response element binding protein 1c (SREBP1c) mRNA. The response to diet was much more pronounced in males than in females, without gender effect on the transcription level of PPARalpha and SREBP1c. Finally, the "linseed oil" diet decreased the insulin resistance index (-80 %, P<0.001) with a more marked effect in males, in relation to their higher hepatic PPARgamma expression (+90 %, P=0.012). In conclusion, in our model, the response of either TG or CH to dietary fatty acids is modulated differently by gender. The possible relevance of these interactions to dietary practice should be taken into account in man.
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PMID:Gender-related response of lipid metabolism to dietary fatty acids in the hamster. 1657 Nov 50


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