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)

Fibrates and glitazones are two classes of drugs currently used in the treatment of dyslipidemia and insulin resistance (IR), respectively. Whereas glitazones are insulin sensitizers acting via activation of the peroxisome proliferator-activated receptor (PPAR) gamma subtype, fibrates exert their lipid-lowering activity via PPARalpha. To determine whether PPARalpha activators also improve insulin sensitivity, we measured the capacity of three PPARalpha-selective agonists, fenofibrate, ciprofibrate, and the new compound GW9578, in two rodent models of high fat diet-induced (C57BL/6 mice) or genetic (obese Zucker rats) IR. At doses yielding serum concentrations shown to activate selectively PPARalpha, these compounds markedly lowered hyperinsulinemia and, when present, hyperglycemia in both animal models. This effect relied on the improvement of insulin action on glucose utilization, as indicated by a lower insulin peak in response to intraperitoneal glucose in ciprofibrate-treated IR obese Zucker rats. In addition, fenofibrate treatment prevented high fat diet-induced increase of body weight and adipose tissue mass without influencing caloric intake. The specificity for PPARalpha activation in vivo was demonstrated by marked alterations in the expression of PPARalpha target genes, whereas PPARgamma target gene mRNA levels did not change in treated animals. These results indicate that compounds with a selective PPARalpha activation profile reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR.
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PMID:Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. 1082 60

Excess tissue glucocorticoid action may underlie the dyslipidemia, insulin resistance, and impaired glucose tolerance of the metabolic syndrome. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyzes conversion of circulating inert 11-dehydrocorticosterone into active corticosterone, thus amplifying local intracellular glucocorticoid action, particularly in liver. The importance of 11beta-HSD-1 in glucose homeostasis is suggested by the resistance of 11beta-HSD-1(-/-) mice to hyperglycemia upon stress or obesity, due to attenuated gluconeogenic responses. The present study further investigates the metabolic consequences of 11beta-HSD-1 deficiency, focusing on the lipid and lipoprotein profile. Ad lib fed 11beta-HSD-1(-/-) mice have markedly lower plasma triglyceride levels. This appears to be driven by increased hepatic expression of enzymes of fat catabolism (carnitine palmitoyltransferase-I, acyl-CoA oxidase, and uncoupling protein-2) and their coordinating transcription factor, peroxisome proliferator-activated receptor-alpha (PPARalpha). 11beta-HSD-1(-/-) mice also have increased HDL cholesterol, with elevated liver mRNA and serum levels of apolipoprotein AI. Conversely, liver Aalpha-fibrinogen mRNA levels are decreased. Upon fasting, the normal elevation of peroxisome proliferator-activated receptor-alpha mRNA is lost in 11beta-HSD-1(-/-) mice, consistent with attenuated glucocorticoid induction. Despite this, crucial oxidative responses to fasting are maintained; carnitine palmitoyltransferase-I induction and glucose levels are similar to wild type. Refeeding shows exaggerated induction of genes encoding lipogenic enzymes and a more marked suppression of genes for fat catabolism in 11beta-HSD-1(-/-) mice, implying increased liver insulin sensitivity. Concordant with this, 24-h refed 11beta-HSD-1(-/-) mice have higher triglyceride but lower glucose levels. Further, 11beta-HSD-1(-/-) mice have improved glucose tolerance. These data suggest that 11beta-HSD-1 deficiency produces an improved lipid profile, hepatic insulin sensitization, and a potentially atheroprotective phenotype.
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PMID:Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. 1154 66

An exciting and rapidly evolving area in vascular biology and atherosclerosis research over the past 3 years has been the establishment of peroxisome proliferator-activated receptor (PPAR) expression in the vascular and inflammatory cells, and the emerging picture of the roles these ligand-activated nuclear receptor/transcription factors might play in vascular biology and atherosclerosis. Such work is all the more compelling given the ongoing clinical use of PPAR activators in patients. Thiazolidinediones (PPAR-g agonists) are used as insulin sensitizers in diabetic patients known to be at extraordinarily high risk for cardiovascular disease, whereas fibrates (PPAR-a agonists) are used to treat dyslipidemia, particularly in the case of high triglycerides and low high-density lipoprotein cholesterol.
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PMID:Peroxisome proliferator-activated receptors. 1177 24

Familial partial lipodystrophies (FPL) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia. Recently, lamin A/C gene mutations were found in patients with FPL, Dunnigan variety. However, the genetic basis of other phenotypes remains unknown. We studied peroxisome proliferator-activated receptor-gamma (PPARgamma) gene as a candidate gene in seven FPL patients who did not appear to have Dunnigan variety. Analysis of the coding region of PPARG revealed C to T heterozygous mutation at nucleotide 1273 in exon 6 which changes a highly conserved residue, arginine at position 425 to cysteine (R425C) in the patient FX200.21. The patient is a 64-year-old nonHispanic white woman who developed diabetes mellitus and hypertriglyceridemia at age 32 years and lipodystrophy of the extremities and face at age 50 years. She also had hirsutism. Anthropometry and whole body magnetic resonance imaging revealed marked loss of sc fat particularly from the extremities but sc truncal fat was slightly increased. None of the four unaffected family members harbored the mutation. We conclude that heterozygous, R425C, mutation in PPARG could be the molecular basis for one of the familial partial lipodystrophy phenotypes.
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PMID:A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. 1178 85

The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPAR gamma, PPAR alpha, and PPAR delta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.
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PMID:The mechanisms of action of PPARs. 1181 83

In the last few years there has been an explosion of research that has improved our understanding of the pathogenesis of Type 2 diabetes mellitus (DM-2) and has led to the development of new oral antidiabetic drugs. Thiazolidinediones (TZDs) are the newest of these antidiabetic agents. TZDs are insulin sensitisers that depend on the presence of insulin for their action. They target insulin resistance, which is thought to play a central role in DM-2 and the associated metabolic syndrome characterised by central obesity, hypertension, dyslipidemia and hypercoagulability, all leading to increased cardiovascular morbidity and mortality. As a result, TZDs have the potential to improve other conditions associated with the metabolic syndrome, in addition to their glycaemic action. TZDs act by activating peroxisome proliferator-activated receptor (PPAR) phi a nuclear receptor implicated not only in lipid and glucose metabolism but other physiological functions as well. TZDs may have wide clinical applications beyond DM-2, as they can potentially be used to treat other conditions associated with insulin resistance and PPAR-phi receptors, such as impaired glucose tolerance, polycystic ovarian syndrome and HIV lipodystrophy.
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PMID:Thiazolidinediones in the treatment of type 2 diabetes. 1199 32

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor isoforms, including PPARgamma, PPARalpha, and PPARdelta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors increasing the rate of transcription initiation. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Natural ligands for the PPARs include fatty acids and eicosanoids. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, are effective in the treatment of dyslipidemia and diabetes. Use of selective ligands led to the discovery of additional potential roles for the PPARs in pathological states, including atherosclerosis, inflammation, and hypertension. This review provides an overview of the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.
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PMID:Physiological and therapeutic roles of peroxisome proliferator-activated receptors. 1207 20

Dyslipidaemia is a major risk factor in the development of atherosclerosis, and lipid lowering is achieved clinically using fibrate drugs and statins. Fibrate drugs are ligands for the fatty acid receptor peroxisome proliferator-activated receptor (PPAR)alpha, and the lipid-lowering effects of this class of drugs are mediated by the control of lipid metabolism, as directed by PPARalpha. PPARalpha ligands also mediate potentially protective changes in the expression of several proteins that are not involved in lipid metabolism, but are implicated in the pathogenesis of heart disease. Clinical studies with bezafibrate and gemfibrozil support the hypothesis that these drugs may have a significant protective effect against cardiovascular disease. The thiazolidinedione group of insulin-sensitising drugs are PPARgamma ligands, and these have beneficial effects on serum lipids in diabetic patients and have also been shown to inhibit the progression of atherosclerosis in animal models. However, their efficacy in the prevention of cardiovascular-associated mortality has yet to be determined. Recent studies have found that PPARdelta is also a regulator of serum lipids. However, there are currently no drugs in clinical use that selectively activate this receptor. It is clear that all three forms of PPARs have mechanistically different modes of lipid lowering and that drugs currently available have not been optimised on the basis of PPAR biology. A new generation of rationally designed PPAR ligands may provide substantially improved drugs for the prevention of cardiovascular disease.
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PMID:Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis. 1216 27

Insulin resistance is a major contributor to the pathogenesis of type 2 diabetes and plays a key role in associated metabolic abnormalities, such as dyslipidemia and hypertension. Obesity, especially visceral adiposity, is negatively correlated with insulin sensitivity. The release of free fatty acids from adipocytes can block insulin-signaling pathways and lead to insulin resistance. In addition, recently identified adipocyte-specific chemical messengers, the adipocytokines, such as tumor necrosis factor-alpha, adiponectin, and resistin, appear to modulate the underlying insulin resistance. When insulin resistance is combined with beta-cell defects in glucose-stimulated insulin secretion, impaired glucose tolerance, hyperglycemia, or type 2 diabetes can result. The thiazolidinediones are potent peroxisome proliferator-activated receptor-gamma agonists and directly improve insulin resistance and glycemic control in patients with type 2 diabetes. Increasing evidence supports the early use of thiazolidinediones for preventing, delaying, or treating diabetes by improving insulin sensitivity and beta-cell insulin secretion.
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PMID:Insulin resistance as the core defect in type 2 diabetes mellitus. 1223 Oct 73

The insulin resistance syndrome, a cluster of metabolic abnormalities involving dyslipidemia, hypertension, diabetes, impaired glucose tolerance, and hypercoagulability, carries an increased risk of atherosclerosis. Although interventions targeting elements of this syndrome have dramatically reduced cardiovascular risk, the impact of glucose-lowering has been more disappointing. Thiazolidinediones (TZDs) are a new class of insulin-sensitizing agents that activate the nuclear receptor peroxisome proliferator-activated receptor-g. TZDs may improve not only glucose levels but also other metabolic parameters associated with insulin resistance. The TZD data are reviewed, with a focus on their potential cardiovascular effects.
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PMID:Insulin resistance, diabetes, and atherosclerosis: thiazolidinediones as therapeutic interventions. 1237 75


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