Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptors (PPARs) belongs to the nuclear hormone receptor superfamily. So far three different subtypes of PPAR (alpha, gamma, and delta (beta)) have been identified in amphibians, chicken, rodents and man. These receptors are transcription factors that control the beta-oxidation and transport pathways of fatty acids and adipocyte differentiation containing fatty acid synthesis under the modification of PPAR activation with CBP and its analogs. Thus, PPARs play an important role in lipid metabolism. Furthermore, altered fatty acid levels are associated with obesity, diabetes, hypertension and atherosclerosis, so PPARs may serve as molecular sensors in these metabolic disorders.
 ...
PMID:[Lipid metabolism related nuclear receptor--the structure, function, expression and classification of peroxisome proliferation-activated receptor (PPAR)]. 970 44

Troglitazone and structurally related compounds (pioglitazone, rosiglitazone etc.) containing thiazolidinediones (TZD) are a novel class of antidiabetic agents which decrease blood glucose in diabetic animal models and in patients with Non-Insulin-Dependent Diabetes Mellitus (NIDDM) through alleviating insulin resistance. A large body of evidence is now accumulating indicating that insulin resistance and/or resulting hyperinsulinemia underlie the pathogenesis of not only diabetes but also of the clustering syndrome called "syndrome X" or "insulin resistance syndrome" which includes hypertension, dislipidemia and hypercoagulation. Therefore, TZD class of insulin sensitizers seem to have therapeutic potential to improve this clustering syndrome in addition to diabetes. Moreover, it was demonstrated that the TZD class of insulin sensitizers including troglitazone bind and activate the peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor. Although PPARgamma is predominantly expressed in adipose tissue, one of the target tissues for insulin, it have been subsequently found to be expressed in macrophages, vascular smooth muscle cells (VSMC), endothelial cells and several cancer cell lines. PPARgamma activation by PPARgamma agonists such as TZD class of insulin sensitizers in these cells modulates these cell functions such as the production of inflammatory cytokine by macrophages, proliferation and migration of VSMC, and growth or differentiation in cancer cells. In addition, troglitazone has potent antioxidant effect, and suppresses both L-type and receptor operated Ca2+ channel and protein kinase C. Thus since TZD class of insulin sensitizers has many kind of therapeutic effect in addition to lowering blood glucose, these agents expect to have therapeutic potential beyond diabetes.
 ...
PMID:Troglitazone and related compounds: therapeutic potential beyond diabetes. 1106 64

Patients with insulin resistance and/or type 2 diabetes have a 5-fold increase in cardiovascular mortality rate. Therefore, it is a current issue of discussion that arterial hypertension, lipid disorders as well as visceral obesity are coronary risk factors, which might belong to a syndrome that is caused by decreased insulin sensitivity. Concerning a possible molecular link between insulin resistance, atherosclerosis and obesity, we focus in our research on questions looking for a molecular link between lipid metabolism, insulin action, and obesity at a gene regulatory level. Alterations in the structure, function and regulation of transcription factors appear to be such signalling steps which might play an essential role in the pathogenesis and therapy of cardiovascular risk factors associated with insulin resistance, eg the so called metabolic syndrome. Recent examples are members of the nuclear hormone receptor superfamily, eg peroxisome proliferator-activated receptor (PPAR) isoforms and sterol regulatory element-binding proteins (SREBPs). Beside their regulation by different metabolites, these transcription factors are also targets of hormones, like insulin and leptin, growth factors, and inflammatory signals. Therefore, they appear to be a point of signalling convergence at a gene regulatory level. Major signalling pathways coupling receptors at the cell surface for hormones, growth factors as well as cytokines to gene regulatory events in the nucleus are the MAP-kinase cascades. We have recently defined different postreceptor defects in these pathways in patients with clinical phenotypes corresponding to congenital lipoatrophy. Therefore, these studies may identify novel pathways which play a role in the control of body weight, insulin sensitivity and cardiovascular risk.
 ...
PMID:Insulin-regulated transcription factors: molecular link between insulin resistance and cardiovascular risk factors. 1146 84

The prenyl-phenol antibiotics ascochlorin-related compounds, are known to reduce serum cholesterol and triglyceride, suppress hypertension, and ameliorate types-I and II diabetes. However, little is known about the molecular mechanism for these physiological effects. Here we report that the ascochlorin derivative, 4-O-carboxymethyl ascochlorin (AS-6) acts as a potent activator of the nuclear hormone receptor, PPARgamma, although it does not activate the related receptors, PPARalpha, PPARdelta or RARalpha. AS-6 interacts directly with the PPARgamma molecule in vitro, and induces differentiation of the mouse preadipocyte cell line 3T3-L1. Our results suggest that AS-6 is a partial agonist for PPARgamma with a novel chemical structure.
 ...
PMID:PPARgamma activation and adipocyte differentiation induced by AS-6, a prenyl-phenol antidiabetic antibiotic. 1206 50

We previously reported a syndrome of severe hyperinsulinemia and early-onset hypertension in three patients with dominant-negative mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-gamma. We now report the results of further detailed pathophysiological evaluation of these subjects, the identification of affected prepubertal children within one of the original families, and the effects of thiazolidinedione therapy in two subjects. These studies 1) definitively demonstrate the presence of severe peripheral and hepatic insulin resistance in the affected subjects; 2) describe a stereotyped pattern of partial lipodystrophy associated with all the features of the metabolic syndrome and nonalcoholic steatohepatitis; 3) document abnormalities in the in vivo function of remaining adipose tissue, including the inability of subcutaneous abdominal adipose tissue to trap and store free fatty acids postprandially and the presence of very low circulating levels of adiponectin; 4) document the presence of severe hyperinsulinemia in prepubertal carriers of the proline-467-leucine (P467L) PPAR-gamma mutation; 5) provide the first direct evidence of cellular resistance to PPAR-gamma agonists in mononuclear cells derived from the patients; and 6) report on the metabolic response to thiazolidinedione therapy in two affected subjects. Although the condition is rare, the study of humans with dominant-negative mutations in PPAR-gamma can provide important insight into the roles of this nuclear receptor in human metabolism.
 ...
PMID:Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. 1266 60

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPARgamma is expressed by macrophages, endothelial cells, and vascular smooth muscle cells. It regulates gene expression of key proteins involved in lipid metabolism, vascular inflammation, and proliferation contributing to atherogenesis and postangioplasty restenosis. The discovery of synthetic ligands for PPARgamma has led to significant enhancement of our understanding of the mechanism of their ligand-dependent activation and subsequent biological effects, particularly with respect to the role of PPARgamma in vascular pathophysiology. The thiazolidinedione PPARgamma agonists not only improve insulin resistance in patients with type II diabetes but also exert a broad spectrum of antiatherogenic effects in vitro and in animal models of atherosclerosis. In this review, we summarize the important role of PPARgamma as a molecular target for thiazolidinediones and its implications for the control of vascular inflammation and proliferation for the cardiovascular system.
Hypertension 2004 Feb
PMID:Peroxisome proliferator-activated receptor gamma: implications for cardiovascular disease. 1473 33

Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Three PPAR isoforms, designated PPARalpha, -beta/delta, and -gamma, have been identified and attracted enormous attention as a result of the key role that these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and BP. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type 2 diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPAR-alpha activators, such as the fibric acid class of hypolipidemic drugs, and PPAR-gamma agonists, including antidiabetic thiazolidinediones, have been proved to be effective for improving diverse aspects of the metabolic syndrome. All three PPAR isoforms seem to play important roles in the development of diabetic nephropathy in type 2 diabetes. Accumulating data suggesting that PPAR may serve as potential therapeutic targets for treating the metabolic syndrome and its related renal complications have begun to emerge. This article reviews the literature pertaining to the action, ligand selectivity, and physiologic role of PPAR. Particular emphasis is placed on their pathogenic roles in the metabolic syndrome and the therapeutic utility of PPAR modulators in the treatment of diabetic nephropathy.
 ...
PMID:Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome. 1550 33

Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear hormone receptor family, is a master regulator of adipogenesis. Humans with dominant negative PPARgamma mutations have features of the metabolic syndrome (severe insulin resistance, dyslipidemia, and hypertension). We created a knock-in mouse model containing a potent dominant negative PPARgamma L466A mutation, shown previously to inhibit wild-type PPARgamma action in vitro. Homozygous PPARgamma L466A knock-in mice die in utero. Heterozygous PPARgamma L466A knock-in (PPARKI) mice exhibit hypoplastic adipocytes, hypoadiponectinemia, increased serum-free fatty acids, and hepatic steatosis. When subjected to high fat diet feeding, PPARKI mice gain significantly less weight than controls. Hyperinsulinemic-euglycemic clamp studies in PPARKI mice revealed insulin resistance and reduced glucose uptake into skeletal muscle. Female PPARKI mice exhibit hypertension independent of diet. The PPARKI mouse provides a novel model for studying the relationship between impaired PPARgamma function and the metabolic syndrome.
 ...
PMID:A dominant negative peroxisome proliferator-activated receptor-gamma knock-in mouse exhibits features of the metabolic syndrome. 1571 67

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand--activated transcription factors. Three PPAR isoforms , designated PPARalpha, -beta/delta, and -gamma, have been identified and attracted enormous attention due to the key role these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation and blood pressure. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type II diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPARalpha activators such as fibric acid class of hypolipidemic drugs and PPARgamma agonists including antidiabetic thiazolidinediones (TZDs) have been proved to be effective for improving metabolic syndrome. All three PPAR isoforms appear to play important roles in the development of type II diabetes and diabetic nephropathy. Accumulating data has begun to emerge suggesting PPARs may serve as potential therapeutic targets for treating the metabolic syndrome and its related complications. Here we review the literature pertaining to the action, ligand selectivity and physiological role of PPARs. Particular emphasis is placed on their pathogenic roles in the metabolic syndrome and the therapeutic utility of PPAR modulators in the treatment of type II diabetes.
 ...
PMID:[PPAR family and its relationship to metabolic syndrome]. 1588 36

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The activation of PPAR-gamma, an isotype of PPARs, can either increase or decrease the transcription of target genes. The genes controlled by this form of PPAR have been shown to encode proteins or peptides that participate in the pathogenesis of insulin resistance. Insulin resistance is defined as a state of reduced responsiveness to normal circulating concentrations of insulin and it often co-exists with central obesity, hypertension, dyslipidemia, and atherosclerosis. There is substantial evidence that links obesity with insulin resistance and type-2 diabetes. The early phase of obesity-related insulin resistance has 2 components: (a) interruption of lipid homeostasis leading to the increased plasma concentration of fatty acids that is normally suppressed by the activation of PPAR-gamma, and (b) activation of factors such as cytokines depressed by PPAR-gamma that cause insulin resistance. Therefore, it is logical to suggest that activation of PPAR-gamma may partially reverse the state of insulin resistance. Evidently, activation of the nuclear receptor, PPAR-gamma, by thiazolidinediones has been reported to ameliorate insulin resistance. Although hepatotoxity and possibility to induce congestive heart failure (CHF) limit the widely use of thiazolodinediones, they are still powerful weapon to fight against insulin resistance and type-2 diabetes if use properly. This article reviews the physiology of PPAR-gamma and insulin-signaling transduction, the pathogenesis of insulin resistance in obesity-related type-2 diabetes, the pharmacological role of PPAR-gamma in insulin resistance, and additional effects of thiazolidinediones.
 ...
PMID:Peroxisome proliferator-activated receptor gamma as a drug target in the pathogenesis of insulin resistance. 1630 9


1 2 3 Next >>