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)

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

Investigating metabolism by unveiling the functions of the nuclear receptors peroxisome proliferator-activated receptors (PPARs) in the numerous intricate pathways ensuring energy homeostasis and fitness has been extremely rewarding. Major lines of research were initially determined by the first-characterized crucial roles of PPARalpha in fatty oxidation and of PPARgamma in adipocyte differentiation and lipid storage. Today, the molecular bases of the functional links between glucose, lipid, and protein metabolism, under the important but nonexclusive control of PPARalpha and PPARgamma, are starting to be uncovered. In addition, in the last couple of years evidence has been provided for an important role of PPARbeta (delta) in lipid metabolism. Inevitably, such actors of metabolic homeostasis are implicated in the physiopathology of complex metabolic disorders, such as those constituting the metabolic syndrome, resulting in atherosclerosis and cardiovascular diseases. This review presents a summary of the recent findings on their dual involvement in health and disease.
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PMID:Be fit or be sick: peroxisome proliferator-activated receptors are down the road. 1508 71

Dietary conjugated linoleic acid (CLA) is being investigated for beneficial effects for disease prevention and treatment in a variety of experimental models, including obesity and type 2 diabetes. To date, rodent studies suggest that trans-10,cis-12 (t10,c12) CLA is associated with greater insulin resistance, despite lower body fat, and that a CLA mixture (and perhaps c9,t11) could be beneficial for the management of insulin resistance. Studies investigating the mechanisms by which CLA operates at the cellular level show that the primary targets for CLA are members of the nuclear receptor family, particularly the lipostat transcription factors peroxisome proliferator-activated receptor alpha (PPARalpha), PPARgamma, sterol regulatory element-binding protein 1c, and liver X receptor alpha. Consequently, the effects of CLA on glucose metabolism are likely secondary effects mediated through factors such as PPARgamma coactivator 1 that are controlled by these nuclear receptors. The different responses of normal compared with insulin-resistant obese rodents suggest that interactions of CLA isomers with the cellular components that contribute to development of metabolic syndrome require further investigation.
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PMID:Dietary conjugated linoleic acid and insulin sensitivity and resistance in rodent models. 1515 52

There is increasing evidence of a parallel progression between insulin resistance and endothelial dysfunction, suggesting a close association between insulin action and the endothelium. Numerous studies have demonstrated that endothelial dysfunction occurs early in the insulin-resistant state and is predictive of future cardiovascular events. Similarly, insulin resistance has been associated with the metabolic syndrome, which also increases the risk of adverse cardiovascular outcomes. Approaches that improve endothelial dysfunction, such as treatment with statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or peroxisome proliferator-activated receptor gamma ligands, have been shown to prevent both diabetes and cardiovascular disease. This article reviews the relation between endothelial dysfunction and cardiovascular disease, assesses the endothelium in the spectrum of insulin resistance, and examines the effect of the thiazolidinediones on endothelial function.
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PMID:Insulin resistance and the endothelium. 1523 47

Although peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have an antihypertensive effect in vivo, the precise mechanism has not been fully elucidated. We examined their effects on Rho/Rho kinase pathway, a key regulator of vascular tone. In cultured rat aortic smooth muscle cells (RASMC), Rho kinase stimulated by angiotensin II was suppressed by the pretreatment with pioglitazone and troglitazone, and these effects were explained by the inhibition of the Rho translocation to the cell membrane. We evaluated the role of Vav, a GTP/GDP exchange factor upregulating Rho kinase activity, and Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2), a protein tyrosine phosphatase that dephosphorylated Vav and subsequently inactivated Rho kinase. Both pioglitazone and troglitazone upregulated SHP-2, particularly in the cytosolic fraction, and the SHP-2-bound Vav, and reduced the phosphorylation of Vav. Furthermore, 4-week treatment with pioglitazone lowered systolic blood pressure in spontaneously hypertensive rats (SHR) and suppressed the Rho/Rho kinase activity in aortic tissues isolated from SHR. Consistently, the expression of SHP-2 was upregulated in vascular tissues from pioglitazone-treated SHR. The phosphorylated Vav was increased in SHR, compared with that in normotensive Wistar-Kyoto rats (WKY), which was mitigated by pioglitazone. Finally, both basal and angiotensin II-stimulated levels of Rho kinase activity were greater in RASMC from SHR than those from WKY, and the enhanced Rho kinase activity was blocked by pioglitazone or troglitazone in both strains. Collectively, PPARgamma ligands inhibit the Rho/Rho kinase pathway through upregulation of cytosolic SHP-2 expression and inactivation of Vav, and may contribute to the hemodynamic, in addition to metabolic, action in hypertensive metabolic syndrome. The full text of this article is available online at http://circres.ahajournals.org.
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PMID:Peroxisome proliferator-activated receptor gamma ligands inhibit Rho/Rho kinase pathway by inducing protein tyrosine phosphatase SHP-2. 1530 80

Here we review PPARgamma function in relation to human adipogenesis, insulin sensitization, lipid metabolism, blood pressure regulation and prothrombotic state to perhaps provide justification for this nuclear receptor remaining a key therapeutic target for the continuing development of agents to treat human metabolic syndrome.
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PMID:Peroxisome proliferator-activated receptor gamma: its role in metabolic syndrome. 1546 47

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.
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PMID:Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome. 1550 33

Familial partial lipodystrophy (FPLD) results from coding sequence mutations either in LMNA, encoding nuclear lamin A/C, or in PPARG, encoding peroxisome proliferator-activated receptor gamma (PPARgamma). The LMNA form is called FPLD2 (MIM 151660), and the PPARG form is called FPLD3 (MIM 604367). We now report a 21-yr-old female with FPLD and no coding sequence mutations in either LMNA or PPARG. She was heterozygous for a novel A>G mutation at position -14 of intron B upstream of PPARG exon 1 within the promoter of the PPARgamma4 isoform. Her less severely affected father, who had features of the metabolic syndrome and a paucity of limb and gluteal fat, was also heterozygous for -14A>G. This mutation was absent among 600 alleles from normal Caucasians. A minimal promoter sequence bearing the mutation had significantly reduced promoter activity when used to drive reporter expression in in vitro expression in two cell lines, compared with the wild-type sequence. This is the first report of a human mutation in the promoter of a PPARgamma isoform. Because the mutation affects PPARgamma4 expression and is associated with FPLD, this implies that PPARgamma4 might be important for fat depot distribution and metabolism in vivo.
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PMID:A single-base mutation in the peroxisome proliferator-activated receptor gamma4 promoter associated with altered in vitro expression and partial lipodystrophy. 1553 25

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors playing important regulatory functions in development and metabolism. PPARalpha and PPARgamma are the most extensively examined and characterized, mainly because they are activated by marketed hypolipidemic and insulin sensitizer compounds, such as fibrates and thiazolidinediones. It has been established that the third member of the family, PPARdelta is implicated in developmental regulations, but until recently, its role in metabolism remained unclear. The availability of specific PPARdelta agonists and of appropriate cellular and animal models revealed that PPARdelta plays a crucial role in fatty acid metabolism in several tissues. Treatment of obese animals with PPARdelta agonists results in normalization of metabolic parameters and reduction of adiposity. Activation of the nuclear receptor promotes fatty acid burning in skeletal muscle and adipose tissue by upregulation of fatty acid uptake, beta-oxidation and energy uncoupling. PPARdelta is also involved in the adaptive metabolic responses of skeletal muscle to environmental changes, such as long-term fasting or physical exercise, by controlling the number of oxidative myofibers. These observations strongly suggest that PPARdelta agonists may have therapeutic usefulness in metabolic syndrome by increasing fatty acid consumption and decreasing obesity.
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PMID:Roles of peroxisome proliferator-activated receptor delta (PPARdelta) in the control of fatty acid catabolism. A new target for the treatment of metabolic syndrome. 1558 93

Diabetes mellitus is increasing worldwide, resulting from the interaction of obesity, inflammation, and hyperglycemia. Activated immunity and cytokine production lead to insulin resistance and other components of the metabolic syndrome, establishing the link between diabetes and atherosclerosis. Hyperglycemia-induced endothelial dysfunction is mediated by increased oxidative stress, a promoter of adventitial inflammation and vasa vasorum neovascularization in experimental models of diabetic atherosclerosis. Recent studies have documented increased inflammation, neovascularization, and intraplaque hemorrhage in human diabetic atherosclerosis. This inflammatory microangiopathic process is independently associated with plaque rupture, leading to coronary thrombosis. Tissue factor, the most potent trigger of the coagulation cascade, is increased in diabetic patients with poor glycemic control. Circulating tissue factor microparticles are also associated with apoptosis of plaque macrophages, closing the link among inflammation, plaque rupture, and blood thrombogenicity. High-density lipoproteins, responsible for free cholesterol removal, are reduced in patients with insulin resistance and diabetes. High-density lipoprotein therapy leads to a significant decrease in plaque macrophages and increase in smooth-muscle cells. These beneficial effects may be responsible for coronary plaque stabilization in patients treated with recombinant Apolipoprotein A-I Milano/phospholipid complex. Finally, peroxisomal proliferator-activated receptors (PPARs) are now considered the nuclear transcriptional regulators of atherosclerosis. Three subfamilies, including PPAR-alpha, -delta, and -gamma, have been identified with crucial roles in lipid metabolism, plaque inflammation, expression of adhesion molecules and cytokines, and regulation of matrix metalloproteinases. Multiple experimental studies have documented plaque stabilization with PPAR-gamma agonists, a group of medications holding great promise in the treatment of diabetes atherosclerosis.
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PMID:New aspects in the pathogenesis of diabetic atherothrombosis. 1560 89


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