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)

Dietary fatty acid (FA) absorption across the gastrointestinal (GI) tract is of critical importance for sustenance, however, excessive FA absorption has also been linked to metabolic syndrome and associated disorders. The expression of isoforms that regulate the dietary FA absorption are not as well characterized in the GI tract as they are elsewhere. Peroxisome proliferator-activated receptors (PPARalpha, beta, and gamma) and 9-cis-retinoic acid receptors (RXRalpha, beta, and gamma) are nuclear hormone transcription factors that control FA homeostasis, in part through the regulation of expression of membrane-bound FA transporting proteins. The present study was designed to elucidate the expression of PPAR and RXR isoforms and FA transporting proteins (FABPpm and FAT/CD36) in the rat and human GI tracts using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemical staining. The results revealed rat GI expression of all the PPAR and RXR isoforms, FABPpm and FAT/CD36. PPARalpha, PPARbeta, PPARgamma, RXRalpha, FABPpm, and FAT/CD36 isoforms exhibited ubiquitous expression in human GI tract, whereas RXRbeta was not detected. RXRgamma was observed in a majority of the human GI samples. These results provide a physiological foundation for rational drug design and drug delivery for the mitigation of metabolic syndrome and associated disorders to normalize intestinal FA absorption.
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PMID:Expression of PPAR, RXR isoforms and fatty acid transporting proteins in the rat and human gastrointestinal tracts. 1561 17

The peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) is a novel transcriptional co-activator that holds an important role in lipid and glucose metabolism. PGC-1alpha is a candidate gene for the metabolic syndrome (MS) as well as type 2 diabetes. Recent studies suggested linkage between the chromosomal region of PGC-1alpha and fasting serum insulin levels, and associates a Gly482Ser polymorphism of the gene with type 2 diabetes and hypertension. In this study, we investigated whether the Gly482Ser variant is associated with the MS per se or other phenotypic traits related to this syndrome. The variant was examined, using PCR-RFLP, in the DanMONICA cohort comprising a population-based sample of 2349 subjects. MS was defined using the National Cholesterol Education Program -- Adult Treatment Panel III (NCEP-ATPIII) criteria. The allelic frequency of the Ser482 allele was 35.8% in the MS group and 35.6% in the non-MS group (P = 0.74). There were no significant differences across the three groups of genotypes with respect to any of the examined variables, including BMI, waist, fasting serum lipids, plasma glucose, serum insulin, HOMA estimates of insulin resistance and insulin secretion, 24-ambulatory blood pressure or left ventricular mass index. In conclusion, the Gly482Ser polymorphism of the PGC-1alpha gene is not associated with the metabolic syndrome, related quantitative traits or cardiac hypertrophy among Danish Caucasian subjects.
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PMID:Studies of the Gly482Ser polymorphism of the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) gene in Danish subjects with the metabolic syndrome. 1564 78

The consequence of activating the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), which coordinates adipocyte differentiation, validates the concept, 'you are what you eat'. Excessive caloric intake leads to fat formation if the energy from these nutrients is not expended. However, this evolutionary adaptation to store energy in fat, which can be released under the form of fatty acids, potent PPARgamma agonists, has become a disadvantage in today's affluent society as it results in numerous metabolic imbalances, collectively known as the metabolic syndrome. With the surge of human and genetic studies on PPARgamma function, the limitations to the benefits of PPARgamma signalling have been realized. It is now evident that the most effective strategy for resetting the balance of this thrifty gene is through its modulation rather than full activation, with the goal to improve glucose homeostasis while preventing adipogenesis. Finally, as more PPARgamma targeted pathways are revealed such as bone homeostasis, atherosclerosis and longevity, it is most certain that the PPARgamma thrifty gene hypothesis will evolve to incorporate these.
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PMID:Peroxisome proliferator-activated receptor gamma: the more the merrier? 1566 78

Progresses in molecular biology have highlighted the central role of adipocytes in the development of obesity and other nutrition based disorders. Adipocytes, by virtue of their excellent and sensitive molecular machinery, seem to reflect nutritional alterations very precisely. Adipocyte determination and differentiation factor 1 (ADD1)/sterol regulatory element binding protein-1c (SREBP-1c), which is the main transcription factor, regulates the characteristic features of adipocyte, senses the glucose and fat excess and draws the excess into the adipocyte to preserve energy, and maintains the blood biochemistry within physiological ranges. ADD1/SREBP-1c has regulatory functions via transactivation over the other important mature adipocyte markers such as leptin, peroxisome proliferator-activated receptor gamma (PPARgamma) and lipogenic enzymes. In this paper, considering to the role of ADD1/SREBP-1c on adipogenic markers, two new concepts have been defined: the first is sensitive adipocyte, implying a fat cell that functions perfectly at molecular level; and the second is adipocyte insensitivity syndrome (AIS), in which deviations from the optimal function of adipocyte leads to various metabolic abnormalities. The two extreme ends for adipocyte function; obesity and lipodystrophy, and intermediate spectrums between these are categorized into four subgroups. According to this categorization, responses of adipogenic markers to the stimulation of the master transcription factor, ADD1/SREBP-1c might be different in adipocytes: higher lipogenic enzymes activities in type I AIS, insufficient transactivation of leptin in type II AIS, failure in the expression of PPARgamma in type III AIS, and insufficient increases of lipogenic enzymes in type IV AIS. The novel AIS classification, which asserts that the adipocyte has a central importance for the development of metabolic devastating diseases like obesity, metabolic syndrome, type 2 diabetes and atherosclerosis, provides simpler but effective answers for the puzzle by unifying the recent, good quality studies and points out to new therapeutic approaches, highlighting the possible molecular defects.
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PMID:Adipocyte insensitivity syndromes -- novel approach to nutritional metabolic problems including obesity and obesity related disorders. 1569 4

Familial partial lipodystrophy (FPLD) is characterized by adipose tissue repartitioning with multiple metabolic disturbances, including insulin resistance and dyslipidemia. Classical FPLD results from mutations in LMNA encoding nuclear lamin A/C (FPLD2), but recently some families with partial lipodystrophy and normal LMNA sequence were found to have germline mutations in PPARgamma (FPLD3). For instance, all four affected subjects in a three-generation Canadian FPLD3 kindred ascertained based upon a clinical diagnosis of partial lipodystrophy were heterozygous for the PPARgamma F388L mutation, which altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPARgamma. The mutation was absent from normal subjects, and functional studies showed that the mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by rosiglitazone, with no evidence of a dominant-negative mechanism. Other reported FPLD3 patients with mutant PPARgamma were ascertained either directly based on a clinical diagnosis of lipodystrophy (R425C mutation), or based on insulin resistance with subsequent demonstration of lipodystrophy (V290M and P467L mutations). Compared to subjects with mutant LMNA, lipodystrophic subjects with mutant PPARgamma had less severe adipose involvement, together with more severe clinical and biochemical manifestations of insulin resistance, and more variable response to treatment with thiazolidinediones. Thus, rare natural mutations affecting PPARgamma ligand binding and/or transactivation functions cause partial lipodystrophy, with associated components that resemble the metabolic syndrome.
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PMID:Lessons from human mutations in PPARgamma. 1571 81

The cardiovascular complications of metabolic syndrome are induced by unfavorable environmental and genetic factors. One of the most important genes under consideration codes peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear transcription factor which has wide influence on metabolism. The activation of PPARg controls glycemia, lipidemia, adipogenesis, and endothelium function and diminishes insulin resistance. This review discusses the role of the most frequent mutations of the ppargamma gene in metabolic syndrome: Pro467Leu and Val290Met, which are connected with severe insulin resistance, Pro115Gln, which is connected with obesity, and Pro12Ala, which can influence the development of diabetes or hypertension.
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PMID:[Mutations of peroxisome proliferator-activated receptor gamma (PPARgamma): clinical implications]. 1576 9

The metabolic syndrome is a worldwide epidemic, setting the stage for type 2 diabetes and its microvascular complications, and acceleration of macrovascular disease. Insulin resistance, hyperglycemia, dyslipidemia, hypertension, thrombotic disorders and adiposity define the metabolic syndrome and contribute to endothelial dysfunction and, subsequently, to accelerated atherosclerosis. Angiotensin II contributes to the development and progression of cardiovascular and renal endpoints and, as such, angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors demonstrate a protective effect. Ligands for the peroxisome proliferator-activated receptor gamma (PPAR gamma), appear to impact favourably on atherosclerosis through both direct and indirect mechanisms. In humans, these ligands improve endothelial function, attenuate albuminuria and hypertension, and potentially prevent conversion of prediabetes to type 2 diabetes. Statins also have proven benefit in decreasing overall cardiovascular and stroke mortality and morbidity. The combination of angiotensin II blockade, statin therapy and PPAR gamma activation might emerge as an important global therapeutic strategy in the metabolic syndrome and diabetes. Further studies are needed to determine whether they have synergistic effects to protect the vasculature.
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PMID:Metabolic syndrome-interdependence of the cardiovascular and metabolic pathways. 1578 Aug 21

Local glucocorticoid (GC) action depends on intracellular GC metabolism by 11beta-hydroxysteroid dehydrogenases (11betaHSDs). 11betaHSD1 activates GCs, while 11betaHSD2 inactivates GCs. Adipocyte-specific amplification of GCs through transgenic overexpression of 11betaHSD1 produces visceral obesity and the metabolic syndrome in mice. To determine whether adipocyte-specific inactivation of GCs protects against this phenotype, we created a transgenic model in which human 11betaHSD2 is expressed under the control of the murine adipocyte fatty acid binding protein (aP2) promoter (aP2-h11betaHSD2). Transgenic mice have increased 11betaHSD2 expression and activity exclusively in adipose tissue, with the highest levels in subcutaneous adipose tissue, while systemic indexes of GC exposure are unchanged. Transgenic mice resist weight gain on high-fat diet due to reduced fat mass accumulation. This improved energy balance is associated with decreased food intake, increased energy expenditure, and improved glucose tolerance and insulin sensitivity. Adipose tissue gene expression in transgenic mice is characterized by decreased expression of leptin and resistin and increased expression of adiponectin, peroxisome proliferator-activated receptor gamma, and uncoupling protein 2. These data suggest that reduction of active GCs exclusively in adipose tissue is an important determinant of a favorable metabolic phenotype with respect to energy homeostasis and the metabolic syndrome.
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PMID:Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity. 1579 40

Peroxisome proliferator-activated receptors (PPAR) mediate some of the transcriptional effects of fatty acids and control many physiological functions, especially in the field of development and metabolism. Three isotypes are known, alpha, gamma, and B/delta. Roles of PPAR alpha and PPARgamma are now quite well-known, particularly since their pharmacologic ligands have been marketed, respectively the lipid-normalizing class of fibrates and the antidiabetic class of thiazolidinediones (glitazones). However, functions of PPARdelta are uncompletely known to date, but some recent data enlight its role in the regulation of fatty acid oxidation in several tissues, such as skeletal muscle and adipose tissue. Overexpression of PPARdelta using a transgenic murine model promotes an increase of muscle oxidative capability. This is accompanied by a redistribution of fatty acid flux, redirected from adipose tissue towards skeletal muscle. Finally, adipose mass is reduced, due to a decreased adipocyte size. These data strongly suggest that PPARdelta play a major role in the metabolic adaptations to western diet characterized by an excessive amount of saturated fat. Considering the metabolic properties of the two other PPAR isotypes, alpha and gamma, it is likely that the three PPAR isotypes have complementary effects in the pathophysiology of obesity and metabolic syndrome. Future therapeutical perspectives in this field should consider combined treatment, adding delta agonists (for all that their safety will be established) to the already available alpha and gamma agonists.
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PMID:PPAR delta: an uncompletely known nuclear receptor. 1580 9

Although 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, Rho kinase activated by angiotensin II was suppressed by the pretreatment with pioglitazone and troglitazone. The roles of Vav, a GTP/GDP exchange factor upregulating Rho kinase activity, and SHP-2, protein tyrosine phosphatase that dephosphorylated Vav and subsequently inactivated Rho kinase were examined. Both pioglitazone and troglitazone upregulated SHP-2, particularly in the cytosolic fraction, and the SHP-2-bound Vav, and reduced the phosphorylation of Vav. These mechanisms may contribute to the hemodynamic, in addition to metabolic, action by PPARgamma ligands in hypertensive, metabolic syndrome.
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PMID:[Anti-hypertensive effects of PPARgamma ligands through the inhibition of Rho/Rho kinase pathway]. 1582 39


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