Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine whether pyruvate dehydrogenase kinase (PDK)4 was expressed in adipocytes and whether PDK4 expression was hormonally regulated in fat cells. Both Northern blot and Western blot analyses were conducted on samples isolated from 3T3-L1 adipocytes after various treatments with prolactin (PRL), growth hormone (GH), and/or insulin. Transfection of PDK4 promoter reporter constructs was performed. In addition, glucose uptake measurements were conducted. Our studies demonstrate that PRL and porcine GH can induce the expression of PDK4 in 3T3-L1 adipocytes. Our studies also show that insulin pretreatment can attenuate the ability of these hormones to induce PDK4 mRNA expression. In addition, we identified a hormone-responsive region in the murine PDK4 promoter and characterized a STAT5 binding site in this region that mediates the PRL (sheep) and GH (porcine) induction in PDK4 expression in 3T3-L1 adipocytes. PDK4 is a STAT5A target gene. PRL is a potent inducer of PDK4 protein levels, results in an inhibition of insulin-stimulated glucose transport in fat cells, and likely contributes to PRL-induced insulin resistance.
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PMID:The STAT5A-mediated induction of pyruvate dehydrogenase kinase 4 expression by prolactin or growth hormone in adipocytes. 1736 Sep 81

Short stature associated with GH deficiency has been estimated to occur in about 1 in 4000 to 1 in 10,000 in various studies. In the last decade new genetic defects have been described in all the levels of the growth hormone-releasing hormone (GH-RH)-GH-IGF (insulin-like growth factor) axis. Genetic defects in the GHRH and in various parts of the Insulin-like growth factor system have been demonstrated. Genetic defects causing isolated GH deficiency (GHD), as well as multiple pituitary hormonal deficiencies have been analysed in detail. Signalling molecules and transcription factors leading to the development of the pituitary gland have been discovered and their function recognized. In animal models and in humans the importance of the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3 has been extensively studied. Genetic alterations of those transcription factors dictate the highly variable phenotype: from isolated hypopituitarism to multiple pituitary hormonal deficiencies with or without malformations (e.g. septo-optic dysplasia or holoprosencephaly). Small for gestational age (SGA) children are increasingly recognized to be a heterogeneous group in which new mechanisms of growth retardation and metabolic disturbances have been proposed. Since SGA is considered to be the main reason for the short stature in 10% of short adults this is a large group with a great potential for novel insights into mechanisms of growth and metabolic disturbances. A group of signalling proteins are involved in prenatal (SGA) growth retardation: IRS-1, PDK1, AKT1, and S6K1. In addition, an attractive modern theory supposes that a disturbed mother-placenta-foetus relation results in the activation of the so-called "thrifty phenotype" of which the IGF system is a vital part. The mechanisms assure short-term postnatal survival in conditions of deficient nutritional supply. However, as a consequence, the abundant postnatal nutritional supply and the "thrifty phenotype" result in increased adult risk of metabolic syndrome, diabetes mellitus type 2 (DM2) and cardiovascular disease. The manuscript reviews in brief genetic alterations in humans leading to growth hormone deficiency (GHD), multiple pituitary hormone deficiencies (MPHD) and SGA.
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PMID:Growth hormone deficiency (GHD) and small for gestational age (SGA): genetic alterations. 2008 48

The pyruvate dehydrogenase complex (PDC) activity is crucial to maintains blood glucose and ATP levels, which largely depends on the phosphorylation status by pyruvate dehydrogenase kinase (PDK) isoenzymes. Although it has been reported that PDC is phosphorylated and inactivated by PDK2 and PDK4 in metabolically active tissues including liver, skeletal muscle, heart, and kidney during starvation and diabetes, the precise mechanisms by which expression of PDK2 and PDK4 are transcriptionally regulated still remains unclear. Insulin represses the expression of PDK2 and PDK4 via phosphorylation of FOXO through PI3K/Akt signaling pathway. Several nuclear hormone receptors activated due to fasting or increased fat supply, including peroxisome proliferator-activated receptors, glucocorticoid receptors, estrogen-related receptors, and thyroid hormone receptors, also participate in the up-regulation of PDK2 and PDK4; however, the endogenous ligands that bind those nuclear receptors have not been identified. It has been recently suggested that growth hormone, adiponectin, epinephrine, and rosiglitazone also control the expression of PDK4 in tissue-specific manners. In this review, we discuss several factors involved in the expressional regulation of PDK2 and PDK4, and introduce current studies aimed at providing a better understanding of the molecular mechanisms that underlie the development of metabolic diseases such as diabetes.
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PMID:Transcriptional regulation of pyruvate dehydrogenase kinase. 2313 Mar 16

Dairy cows mobilise body tissues to support milk production and, because glucose supplies are limited, lipids are used preferentially for energy production. Lipogenic activity is switched off and lipolytic mechanisms in adipose tissue increase through changes in the expression of several key enzymes. This results in a loss of body condition, together with high circulating concentrations of non-esterified fatty acids. Changes in the synthesis, secretion and signalling pathways of somatotrophic hormones (insulin, growth hormone, insulin-like growth factor 1) and adipokines (e.g. leptin) are central to the regulation of these processes. A high reliance on fatty acids as an energy source in the peripartum period causes oxidative damage to mitochondria in metabolically active tissues, including the liver and reproductive tract. The expression of genes involved in insulin resistance (PDK4, AHSG) is increased, together with expression of TIEG1, a transcription factor that can induce apoptosis via the mitochondrial pathway. Polymorphisms in TFAM and UCP2, two autosomal mitochondrial genes, have been associated with longevity in dairy cows. Polymorphisms in many other genes that affect lipid metabolism also show some associations with fertility traits. These include DGAT1, SCD1, DECR1, CRH, CBFA2T1, GH, LEP and NPY. Excess lipid accumulation in oocytes and the regenerating endometrium reduces fertility via reductions in embryo survival and increased inflammatory changes, respectively.
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PMID:Associations between lipid metabolism and fertility in the dairy cow. 2324 28

People are living longer than ever. Consequently, they have a greater chance for developing a functional impairment or aging-related disease, such as a neurodegenerative disease, later in life. Thus, it is important to identify and understand mechanisms underlying aging as well as the potential for rejuvenation. Therefore, we used next-generation sequencing to identify differentially expressed microRNAs (miRNAs) in serum exosomes isolated from young (three-month-old) and old (22-month-old) rats and then used bioinformatics to explore candidate genes and aging-related pathways. We identified 2844 mRNAs and 68 miRNAs that were differentially expressed with age. TargetScan revealed that 19 of these miRNAs are predicated to target the 766 mRNAs. Pathways analysis revealed signaling components targeted by these miRNAs: mTOR, AMPK, eNOS, IGF, PTEN, p53, integrins, and growth hormone. In addition, the most frequently predicted target genes regulated by these miRNAs were EIF4EBP1, insulin receptor, PDK1, PTEN, paxillin, and IGF-1 receptor. These signaling pathways and target genes may play critical roles in regulating aging and lifespan, thereby validating our analysis. Understanding the causes of aging and the underlying mechanisms may lead to interventions that could reverse certain aging processes and slow development of aging-related diseases.
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PMID:Peripheral Circulating Exosomal miRNAs Potentially Contribute to the Regulation of Molecular Signaling Networks in Aging. 3216 75