Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance is a principal underlying defect in type 2 DM along with beta-cell dysfunction, and this insulin resistance underpins many of the abnormalities associated with the metabolic syndrome. Peroxisome-proliferator-activated receptor gamma agonists (PPARgamma agonists), also known as glitazones or thiazolidinediones (TZDs) are powerful insulin sensitisers with recent evidence suggesting that they also have a potential to improve pancreatic beta-cell function. TZDs cause a major redistribution of body fat with a decrease in visceral and hepatic fat content with a resultant increase in insulin sensitivity. The glucose lowering effects of TZDs are similar to those seen with the well-established sulphonylureas and metformin. TZDs have a small reducing effect on blood pressure and have been shown to reduce microalbuminuria independent of their blood glucose lowering effect. Both TZDs in clinical practice, pioglitazone and rosiglitazone, reduce small dense LDL-cholesterol and increase HDL-cholesterol levels but pioglitazone would appear to have a more pronounced benefit on these two parameters with a greater reduction in plasma triglycerides. TZDs improved the pro-coagulant state and show benefits in improving endothelial dysfunction and reducing 'non-traditional' inflammatory cytokines and increasing adiponectin levels. The greatest benefit for the TZDs is to directly influence atherogenesis itself and the potential that these so-called pleiotrophic effects of TZDs to reduce cardiovascular events in type 2 DM will be tested when the results of outcome trials are published in the next few years. If the results are positive for the reduction in vascular end-points, then TZDs will represent a major advance in improving the prognosis of type 2 DM subjects with the metabolic syndrome.
Curr Mol Med 2005 May
PMID:The Clinical Significance of PPAR Gamma Agonism. 1589 54

Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in most living organisms. Mice deficient in ACC2 have continuous fatty acid oxidation and reduced body fat and body weight, validating this enzyme as a target for drug development against obesity, diabetes and other symptoms of the metabolic syndrome. ACC is a biotin-dependent enzyme and catalyzes the carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes, whereas it is a large, multi-domain enzyme in most eukaryotes. The activity of the enzyme can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. This review will summarize the structural information that is now available for both the BC and CT enzymes, as well as the molecular mechanism of action of potent ACC inhibitors. The current intense research on these enzymes could lead to the development of novel therapies against metabolic syndrome and other diseases.
Cell Mol Life Sci 2005 Aug
PMID:Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. 1596 60

The goal of the present study was to assess the association between the metabolic syndrome (MS) and certain polymorphisms in genes involved in lipid transport, insulin resistance, intramitochondrial energy transport, appetite control, vasomotor tone, and adipocyte differentiation. The sample was composed of 601 men and 594 women aged 35-64 years recruited in the north of France that were genotyped for the following polymorphisms (SNPs): uncoupling protein, UCP3 -55 C/T; fatty acid transport protein, FATP1 intron 8 +48 G/A; tumor necrosis factor, TNF-alpha -308 G/A; leptin, LEP 5'UTR +19 G/A; and beta3 subunit of G proteins, GNB3 C825T. Waist girth, plasma triglycerides, HDL-cholesterol, glucose and systolic, and diastolic blood pressure were used to define the MS according to the National cholesterol education program (NCEP-III) guidelines. There were 155 (27.4%) men and 124 (21.8%) women who satisfied the NCEP-III criteria and 855 control subjects. By logistic regression using a dominant model (homozygous for the common allele versus carriers of the rare allele), the odds ratio [95% confidence interval] for the MS were: 0.91 [0.68-1.22] for FATP1, 0.93 [0.68-1.28] for TNF-alpha, 0.97 [0.73-1.29] for UCP3, 1.06 [0.80-1.40] for LEP, and 1.12 [0.84-1.48] for GNB3 SNPs. There was no evidence for a gender-specific effect. In conclusion, this study suggests that among a large sample of French men and women, the above named SNPs in UCP3, FATP1, TNF-alpha, LEP, and GNB3 genes are not major contributors to the MS risk.
Mol Genet Metab
PMID:Lack of association between certain candidate gene polymorphisms and the metabolic syndrome. 1597 56

Human obesity-related diabetes and the accompanying metabolic disorders have been specifically linked to increased visceral adipose tissue mass. Understanding the differences in biology of the two human fat depots (visceral and subcutaneous) might hold the key to therapeutic strategies aimed at reducing obesity-induced insulin resistance and alleviating symptoms of the metabolic syndrome. Visfatin (pre-B-cell colony-enhancing factor, PBEF) is a novel adipokine that appears to be preferentially produced by visceral adipose tissue and has insulin-mimetic actions. Could this molecule hold the key to future treatments for type 1 and 2 diabetes? This article discusses the pros and cons of visfatin action and how it might affect future therapeutic strategies.
Trends Mol Med 2005 Aug
PMID:Visfatin: the missing link between intra-abdominal obesity and diabetes? 1600 82

Upstream transcription factor 1 (USF1), the first gene associated with familial combined hyperlipidemia (FCHL), regulates numerous genes of glucose and lipid metabolism. Phenotypic overlap between FCHL, type 2 diabetes and the metabolic syndrome makes this gene an intriguing candidate in the disease process of these traits as well. As no disease-associated mutations in the coding region of USF1 have been identified, we addressed the functional role of intronic single nucleotide polymorphisms (SNPs) which define the FCHL-risk alleles of USF1, and identified that a 20 bp DNA sequence, containing the critical intronic SNP, binds nuclear protein(s), representing a likely transcriptional regulatory element. This functional role is further supported by the differential expression of USF1-regulated genes in fat biopsy between individuals carrying different allelic variants of USF1. Importantly, apolipoprotein E (APOE) is the most downregulated gene in the risk individuals, linking the potential risk alleles of USF1 with the impaired APOE-dependent catabolism of atherogenic lipoprotein particles.
Hum Mol Genet 2005 Sep 01
PMID:USF1 and dyslipidemias: converging evidence for a functional intronic variant. 1607 49

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1), catalyzing the intracellular activation of cortisone to cortisol, is currently considered a promising target to treat patients with metabolic syndrome; hence, there is considerable interest in the development of selective inhibitors. For preclinical tests of such inhibitors, the characteristics of 11beta-HSD1 from the commonly used species have to be known. Therefore, we determined differences in substrate affinity and inhibitor effects for 11beta-HSD1 from six species. The differences in catalytic activities with cortisone and 11-dehydrocorticosterone were rather modest. Human, hamster and guinea-pig 11beta-HSD1 displayed the highest catalytic efficiency in the oxoreduction of cortisone, while mouse and rat showed intermediate and dog the lowest activity. Murine 11beta-HSD1 most efficiently reduced 11-dehydrocorticosterone, while the enzyme from dog showed lower activity than those from the other species. 7-ketocholesterol (7KC) was stereospecifically converted to 7beta-hydroxycholesterol by recombinant 11beta-HSD1 from all species analyzed except hamster, which showed a slight preference for the formation of 7alpha-hydroxycholesterol. Importantly, guinea-pig and canine 11beta-HSD1 displayed very low 7-oxoreductase activities. Furthermore, we demonstrate significant species-specific variability in the potency of various 11beta-HSD1 inhibitors, including endogenous compounds, natural chemicals and pharmaceutical compounds. The results suggest significant differences in the three-dimensional organization of the hydrophobic substrate-binding pocket of 11beta-HSD1, and they emphasize that species-specific variability must be considered in the interpretation of results obtained from different animal experiments. The assessment of such differences, by cell-based test systems, may help to choose the appropriate animal for safety and efficacy studies of novel potential drug candidates.
J Mol Endocrinol 2005 Aug
PMID:Comparative enzymology of 11beta-hydroxysteroid dehydrogenase type 1 from six species. 1608 24

Factors influencing the severity of the metabolic syndrome among obese subjects or the conversion to cardiovascular disease or type 2 diabetes (T2D) remain largely unknown, but there is strong evidence for genetic susceptibilities. Peroxisome proliferator-activated receptor-gamma co-activator-1 (PPARGC1) is a transcriptional co-activator of many nuclear receptors including PPAR-gamma, involved in the regulation of fatty acid oxidation, skeletal muscle fiber type specificity, and gluconeogenesis. Given the critical role of PPARGC1, it becomes a promising candidate gene for the metabolic syndrome and T2D. This study aimed to investigate whether genetic variations in human PPARGC1 gene are associated with metabolic syndrome-related phenotypes and T2D among obese subjects. Molecular screening of the PPARGC1 gene in 24 morbidly obese French-Canadians revealed 13 variants. Eight genetic variations were in introns: c.55-27T>A, c.234+52C>A, c.553-40A>G, c.553-11T>C, c.757+161T>C, c.1793+19C>G, c.2141+192G>A, and c.2293+146A>G, and five were in coding regions: Thr394Thr, Asp475Asp, Gly482Ser, Thr528Thr, and Thr612Met with a relative allele frequency of 18.5, 5.2, 37.0, 42.5, and 6.8%, respectively. Thr394Thr, Asp475Asp, and Thr528Thr were in linkage disequilibrium with the Gly482Ser variant, the only non-synonymous variant with a relative allele frequency of more than 10%. Association studies were performed with the Gly482Ser variant. In non-diabetics, we compared between genotype differences in metabolic syndrome-related traits (waist girth, SBP, DBP, triglycerides, HDL-cholesterol (C), and fasting glucose levels). There was a difference in mean plasma HDL-C concentrations, the Gly/Gly group had lower concentrations than the Gly/Ser group (P<0.05). These results suggest that the Gly482Ser polymorphism may explain some of the between-obese variance observed in metabolic syndrome-related traits.
Mol Genet Metab
PMID:Effects of the peroxisome proliferator-activated receptor-gamma co-activator-1 Gly482Ser variant on features of the metabolic syndrome. 1612 61

Metabolic syndrome is an increasingly prevalent problem, so effective therapeutic approaches to combat it are currently of interest. Recently, orphan ligands with structural similarity to angiopoietins were identified in the systemic circulation, and have been designated angiopoietin-like proteins (Angptls). Angptl3 and Angptl4 have been shown to regulate fat, lipid or glucose metabolic homeostasis. More recently, AGF (also called Angptl6) has been shown to counteract obesity and related insulin resistance. Notably, these factors are secreted mainly from the liver and act as endocrine signals in the peripheral tissues, suggesting a new role for hepatocyte-derived factors in regulating metabolic homeostasis. As more is discovered about the functions of Angptls, so their potential as therapeutic targets for metabolic syndrome is explored.
Trends Mol Med 2005 Oct
PMID:Angiopoietin-like proteins: potential new targets for metabolic syndrome therapy. 1615 86

Our objective was to search for differences in genotypes of peroxisome proliferator-activated receptor gamma (PPARgamma) (Pro12 Ala) and its coactivator PGC-1alpha (Gly482 Ser) in adolescents harboring features of metabolic syndrome. In a population-based study, we determined medical history, anthropometric variables, biochemical measurements and arterial blood pressures of 934 high-school students of Caucasian origin. We selected 220 adolescents who had systolic or diastolic blood pressures more than the 80th or less than the 20th percentiles based on the previous single set of measurements. One hundred and seventy-five adolescents completed the study and underwent two additional blood pressure measurements on different days, as well as biochemical analysis and genotyping. We found no association between insulin resistance, body mass index (BMI) and leptin levels and PPARgamma and PGC-1alpha genotypes. The 12 Ala PPARgamma allele was associated with increased waist-to-hip ratio (WHR) and carriers seemed to have higher diastolic blood pressure and lower pulse pressure than non-carriers, particularly in the hypertensive and overweight group. Although Ser482 Ser PGC-1alpha homozygotes had lower WHRs than other PGC-1alpha genotypes, they were more frequent in the hypertensive group than in the normotensive (44.4 vs 24.5%, P<0.03), so the 482 Ser PGC-1 allele was in our population a risk factor for hypertension independently of WHR, homeostasis model assessment of insulin resistance, BMI and Pro12 Ala PPARgamma variant (odds ratio=4.0, 95% confidence interval 1.5-10.6, P<0.01). Multiple regression analysis showed that age- and sex-adjusted systolic blood pressure correlated with the 482 Ser PGC-1 allele regardless of those covariates. In conclusion, the Gly482 Ser variant of the PGC-1alpha gene may be an independent genetic risk factor for young-onset hypertension.
J Mol Endocrinol 2005 Oct
PMID:Peroxisome proliferator-activated receptor gamma and its coactivator-1 alpha may be associated with features of the metabolic syndrome in adolescents. 1621 16

Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that control key genes involved in fatty acid metabolism and energy homeostasis. Little is known about PPAR activation in vivo and the existence of overlapping functions between PPARalpha, -delta and -gamma. As skeletal muscle is an important site for insulin action and acts as a significant sensor for life-style-induced influences in whole-body energy metabolism, we investigated the expression of PPARalpha, -delta and -gamma in rat skeletal muscle in response to exercise after four- and twelve-weeks of high-fat feeding, respectively. PPARalpha mRNA expression in skeletal muscle increased in parallel with other signs of developing metabolic syndrome such as increased visceral fat pad volymes, plasma free fatty acids and muscle triglyceride concentrations. PPARalpha mRNA expression was up-regulated 3-fold after four weeks of high-fat feeding (p<0.01). Exercise reversed the high-fat induced increase in PPARalpha expression in young lean rats (p<0.05), but did not change the PPARalpha, -delta and -gamma expression in the skeletal muscle in the normal nutritional state. The increase in PPARalpha expression declined during a longer term of high-fat feeding. In contrast, exercise increased PPARdelta mRNA and protein expression 3- to 6-fold in skeletal muscle after longer-term high-fat feeding (p<0.05). This effect was accompanied by a reduction in skeletal muscle fat content. These findings suggest that parallel activation of PPARalpha and -delta expression in skeletal muscle may be an important adaptive mechanism in response to increased fatty acid loads in young, lean animals, protecting them from insulin resistance, whereas exercise might be needed to mediate the same positive effects in older animals.
Int J Mol Med 2006 Jan
PMID:Differential expression of peroxisomal proliferator activated receptors alpha and delta in skeletal muscle in response to changes in diet and exercise. 1632 10


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