Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60-80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to beta-cells suppressed [(14)C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.
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PMID:Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. 1838 Dec 87

The aim of this study was to compare the prevalence and pattern of metabolic syndrome in children and adolescents in the interval between the Korean National Health and Nutrition Examination Surveys (KNHANES) in 1998 and 2001. Two nationwide surveys (KNHANES) were conducted in Korea in 1998 and 2001. A stratified multistage probability sampling design was used to ensure representation of the entire Korean population. The National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III)-derived definition was used for the definition of metabolic syndrome. A total of 1763 (mean age+/-SD of 14.6+/-2.8 yr) and 1245 (14.1+/-2.8 yr) Korean children and adolescents in the age range 10-19 yr participated in the studies of 1998 and 2001, respectively. The prevalence of metabolic syndrome in male children and adolescents increased significantly from 5.7% in 1998 to 9.0% in 2001. However, there was no increase in females (5.1% in 1998 and 4.9% in 2001). Of the 5 components of metabolic syndrome, low HDL-cholesterolemia showed the highest increase in males and females during the 3 yr. Hypertriglyceridemia increased next in both genders. In contrast, the proportion of female subjects meeting the fasting glucose criterion decreased over the same period. As dyslipidemia was the principal contributor to the increase in metabolic syndrome in Korean male children and adolescents during the 3 yr, a strategy of dietary pattern change and the encouragement of physical activity should be introduced to these groups at a national level.
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PMID:Changes in metabolic syndrome of Korean children and adolescents in the period 1998 to 2001. 1847 51

Atherosclerosis, especially when manifested as coronary artery disease (CAD), continues to be the number one cause of mortality and morbidity in developed nations and will soon become so in developing countries. Survivors of an acute heart attack have an increased risk of illness and death that is 1.5-15 times greater than in the general population. Sudden death occurs in myocardial infarction (MI) survivors at a rate 4-6 times greater than in the general population. After an initial recognized MI, 25% of male and 38% of female survivors die within 1 year. Within 6 years after a recognized MI, 18% of men and 35% of women will have a second MI, 7% of men and 6% of women will suffer sudden death, and 22% of men and 46% of women will be disabled with heart failure. Aggressive secondary prevention, therefore, is the key to containing and reversing the "malignant" natural history of CAD, since patients with CAD or CAD risk equivalents are already in the "high risk" category according to the Adult Treatment Panel III (ATP III) of the National Cholesterol Education rogram (NCEP). Treatment of dyslipidemia, especially the reduction of low-density lipoprotein (LDL) cholesterol levels to below 100 mg/dl, was recommended by the 2001 NCEP-ATP Guidelines. In 2004, based on the increasing evidence from several major clinical trials between 2001 and 2004, the NCEP-ATP reaffirmed its LDL goal of < 100 mg/dl in patients with CAD or coronary disease risk equivalents (including multiple risk factors), with an optional LDL goal of < 70 mg/dl in very-high-risk patients (including patients with established coronary heart disease plus other highrisk conditions) Findings from major studies, such as the Treating to New Targets (TNT) study, the Scandinavian Simvastatin Survival Study (4S), the Collaborative Atorvastatin Diabetes Study (CARDS), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial and, more recently, the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LAA), lend support to the idea that greater LDL cholesterol lowering than that achieved with standard doses of statins may be warranted in patients with CAD and metabolic syndrome, CAD and diabetes, CAD and congestive heart failure, and CAD and renal insufficiency. On the other hand, additional lipid reduction may also be warranted in patients with risk factors such as diabetes, hypertension or a history of stroke, but without manifest CAD and despite relatively normal cholesterol levels. These newer indications for statins, atorvastatin in particular, as part of more aggressive secondary and primary prevention, are reviewed in this paper.
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PMID:Expanding roles for atorvastatin. 1859 99

It is firmly established that poor metabolic control in diabetes inhibits beta cell function. Chronic hyperglycaemia is probably the most important factor, exerting both primary negative effects (by glucose per se and/or metabolites) and secondary ones (by beta cell exhaustion). Dyslipidemia in diabetes aggravates the glucose effects both by inducing insulin resistance and by direct effects on beta cells. Much experimental and some clinical evidence indicates that therapies that promote "beta cell rest" such as early and intensive insulin treatment and K-ATP channel blockers can be beneficial.
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PMID:Impact of metabolic abnormalities for beta cell function: clinical significance and underlying mechanisms. 1862 Oct 94

Among the adverse effects attributed to antiretroviral therapy, one of the most striking is probably the appearance of the lipodystrophy syndrome and its associated metabolic derangements, given its potential long-term effect as a cardiovascular risk factor. Since not all patients who receive antiretroviral drugs experience these adverse effects, a host genetic predisposition has been postulated. However, currently available data on this issue is inconclusive and preliminary. It has been consistently demonstrated that polymorphisms in the genes that encode for apolipoproteins A5, C3 and E, for the cholesterol ester transporter proteins (CETP), and in the ATP binding cassette type A1 (ABCA1) influence the development of dyslipidemia in patients treated with antiretroviral drugs, particularly if the therapeutic regimen includes protease inhibitors. Data on the effect of polymorphisms in the sterol regulatory ester binding protein type 1 (SREBP1) are inconsistent. The effect of mitochondrial DNA mutations on the risk of lipodystrophy has been assessed, with inconclusive data. No polymorphisms in the lamin A gene have been detected. Investigations have assessed the effect of diverse polymorphisms in the genes that encode for several proinflammatory cytokines such as tumour necrosis factor alpha (TNF-alpha), interleukin-1-beta (IL-1beta) and interleukin-6 (IL-6). The results show inconsistent data in the case of TNF-alpha, no association in the case of IL-6, and preliminary positive associations in IL-1beta. In contrast, polymorphisms in the genes encoding for stromal derived factor 1 (SDF-1) and for monocyte chemoattractant protein 1 (MCP-1) have been shown to influence the development of subclinical atherosclerosis in HIV-1-infected patients treated with antiretroviral drugs.
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PMID:[Toxicogenetics of antiretroviral treatment (1): lipodystrophy, metabolic perturbations and atherosclerosis]. 1868 Jun 92

The clustering of central obesity, dyslipidemia, hypertension, and hyperglycemia known as metabolic syndrome has been associated with a two- to three-fold increase in type 2 diabetes (T2DM) and cardiovascular disease (CVD). It is recognized that the features of the metabolic syndrome can be present 10 years preceding T2DM and CVD. The objective of our study was to determine the prevalence of metabolic syndrome in adults aged 25 years and older from an urban population of Karachi, Pakistan, according to the International Diabetes Federation (IDF) definition and modified Adult Treatment Panel III (ATP III) criteria. This study involved a survey conducted from July, 2004, to December, 2004, by generating a computerized random sample of households in Lyari Town using a geographical imaging system (GIS). Out of the 85,520 households, 532 households were randomly selected and 867 adults > or =25 years old consented to take part in the survey; 363 of these subjects gave blood samples. The prevalence of diabetes was 9.4%, whereas 5.6% had impaired fasting glucose (abnormal glucose tolerance 15%). The prevalence of metabolic syndrome according to the IDF definition and modified ATP III criteria was 34.8% and 49%, respectively. Inclusion of modified waist circumference and specific body mass index (BMI) cut offs for Asians may help predict metabolic syndrome at an early stage. High prevalence of metabolic syndrome was identified irrespective of the definition applied in this population. This may call for immediate action to halt the accelerating risk of diabetes and CVD that would lead to a possible unparalleled rise in the cost of health care and human suffering.
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PMID:Prevalence of metabolic syndrome in urban Pakistan (Karachi): comparison of newly proposed International Diabetes Federation and modified Adult Treatment Panel III criteria. 1892 98

The term metabolic syndrome (MS) refers to a clustering of risk factors of metabolic origin that promote the development of cardiovascular disease and type 2 diabetes. Metabolic syndrome includes such pathological factors as insulin resistance, hyperinsulinemia, abdominal obesity, impaired glucose tolerance, type 2 diabetes, microalbuminuria, high level of triglycerides, low level of HDL cholesterol, elevated blood pressure, and proinflammatory and prothrombotic state. Several organizations have recommended clinical criteria for the diagnosis of metabolic syndrome. The most widely accepted were the worked out by the World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR), and the National Cholesterol Education Program--Third Adult Treatment Panel (NCEP-ATP III). In 2005, IDF experts proposed a universally accepted diagnostic tool that is easy to use in clinical practice and does not rely on measurements available only in research settings. All groups agreed on the core components of the metabolic syndrome: obesity, insulin resistance, dyslipidemia, and hypertension. Their criteria are similar in many aspects, but they also reveal fundamental differences in their positioning of the predominant causes of the syndrome. This study provides a brief overview of current definitions of metabolic syndrome, with particular reference to the differences between them, and presents critical remarks on the concept of metabolic syndrome and its usefulness. It also presents epidemiological data which consider metabolic syndrome and its association with increased risk of cardiovascular disease and type 2 diabetes.
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PMID:[The metabolic syndrome. Part I: definitions and diagnostic criteria for its identification. Epidemiology and relationship with cardiovascular and type 2 diabetes risk]. 1893 29

The objective of this study was to estimate the prevalence of dyslipidemia as defined by NCEP ATP III criteria in the Trabzon Region of Turkey and to determine its associations with cardiovascular risk factors [hypertension (HT), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and fasting serum glucose (FBG)] demographic factors (age, sex, obesity, marital status, reproductive history in women, and level of education), socioeconomic factors (household income and occupation), a family history of selected medical conditions (diabetes, HT, obesity, and cardiovascular disease), and lifestyle factors (smoking habits, physical activity, and alcohol consumption) in the adult population. In this cross-sectional survey, a sample of households was systematically selected from the central province of Trabzon city and its nine towns, namely, Akcaabat, Duzkoy, Vakfikebir, Yomra, Arakli, Of, Caykara, Surmene, and Macka. A total of 4,809 subjects (2,601 women and 2,208 men) were included in the study. Individuals older than 20 years were selected from their family health cards. Demographic and socioeconomic factors, a family history of selected medical conditions, and lifestyle factors were obtained for all participants. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels were measured for all subjects. The individuals included in the questionnaire were invited to the local medical centers for blood tests between 08:00 and 10:00 after 12 h of fasting. The levels of serum glucose (FBG), total cholesterol (TC), high-density cholesterol (HDL-C), low-density cholesterol (LDL-C), and trigylcerides were measured with autoanalyzer. Dyslipidemia was defined according to guidelines from the US NCEP ATP III diagnostic criteria. The ratio of TC to HDL-C was calculated. Definition and classification of HT were performed according to guidelines from the US JNC-7 report. The results obtained indicated that the age-adjusted mean values (mg/dl) of TC, LDL-C, HDL-C, [TC/HDL-C ratio], and TG were 190 +/- 0.6, 127.5 +/- 0.5, 50.3 +/- 0.3, 3.96 +/- 0.02, and 137.3 +/- 1.5, respectively. Overall, the mean levels of LDL-C, TG and TC/HDL-C ratio were higher in men than in women, whereas the mean level of HDL-C was higher in women than in men. The prevalences of hypercholesterolemia (> or =200 mg/dl), elevated LDL-C (> or =130 mg/dl), low HDL-C (<40 mg/dl), and hypertriglyceridemia (> or =150 mg/dl) were 37.5, 44.5, 21.1, and 30.4%, respectively. Prevalences of dyslipidemia were higher in men than in women, except for TC (P < 0.0001). The prevalences of high TC, LDL-C, TG, and TC/HDL-C ratio increased with age, with the highest prevalences in the 60-69-year-old group, and declined thereafter. The prevalences of high TC, LDL-C and TG, a high TC/HDL-C ratio and low HDL-C increased steadily in line with BP, BMI, WC, WHR, and FBG (P < 0.0001). Dyslipidemia was positively associated with marital status, parity, cessation of cigarette smoking and current cigarette use, and alcohol consumption, and negatively associated with the level of education, household income, and physical activity. Multiple logistic regression analysis revealed that dyslipidemia was significantly associated with the factors of age, male gender, BMI, WC (except for TC and LDL-C), HT (only for LDL-C and TG), FBG (only for LDL-C and TG), education level, cigarette smoking (only for HDL-C and TC/HDL-C ratio), alcohol consumption (except for HDL-C and TC/HDL-C ratio), occupation (especially housewives), marital status (widows and widowers), and a family history of selected medical conditions (for only TC). In conclusion, Trabzon Lipid Study data indicate that dyslipidemias are very common and an important health problem among the adult population of Trabzon. To control dyslipidemias, effective public health education and urgent measures are essential.
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PMID:Prevalence of dyslipidemia and associated risk factors among Turkish adults: Trabzon lipid study. 1900 44

ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. The ACL-dependent synthesis of acetyl-CoA is thought to be an essential step for the de novo synthesis of fatty acids and cholesterol. For this reason, inhibition of ACL has been pursued as a strategy to treat dyslipidemia and obesity. Traditionally, ACL enzyme activity is measured indirectly by coupling to enzymes such as malate dehydrogenase or chloramphenicol acetyl transferase. In this report, however, we describe a novel procedure to directly measure ACL enzyme activity. We first identified a convenient method to specifically detect [(14)C]acetyl-CoA without detecting [(14)C]citrate by MicroScint-O. Using this detection system, we devised a simple, direct, and homogeneous ACL assay in 384-well plate format that is suitable for high-throughput screening. The current assay consists of 1) incubation of ACL enzyme with [(14)C]citrate and other substrates/cofactors CoA, ATP, and Mg(2+), 2) EDTA quench, 3) addition of MicroScint-O, the agent that specifically detects product [(14)C]acetyl-CoA, and 4) detection of signal by TopCount. This unique ACL assay may provide more efficient identification of new ACL inhibitors and allow detailed mechanistic characterization of ACL/inhibitor interactions.
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PMID:A novel direct homogeneous assay for ATP citrate lyase. 1928 49

Since the introduction of HAART, there was a remarkably change in the natural history of HIV disease, leading to a notable extension of life expectancy, although prolonged metabolic imbalances could significantly act on the longterm prognosis and outcome of HIV-infected persons, and there is an increasing concern about the cardiovascular risk in this population. Current recommendations suggest that HIV-infected perons undergo evaluation and treatment on the basis of the Third National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) guidelines for dyslipidemia, with particular attention to potential drug interactions with antiretroviral agents and maintenance of virologic control of HIV infection. While a hypolipidemic diet and physical activity may certainly improve dyslipidemia, pharmacological treatment becomes indispensable when serum lipid are excessively high for a long time or the patient has a high cardiovascular risk, since the suspension or change of an effective antiretroviral therapy is not recommended. Moreover, the choice of a hypolipidemic drug is often a reason of concern, since expected drug-drug interactions (especially with antiretroviral agents), toxicity, intolerance, effects on concurrent HIV-related disease and decrease patient adherence to multiple pharmacological regimens must be carefully evaluated. Often the lipid goals of patients in this group are not achieved by the therapy recommended in the current lipid guidelines and in this article we describe other possibilities to treat lipid disorders in HIV-infected persons, like rosuvastatin, ezetimibe and fish oil.
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PMID:New options in the treatment of lipid disorders in HIV-infected patients. 1963 34


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