Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcriptional coactivator PPAR gamma coactivator 1 alpha (PGC-1alpha) is a key regulator of metabolic processes such as mitochondrial biogenesis and respiration in muscle and gluconeogenesis in liver. Reduced levels of PGC-1alpha in humans have been associated with type II diabetes. PGC-1alpha contains a negative regulatory domain that attenuates its transcriptional activity. This negative regulation is removed by phosphorylation of PGC-1alpha by p38 MAPK, an important kinase downstream of cytokine signaling in muscle and beta-adrenergic signaling in brown fat. We describe here the identification of p160 myb binding protein (p160MBP) as a repressor of PGC-1alpha. The binding and repression of PGC-1alpha by p160MBP is disrupted by p38 MAPK phosphorylation of PGC-1alpha. Adenoviral expression of p160MBP in myoblasts strongly reduces PGC-1alpha's ability to stimulate mitochondrial respiration and the expression of the genes of the electron transport system. This repression does not require removal of PGC-1alpha from chromatin, suggesting that p160MBP is or recruits a direct transcriptional suppressor. Overall, these data indicate that p160MBP is a powerful negative regulator of PGC-1alpha function and provide a molecular mechanism for the activation of PGC-1alpha by p38 MAPK. The discovery of p160MBP as a PGC-1alpha regulator has important implications for the understanding of energy balance and diabetes.
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PMID:Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK. 1474 33

Transcriptional coregulators modulate the activity of transcription factors and are required for the proper regulation of gene expression. One transcriptional coactivator, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), plays an important role in the control of energy metabolism and has been associated with type 2 diabetes. A recent paper by Fan et al. provides new information about the posttranslational regulation of PGC-1alpha activity. This Perspective discusses the implications of these findings with respect to diabetes and aging.
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PMID:Regulation of transcriptional coactivator PGC-1alpha. 1499 29

Estrogen-related receptor alpha (ERRalpha) is one of the first orphan nuclear receptors to be identified, yet its physiological functions are still unclear. We show here that ERRalpha is an effector of the transcriptional coactivator PGC-1alpha [peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha], and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERRalpha compromises the ability of PGC-1alpha to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content. A constitutively active form of ERRalpha is sufficient to elicit both responses. ERRalpha binding sites are present in the transcriptional control regions of ERRalpha/PGC-1alpha-induced genes and contribute to the transcriptional response to PGC-1alpha. The ERRalpha-regulated genes described here have been reported to be expressed at reduced levels in humans that are insulin-resistant. Thus, changes in ERRalpha activity could be linked to pathological changes in metabolic disease, such as diabetes.
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PMID:The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis. 1508 3

Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator implicated in transcriptional programs of hepatic gluconeogenesis, oxidative phosphorylation, and insulin release by beta-cells. To study associations of the PGC-1alpha gene locus with carbohydrate metabolism and type 2 diabetes in humans, we identified several polymorphisms in the promoter region that were located in a haplotype block distinct from a second haplotype block containing part of intron 2 and extending beyond exon 13. Each block contained five common haplotypes. Oral glucose tolerance testing revealed associations of promoter haplotype combinations with 30- and 60-min postload plasma glucose levels, whereas haplotypes in both blocks were associated with indexes of beta-cell function. The associations of promoter haplotypes are supported by functional studies showing that some polymorphisms are located in transcription factor binding sites and affect transactivation in an allele-specific manner. By comparing patients with type 2 diabetes and control subjects, we observed borderline significant differences of four-loci haplotype distributions in the downstream haplotype block. Moreover, the haplotype that was associated with the strongest insulin response to glucose conferred the lowest risk of type 2 diabetes (P < 0.01). Thus, the PGC-1alpha gene locus influences carbohydrate metabolism and contributes to type 2 diabetes in the population studied.
Diabetes 2004 May
PMID:Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes. 1511 10

Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha) is a transcriptional coactivator that is a key component in the regulation of energy production and utilization in metabolic tissues. Recent work has identified PGC-1alpha as a strong coactivator of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha), implicating ERRalpha as a potential mediator of PGC-1alpha action. To understand the role of ERRalpha in PGC-1alpha signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERRalpha small-molecule regulators and target genes. We report here the identification of a potent and selective ERRalpha inverse agonist that interferes effectively with PGC-1alpha/ERRalpha-dependent signaling. This inverse agonist inhibits the constitutive activity of ERRalpha in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERRalpha target gene whose expression is regulated by PGC-1alpha and ERRalpha and inhibited by the ERRalpha inverse agonist. The discovery of potent and selective ERRalpha modulators and their effect on PGC-1alpha signaling provides mechanistic insight into gene regulation by PGC-1alpha. These findings validate ERRalpha as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.
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PMID:Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand. 1518 75

Transcriptional coactivators can be important targets for physiologic regulation. PPARgamma coactivator-1alpha (PGC-1alpha), in cooperation with several transcription factors, has emerged as a key regulator of several aspects of mammalian energy metabolism including mitochondrial biogenesis, adaptive thermogenesis in brown adipose tissue, glucose uptake, fiber type-switching in skeletal muscle, gluconeogenesis in liver and insulin secretion from pancreas. Recent studies have shown a reduced expression of PGC-1alpha in skeletal muscle of diabetic and prediabetic humans. Moreover, expression of PGC-1alpha in white fat cells activates a broad program of adaptive thermogenesis characteristic of brown fat cells. PGC-1alpha could be a target for antiobesity or diabetes drugs. The aim of this article was to summarize the molecular mechanisms and biological programs controlled by the transcriptional coactivator PGC-1alpha.
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PMID:[PGC-1alpha, a transcriptional coactivator involved in metabolism]. 1563 20

Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1--which modulates ageing in several species--controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1alpha. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.
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PMID:Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. 1574 10

Physical activity enhances muscle mitochondrial gene expression, while inactivity and mitochondrial dysfunction are both risk factors for developing diabetes. Defective activation of the transcriptional coactivator PGC-1alpha may contribute to the gene expression pattern observed in diabetic and insulin-resistant skeletal muscle. We proposed that greater insight into the mitochondrial component of skeletal muscle "diabetes" would be possible if the clinical transcriptome data were contrasted with local muscle inactivity-induced modulation of mitochondrial genes in otherwise healthy subjects. We studied PPARGC1A (PGC-1alpha), PPARGC1B (PGC-1beta), NRF1, and a variety of mitochondrial DNA (mtDNA) and nuclear-encoded mitochondrial genes critical for oxidative phosphorylation in soleus muscle biopsies obtained from six healthy men and women before and after 5 weeks of local muscle inactivity. Muscle inactivity resulted in a coordinated down-regulation of PGC-1alpha and genes involved with mitochondrial metabolism, including muscle substrate delivery genes. Decreased expression of the mtDNA helicase Twinkle was related to the decline in mitochondrial RNA polymerase (r = 0.83, p < 0.04), suggesting that mtDNA transcription and replication are coregulated in human muscle tissue. In contrast to the situation in diabetes, PGC-1beta expression was not significantly altered, while NRF1 expression was actually up-regulated following muscle inactivity. We can conclude that reduced PGC-1alpha expression described in Type 2 diabetes may be partly explained by muscle inactivity. Further, although diabetes patients are typically inactive, our analysis indicates that local muscle inactivity may not be expected to contribute to the decreased NRF1 and PGC-1beta expression noted in insulin-resistant and Type 2 diabetes patients, suggesting these changes may be more disease specific.
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PMID:Expression profiling following local muscle inactivity in humans provides new perspective on diabetes-related genes. 1632 70

Among the putative candidate genes for insulin resistance, the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator of PPARgamma and alpha, regulating a wide range of processes involved in energy production and utilization, such as thermogenesis, liver gluconeogenesis, glucose uptake in muscle. In population studies a Gly482Ser substitution in PGC-1alpha has been reported to be associated with increased risk of type diabetes 2 and insulin resistance. In the present study we have analysed the association between the Gly482Ser missense mutation of the PGC-1alpha gene and insulin sensitivity and glucose tolerance in a population of obese non-diabetic subjects. The Gly482Ser SNPs was detected by PCR-RFLP in a cohort of 358 Caucasian obese subjects (223 with normal glucose tolerance (NGT) and 125 with impaired glucose tolerance (IGT). We observed a significant association (p <0.007) between carriers of the Gly482Ser variant of the PGC-1alpha gene and insulin resistance measured by HOMAIR. Multivariate analysis confirmed that the Gly482Ser SNP was a significant (p < 0.02) determinant of decreased insulin sensitivity, independently from other well-known modulators of insulin action. In conclusion, we have found significant association between the Gly482Ser variant of the PGC-1alpha gene and reduced insulin sensitivity in obese subjects. This association resulted independent from all other known modulators of insulin resistance, and suggests a primary role for the PGC-1alpha gene on the genetic susceptibility to insulin resistance in obesity.
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PMID:The Gly482Ser missense mutation of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) gene associates with reduced insulin sensitivity in normal and glucose-intolerant obese subjects. 1640 52

Dietary restriction of calories (caloric restriction [CR]) increases longevity in phylogenetically diverse species. CR retards or prevents age-dependent deterioration of tissues and an array of spontaneous and chemically induced diseases associated with obesity including cardiovascular disease, diabetes, and cancer. An understanding of the molecular mechanisms that underlie the beneficial effects of CR will help identify novel dietary, pharmacological, and lifestyle strategies for slowing the rate of aging and preventing these diseases as well as identify factors which modulate chemical toxicity. Here, we review the involvement of transcriptional coactivator proteins, peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 (PGC-1) alpha and beta, and regulated nuclear receptors (NR) in mediating the phenotypic changes found in models of longevity which include rodent CR models and mouse mutants in which insulin and/or insulin-like growth factor-I signaling is attenuated. PGC-1alpha is transcriptionally or posttranslationally regulated in mammals by: 1) forkhead box "other" (FoxO) transcription factors through an insulin/insulin-like growth factor-I -dependent pathway, 2) glucagon-stimulated cellular AMP (cAMP) response element binding protein, 3) stress-activated kinase signaling through p38 mitogen-activated protein kinase, and 4) the deacetylase and longevity factor sirtuin 1 (SIRT1). PGC-1alpha and PGC-1beta regulate the ligand-dependent and -independent activation of a large number of NR including PPARalpha and constitutive activated receptor (CAR). These NR regulate genes involved in nutrient and xenobiotic transport and metabolism as well as resistance to stress. CR reverses age-dependent decreases in PGC-1alpha, PPARalpha, and regulated genes. Strategies that target one or multiple PGC-1-regulated NR could be used to mimic the beneficial health effects found in models of longevity.
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PMID:Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. 1642 81


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