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

The mobilization of triacylglycerides from storage in adipocytes to the liver is a vital response to the fasting state in mammalian metabolism. This is accompanied by a rapid translational activation of genes encoding mitochondrial, microsomal, and peroxisomal beta-oxidation in the liver, in part under the regulation of peroxisome proliferator-activated receptor-alpha (PPAR-alpha). A failure to express PPAR-alpha results in profound metabolic perturbations in muscle tissue as well as the liver. These changes represent a number of deficits that accompany diabetes, dyslipidemia, and the metabolic syndrome. In this study, the metabolic role of PPAR-alpha has been investigated in heart, skeletal muscle, liver, and adipose tissue of PPAR-alpha null mice at 1 mo of age using metabolomics. To maximize the coverage of the metabolome in these tissues, (1)H-NMR spectroscopy, magic angle spinning (1)H-NMR spectroscopy, gas chromatography-mass spectrometry, and liquid chromatography-mass spectrometry were used to examine metabolites in aqueous tissue extracts and intact tissue. The data were analyzed by the multivariate approaches of principal components analysis and partial least squares. Across all tissues, there was a profound decrease in glucose and a number of amino acids, including glutamine and alanine, and an increase in lactate, demonstrating that a failure to express PPAR-alpha results in perturbations in glycolysis, the citric acid cycle, and gluconeogenesis. Furthermore, despite PPAR-alpha being weakly expressed in adipose tissue, a profound metabolic perturbation was detected in this tissue.
 ...
PMID:A combined 1H-NMR spectroscopy- and mass spectrometry-based metabolomic study of the PPAR-alpha null mutant mouse defines profound systemic changes in metabolism linked to the metabolic syndrome. 1686 74

Atherogenic dyslipidemia, a component of metabolic syndrome, is characterized by high levels of apolipoprotein B (apo B)-containing lipoproteins, including very-low-density lipoprotein remnants and small low-density lipoprotein particles, and reduced levels of high-density lipoprotein cholesterol. Although the National Cholesterol Education Program Adult Treatment Panel III includes elevations in blood pressure and plasma glucose in the definition of metabolic syndrome, the broader scope of metabolic syndrome includes proinflammatory and prothrombotic states, which derive from the secretory activity of adipose tissue. Abdominal fat can adversely affect insulin action and the disposal of glucose through an increase in the release of free fatty acid, resulting in accumulation of triglyceride in muscle and liver, thereby depressing insulin action and increasing output of apo B-containing lipoproteins. Impaired regulation of adipokines, bioactive substances secreted from adipose tissue, likely produces systemic inflammation, which can promote atherogenesis. Insulin resistance is recognized as an important metabolic defect linking the components of metabolic syndrome. One molecule that may play an important role in metabolic syndrome to regulate metabolic and vascular pathways is the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Studies have established PPAR-gamma deficiency as a cause of lipodystrophy and confirmed its adipogenic role. Patients with atherogenic dyslipidemia and metabolic syndrome should undergo global risk assessment for cardiovascular disease and future cardiovascular events to determine an overall treatment strategy.
 ...
PMID:Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance. 1690 66

The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.
 ...
PMID:Design and synthesis of dual peroxisome proliferator-activated receptors gamma and delta agonists as novel euglycemic agents with a reduced weight gain profile. 1697 Mar 91

The discovery of the crucial role of peroxisome proliferator-activated receptors (PPARs) as regulators of lipid and glucose metabolism has raised interest in the development of synthetic ligands as potential tools for therapeutic intervention in type 2 diabetes and the metabolic syndrome. PPARalpha activators primarily improve dyslipidemia, whereas thiazolidinediones are potent PPARgamma activators that improve insulin resistance. Important research programs to develop agonists that combine the therapeutic effects of both PPARalpha- and PPARgamma-selective agonists, creating the expectation of greater efficacy and other advantages in the treatment of type 2 diabetes and the metabolic syndrome, have therefore been undertaken. Among these dual PPARalpha/gamma agonists, compounds that belong to the glitazar class are in the most advanced stage of development. However, although they demonstrated beneficial impact over selective PPAR agonists by improving both lipid and glucose homeostasis, safety has been a critical issue and has led to the discontinuation of their development because of adverse toxicity profiles. However, the target-related mechanism responsible for the identified safety issues and the relevance of rodent toxicities to the human situation are unclear. Therefore, future development of dual PPARalpha/gamma agonists with selective PPAR modulator activity appears appropriate and should be feasible.
 ...
PMID:PPARalpha and PPARgamma dual agonists for the treatment of type 2 diabetes and the metabolic syndrome. 1697 18

High-fructose consumption is associated with insulin resistance and diabetic dyslipidemia, but the underlying mechanism is unclear. We show in hamsters that high-fructose feeding stimulated forkhead box O1 (FoxO1) production and promoted its nuclear redistribution in liver, correlating with augmented apolipoprotein C-III (apoC-III) production and impaired triglyceride metabolism. High-fructose feeding upregulated peroxisome proliferator-activated receptor-gamma coactivator-1beta and sterol regulatory element binding protein-1c expression, accounting for increased fat infiltration in liver. High-fructose-fed hamsters developed hypertriglyceridemia, accompanied by hyperinsulinemia and glucose intolerance. These metabolic aberrations were reversible by fenofibrate, a commonly used anti-hypertriglyceridemia agent that is known to bind and activate peroxisome proliferator-activated receptor-alpha (PPARalpha). PPARalpha physically interacted with, but functionally antagonized, FoxO1 in hepatic apoC-III expression. These data underscore the importance of FoxO1 deregulation in the pathogenesis of hypertriglyceridemia in high-fructose-fed hamsters. Counterregulation of hepatic FoxO1 activity by PPARalpha constitutes an important mechanism by which fibrates act to curb apoC-III overproduction and ameliorate hypertriglyceridemia.
 ...
PMID:PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1. 1698 62

Type 2 diabetes is a global epidemic contributing to significant cardiovascular morbidity and mortality. The high prevalence of cardiovascular disease can largely be attributed to the metabolic syndrome with its multiple cardiovascular risk factors, including central obesity, hypertension, glucose intolerance, chronic inflammation, and dyslipidemia. The peroxisome proliferator-activated receptor-gamma agonists, the thiazolidinediones, may potentially correct the inflammatory disarray, endothelial dysfunction, dyslipidemia, and plaque vulnerability associated with diabetic cardiovascular disease through their effects on insulin resistance and fat metabolism, yet they can also exacerbate congestive heart failure. This review summarizes basic science, animal, and human data on the effects of thiazolidinediones on cardiovascular disease.
 ...
PMID:Are thiazolidinediones good or bad for the heart? 1707 99

The metabolic syndrome or cardiovascular dysmetabolic syndrome is characterized by obesity, central obesity, insulin resistance, atherogenic dyslipidemia, and hypertension. The major risk factors leading to this syndrome are physical inactivity and an atherogenic diet and cornerstone clinical feature is abdominal obesity or adiposity. In addition, patients usually have elevated triglycerides, low HDL cholesterol, elevated LDL cholesterol, other abnormal lipid parameters, hypertension, and elevated fasting blood glucose. Impaired fibrinolysis, increased susceptibility to thrombotic events, and raised inflammatory markers are also observed. Given that India has the largest number of subjects with type-2 diabetes in the world it can be extrapolated that this country also has the largest number of patients with the metabolic syndrome. Epidemiological studies confirm a high prevalence. Therapeutic approach involves intervention at a macro-level and control of multiple risk factors using therapeutic lifestyle approaches (diet control and increased physical activity, pharmacotherapy - anti-obesity agents) for control of obesity and visceral obesity, and targeted approach for control of individual risk factors. Pharmacological therapy is a critical step in the management of patients with metabolic syndrome when lifestyle modifications fail to achieve the therapeutic goals. Anti-obesity drugs such as sibutramine and orlistat can be tried to reduce weight and central obesity and jointly control the metabolic syndrome components. Other than weight loss, there is no single best therapy and treatment should consist of treatment of individual components of the metabolic syndrome. Newer drugs such as the endocannabinoid receptor blocker,rimonabant, appear promising in this regard. Atherogenic dyslipidemia should be controlled initially with statins if there is an increase in LDL cholesterol. If there are other lipid abnormalities then combination therapy of statin with fibrates, nicotinic acid, or ezetimibe should be considered. For insulin resistance, drugs such as thiazolidinediones and renin-angiotensin system blockers are available. Available evidence suggests that angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBS) may be more beneficial for treatment of hypertension in patients with metabolic syndrome compared to others as these drugs also prevent development of diabetes. Patients with metabolic syndrome also have elevations in fibrinogen and other coagulation factors leading to prothrombotic state and aspirin may be beneficial for primary prevention in these patients. The new developments in the treatment of metabolic syndrome with drugs, such as peroxisome proliferator-activated receptor (PPAR) agonists and cannabinoid receptor-1 antagonists, will broaden the horizons of the current treatment options. Fixed-dose combination polypharmacy using a single pill is an interesting concept that needs to be evaluated in long-term prospective trials in such patients.
 ...
PMID:Management issues in the metabolic syndrome. 1721 77

Type 2 diabetes mellitus is a disease of complex pathogenesis and pleiotropic clinical manifestations. The greatest clinical challenge in this disease is the prevention of the long-term complications, many of which involve cardiovascular outcomes. The peroxisome proliferator-activated receptor (PPAR) alpha and gamma isoforms of the family of nuclear transcription factors are pharmaceutical targets for therapeutic intervention because they can potentially ameliorate not only the hyperglycemia of diabetes, but also the dyslipidemia that is characteristic of this disorder (low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein particles). Novel drugs with dual PPAR alpha and gamma activity have been under clinical development for type 2 diabetes, and they have shown promise in early studies with regard to glucose lowering and improved lipid profile when compared with the PPAR-gamma-specific thiazolidinediones. Unfortunately, the dual PPARs available to date have some of the PPAR-gamma-associated side effect profile, including fluid retention and weight gain, which have limited the further clinical development of higher doses that show improved efficacy. This review will briefly summarize our understanding of the pathogenesis of type 2 diabetes, the role of the PPAR family of receptors, and the potential for clinical use of this novel emerging class of agents that serve as dual activators of both PPAR-alpha and PPAR-gamma.
 ...
PMID:Dual PPAR alpha/gamma agonists: promises and pitfalls in type 2 diabetes. 1730 76

MK-0767, a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, has been studied as a potential treatment of type 2 diabetes and dyslipidemia. The pharmacokinetics and interconversion of (+)-(R)-MK-0767 and (-)-(S)-MK-0767 were evaluated following oral administration of each single enantiomer and the racemate to healthy subjects. The results demonstrate that, consistent with in vitro experiments, chiral inversion occurs rapidly in vivo, and interconversion equilibrium favors (+)-(R). After all treatments, a stable ratio (R/S) of 2 to 2.5 was achieved within 8 hours in most individuals, congruent with model-based estimates of interconversion half-life. In addition, the pharmacokinetics of each enantiomer were generally similar regardless of treatment. Modeling and simulation of enantiomer disposition suggest that the observed predominance of (+)-(R)-MK-0767 in plasma may result from differential volumes of distribution between (-)-(S) and (+)-(R), preferential conversion from (-)-(S) to (+)-(R), or a combination of these, but not faster clearance of (-)-(S) compared to (+)-(R).
 ...
PMID:Human pharmacokinetics and interconversion of enantiomers of MK-0767, a dual PPARalpha/gamma agonist. 1732 44

Fibrates are an important class of drugs for the management of dyslipidemia. This class of drugs is generally well tolerated but is infrequently associated with several safety issues. Fibrates, most likely by an effect mediated by peroxisome proliferator-activated receptor-alpha, may reversibly increase creatinine and homocysteine but are not associated with an increased risk for renal failure in clinical trials. Fibrates are associated with a slightly increased risk (<1.0%) for myopathy, cholelithiasis, and venous thrombosis. In clinical trials, patients without elevated triglycerides and/or low high-density lipoprotein cholesterol (HDL) levels, fibrates are associated with an increase in noncardiovascular mortality. In combination with statins, gemfibrozil generally should be avoided. The preferred option is fenofibrate, which is not associated with an inhibition of statin metabolism. Clinicians are advised to measure serum creatinine before fibrate use and adjust the dose accordingly for renal impairment. Routine monitoring of creatinine is not required, but if a patient has a clinically important increase in creatinine, and other potential causes of creatinine increase have been excluded, consideration should be given to discontinuing fibrate therapy or reducing the dose.
 ...
PMID:Safety considerations with fibrate therapy. 1736 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>