Home About us Contact
|
Home About us Contact | ||
|
|
||
Metabolic Regulation (metabolic + regulation)
Selected AbstractsAmino acid-dependent modulation of glucose metabolism in humansEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2005M. Krebs Abstract Despite its high prevalence and severe complications, the aetiology of the primary defects leading to Type 2 diabetes mellitus remain unknown. In addition to polygenic predisposition, environmental factors including dietary behaviour are increasingly recognized as being of crucial importance for the development of this disease. This strongly supports the concept that nutrient excess leading to increased availability of substrates adversely influences whole-body metabolic regulation and plays a major role in the development of type 2 diabetes. We have shown previously that a short-term increase in free fatty acid availability impairs glucose metabolism in liver and skeletal muscle. Despite the widespread interest in protein-rich diets, the effects of plasma amino acid elevation on human glucose metabolism have not yet been studied in detail. This editorial summarizes recent advances in the identification of mechanisms responsible for amino acid-dependent modulation of glucose metabolism in liver and skeletal muscle in vivo. [source] Prediction of temporal gene expressionFEBS JOURNAL, Issue 22 2002Metabolic optimization by re-distribution of enzyme activities A computational approach is used to analyse temporal gene expression in the context of metabolic regulation. It is based on the assumption that cells developed optimal adaptation strategies to changing environmental conditions. Time-dependent enzyme profiles are calculated which optimize the function of a metabolic pathway under the constraint of limited total enzyme amount. For linear model pathways it is shown that wave-like enzyme profiles are optimal for a rapid substrate turnover. For the central metabolism of yeast cells enzyme profiles are calculated which ensure long-term homeostasis of key metabolites under conditions of a diauxic shift. These enzyme profiles are in close correlation with observed gene expression data. Our results demonstrate that optimality principles help to rationalize observed gene expression profiles. [source] DNA supercoiling in Escherichia coli is under tight and subtle homeostatic control, involving gene-expression and metabolic regulation of both topoisomerase I and DNA gyraseFEBS JOURNAL, Issue 6 2002Jacky L. Snoep DNA of prokaryotes is in a nonequilibrium structural state, characterized as ,active' DNA supercoiling. Alterations in this state affect many life processes and a homeostatic control of DNA supercoiling has been suggested [Menzel, R. & Gellert, M. (1983) Cell34, 105,113]. We here report on a new method for quantifying homeostatic control of the high-energy state of in vivo DNA. The method involves making small perturbation in the expression of topoisomerase I, and measuring the effect on DNA supercoiling of a reporter plasmid and on the expression of DNA gyrase. In a separate set of experiments the expression of DNA gyrase was manipulated and the control on DNA supercoiling and topoisomerase I expression was measured [part of these latter experiments has been published in Jensen, P.R., van der Weijden, C.C., Jensen, L.B., Westerhoff, H.V. & Snoep, J.L. (1999) Eur. J. Biochem.266, 865,877]. Of the two regulatory mechanisms via which homeostasis is,conferred, regulation of enzyme activity or regulation of enzyme expression, we quantified the first to be responsible for 72% and the latter for 28%. The gene expression regulation could be dissected to DNA gyrase (21%) and to topoisomerase I (7%). On a scale from 0 (no homeostatic control) to 1 (full homeostatic control) we quantified the homeostatic control of DNA supercoiling at 0.87. A 10% manipulation of either topoisomerase I or DNA gyrase activity results in a 1.3% change of DNA supercoiling only. We conclude that the homeostatic regulation of the nonequilibrium DNA structure in wild-type Escherichia coli is almost complete and subtle (i.e. involving at least three regulatory mechanisms). [source] Seasonal dynamics, typhoons and the regulation of lake metabolism in a subtropical humic lakeFRESHWATER BIOLOGY, Issue 10 2008JENG-WEI TSAI Summary 1. We used high-frequency in situ dissolved oxygen measurements to investigate the seasonal variability and factors regulating metabolism in a subtropical alpine lake in Taiwan between May 2004 and October 2005, specifically exploring how the typhoon season (from June or July to October) affects lake metabolism. 2. Gross primary production (GPP) and ecosystem respiration (R) both peaked in early summer and mid-autumn but dropped during the typhoon season and winter. Yuan-Yang Lake is a net heterotrophic ecosystem (annual mean net ecosystem production ,39.6 ,mole O2 m,3). 3. Compared to the summer peaks, seasonal averages of GPP and R decreased by approximately 50% and 25%, respectively, during the typhoon season. Ecosystem respiration was more resistant to external disturbances than GPP and showed strong daily variation during typhoon seasons. 4. Changes in the quality and quantity of dissolved organic carbon controlled the temporal dynamics and metabolic regulation. External disturbances (typhoons) caused increased allochthony, increasing DOC and water colour and influencing lake metabolism. 5. Seasonal winter mixing and typhoon-induced water mixing in summer and autumn play a key role in determining the extent to which the lake is a seasonal carbon sink or source to the atmosphere. [source] Transcription factor HNF and hepatocyte differentiationHEPATOLOGY RESEARCH, Issue 10 2008Masahito Nagaki To know the precise mechanisms underlying the life or death and the regeneration or differentiation of cells would be relevant and useful for the development of a regenerative therapy for organ failure. Liver-specific gene expression is controlled primarily at a transcriptional level. Studies on the transcriptional regulatory elements of genes expressed in hepatocytes have identified several liver-enriched transcriptional factors, including hepatocyte nuclear factor (HNF)-1, HNF-3, HNF-4, HNF-6 and CCAAT/enhancer binding protein families, which are key components of the differentiation process for the fully functional liver. The transcriptional regulation by these HNFs, which form a hierarchical and cooperative network, is both essential for hepatocyte differentiation during mammalian liver development and also crucial for metabolic regulation and liver function. Among these liver-enriched transcription factors, HNF-4 is likely to act the furthest upstream as a master gene in transcriptional cascade and interacts with other liver-enriched transcriptional factors to stimulate hepatocyte-specific gene transcription. A link between the extracellular matrix, changes in cytoskeletal filament assembly and hepatocyte differentiation via HNF-4 has been shown to be involved in the transcriptional regulation of liver-specific gene expression. This review provides an overview of the roles of liver-enriched transcription factors in liver function. [source] The role of PAS kinase in regulating energy metabolismIUBMB LIFE, Issue 4 2008Huai-Xiang Hao Abstract Metabolic disorders, such as diabetes and obesity, are fundamentally caused by cellular energy imbalance and dysregulation. Therefore, understanding the regulation of cellular fuel and energy metabolism is of great importance to develop effective therapies for metabolic disease. The cellular nutrient and energy sensors, AMPK and TOR, play a key role in maintaining cellular energy homeostasis. Like AMPK and TOR, PAS kinase (PASK) is also a nutrient responsive protein kinase. In yeast, PAS kinase phosphorylates the enzyme Ugp1 and thereby shifts glucose partitioning toward cell wall glucan synthesis at the expense of glycogen synthesis. Consistent with this function, yeast PAS kinase is activated by both cell integrity stress and growth in non-fermentative carbon sources. PASK is also important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular level. In cultured pancreatic ,-cells, PASK is activated by elevated glucose concentrations and is required for glucose-stimulated transcription of the insulin gene. PASK knockdown in cultured myoblasts causes increased glucose oxidation and elevated cellular ATP levels. Mice lacking PASK exhibit increased metabolic rate and resistance to diet-induced obesity. Interestingly, PGC-1 expression and AMPK and TOR activity were not affected in PASK deficient mice, suggesting PASK may exert its metabolic effects through a new mechanism. We propose that PASK plays a significant role in nutrient sensing, metabolic regulation, and energy homeostasis, and is a potential therapeutic target for metabolic disease. © 2008 IUBMB IUBMB Life, 60(4): 204,209, 2008 [source] Tissue-specific dysregulation of DNA methylation in agingAGING CELL, Issue 4 2010Reid F. Thompson Summary The normal aging process is a complex phenomenon associated with physiological alterations in the function of cells and organs over time. Although an attractive candidate for mediating transcriptional dysregulation, the contribution of epigenetic dysregulation to these progressive changes in cellular physiology remains unclear. In this study, we employed the genome-wide HpaII tiny fragment enrichment by ligation-mediated PCR assay to define patterns of cytosine methylation throughout the rat genome and the luminometric methylation analysis assay to measure global levels of DNA methylation in the same samples. We studied both liver and visceral adipose tissues and demonstrated significant differences in DNA methylation with age at > 5% of sites analyzed. Furthermore, we showed that epigenetic dysregulation with age is a highly tissue-dependent phenomenon. The most distinctive loci were located at intergenic sequences and conserved noncoding elements, and not at promoters nor at CG-dinucleotide-dense loci. Despite this, we found that there was a subset of genes at which cytosine methylation and gene expression changes were concordant. Finally, we demonstrated that changes in methylation occur consistently near genes that are involved in metabolism and metabolic regulation, implicating their potential role in the pathogenesis of age-related diseases. We conclude that different patterns of epigenetic dysregulation occur in each tissue over time and may cause some of the physiological changes associated with normal aging. [source] Differences in efficient metabolite management and nutrient metabolic regulation between wild and cultivated barley grown at high salinityPLANT BIOLOGY, Issue 4 2010Sabah Yousfi Abstract Physiological and biochemical responses of Hordeum maritimum and H. vulgare to salt stress were studied over a 60-h period. Growth at increasing salinity levels (0, 100, 200 and 300 mM NaCl) was assessed in hydroponic culture. H. maritimum was shown to be a true halophyte via its typical behaviour at high salinity. Shoot growth of cultivated barley was gradually reduced with increasing salinity, whereas that of wild barley was enhanced at 100 and 200 mm NaCl then slightly reduced at 300 mM NaCl. The higher salt tolerance of H. maritimum as compared to H. vulgare was due to its higher capacity to maintain cell turgor under severe salinity. Furthermore, H. maritimum exhibited fine regulation of Na+ transport from roots to shoots and, unlike H. vulgare, it accumulated less Na+ in shoots than in roots. In addition, H. maritimum can accumulate more Na+ than K+ in both roots and shoots without the appearance of toxicity symptoms, indicating that Na+ was well compartmentalized within cells and substituted K+ in osmotic adjustment. The higher degree of salt tolerance of H. maritimum is further demonstrated by its economic strategy: at moderate salt treatment (100 mm NaCl), it used inorganic solutes (such as Na+) for osmotic adjustment and kept organic solutes and a large part of the K+ for metabolic activities. Indeed, K+ use efficiency in H. maritimum was about twofold that in H. vulgare; the former started to use organic solutes as osmotica only at high salinity (200 and 300 mm NaCl). These results suggest that the differences in salt tolerance between H. maritimum and H. vulgare are partly due to (i) differences in control of Na+ transport from roots to shoots, and (ii) H. maritimum uses Na+ as an osmoticum instead of K+ and organic solutes. These factors are differently reflected in growth. [source] Carbon metabolite sensing and signallingPLANT BIOTECHNOLOGY JOURNAL, Issue 6 2003Nigel G. Halford Abstract The regulation of carbon metabolism in plant cells responds sensitively to the levels of carbon metabolites that are available. The sensing and signalling systems that are involved in this process form a complex web that comprises metabolites, transporters, enzymes, transcription factors and hormones. Exactly which metabolites are sensed is not yet known, but candidates include sucrose, glucose and other hexoses, glucose-6-phosphate, trehalose-6-phosphate, trehalose and adenosine monophosphate. Important components of the signalling pathways include sucrose non-fermenting-1-related protein kinase-1 (SnRK1) and hexokinase; sugar transporters are also implicated. A battery of genes and enzymes involved in carbohydrate metabolism, secondary metabolism, nitrogen assimilation and photosynthesis are under the control of these pathways and fundamental developmental processes such as germination, sprouting, pollen development and senescence are affected by them. Here we review the current knowledge of carbon metabolite sensing and signalling in plants, drawing comparisons with homologous and analogous systems in animals and fungi. We also review the evidence for cross-talk between carbon metabolite and other major signalling systems in plant cells and the prospects for manipulating this fundamentally important aspect of metabolic regulation for crop improvement. [source] Functional proteomic view of metabolic regulation in "Aromatoleum aromaticum" strain EbN1PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 13 2007Lars Wöhlbrand Abstract The denitrifying "Aromatoleum aromaticum" strain EbN1 utilizes a wide range of aromatic and nonaromatic compounds under anoxic and oxic conditions. The recently determined genome revealed corresponding degradation pathways and predicted a fine-tuned regulatory network. In this study, differential proteomics (2-D DIGE and MS) was used to define degradation pathway-specific subproteomes and to determine their growth condition dependent regulation. Differential protein profiles were determined for cultures adapted to growth under 22 different substrate and redox conditions. In total, 354 different proteins were identified, 199 of which displayed significantly changed abundances. These regulated proteins mainly represented enzymes of the different degradation pathways, and revealed different degrees of growth condition specific regulation. In case of three substrate conditions (e.g. phenylalanine, anoxic), proteins previously predicted to be involved in their degradation were apparently not involved (e.g. Pdh, phenylacetaldehyde dehydrogenase). Instead, previously not considered proteins were specifically increased in abundance (e.g. EbA5005, predicted aldehyde:ferredoxin oxidoreductase), shedding new light on the respective pathways. Moreover, strong evidence was obtained for thus far unpredicted degradation pathways of three hitherto unknown substrates (e.g. o -aminobenzoate, anoxic). Comparing all identified regulated and nonregulated proteins provided first insights into regulatory hierarchies of special degradation pathways versus general metabolism in strain EbN1. [source] Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models,ANNALS OF NEUROLOGY, Issue 4 2009Carl E. Stafstrom MD Objective Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Because carbohydrates are restricted in patients on the ketogenic diet, we evaluated the effects of limiting carbohydrate availability by reducing glycolysis using the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in experimental models of seizures and epilepsy. Methods Acute anticonvulsant actions of 2DG were assessed in vitro in rat hippocampal slices perfused with 7.5mM [K+]o, 4-aminopyridine, or bicuculline, and in vivo against seizures evoked by 6Hz stimulation in mice, audiogenic stimulation in Fring's mice, and maximal electroshock and subcutaneous pentylenetetrazol (Metrazol) in rats. Chronic antiepileptic effects of 2DG were evaluated in rats kindled from olfactory bulb or perforant path. Results 2DG (10mM) reduced interictal epileptiform bursts induced by 7.5mM [K+]o, 4-aminopyridine, and bicuculline, and electrographic seizures induced by high [K+]o in CA3 of hippocampus. 2DG reduced seizures evoked by 6Hz stimulation in mice (effective dose [ED]50 = 79.7mg/kg) and audiogenic stimulation in Fring's mice (ED50 = 206.4mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a twofold slowing in progression of kindled seizures at both stimulation sites. 2DG did not protect against maximal electroshock or Metrazol seizures. Interpretation The glycolytic inhibitor 2DG exerts acute anticonvulsant and chronic antiepileptic actions, and has a novel pattern of effectiveness in preclinical screening models. These results identify metabolic regulation as a potential therapeutic target for seizure suppression and modification of epileptogenesis. Ann Neurol 2009;65:435,448. [source] Effects of carbon sources on fungal morphology and lovastatin biosynthesis by submerged cultivation of Aspergillus terreusASIA-PACIFIC JOURNAL OF CHEMICAL ENGINEERING, Issue 5 2009Zhihua Jia Abstract The influences of various carbon sources on fungal morphological changes and lovastatin production were investigated in submerged cultivation of a mutant of Aspergillus terreus. Lactose produced the least biomass (2.3 ± 0.15 gDCW l,1); however, the highest maximal specific lovastatin productivity (,max) was obtained. Glycerol achieved the highest lovastatin titer (937.5 ± 12.5 mg l,1), while soluble starch resulted in the highest biomass (12.05 ± 0.05 gDCW l,1) and the second highest lovastatin titer (501.3 ± 23.4 mg l,1). With the carbon source turning to be more easily metabolized, the values of ,max dropped gradually while the corresponding Dp and mean filament ratio rose tardily. The value of ,max (19.8 mg gDCW,1 d,1) was obtained in the presence of lactose while glucose resulted in the least ,max (3.0 mg gDCW,1 d,1). This led to a 6.6-fold decrease. The corresponding Dp and mean filament ratios appeared to reverse the effects, thus producing 1.9 and 3.3-fold increases, respectively. The slowly utilizable carbon sources regulated the lovastatin production through both the inducement of fungal morphology differentiation and the control of metabolic regulation. Copyright © 2009 Curtin University of Technology and John Wiley & Sons, Ltd. [source] A hybrid model of anaerobic E. coli GJT001: Combination of elementary flux modes and cybernetic variablesBIOTECHNOLOGY PROGRESS, Issue 5 2008Jin Il Kim Flux balance analysis (FBA) in combination with the decomposition of metabolic networks into elementary modes has provided a route to modeling cellular metabolism. It is dependent, however, on the availability of external fluxes such as substrate uptake or growth rate before estimates can become available of intracellular fluxes. The framework classically does not allow modeling of metabolic regulation or the formulation of dynamic models except through dynamic measurement of external fluxes. The cybernetic modeling approach of Ramkrishna and coworkers provides a dynamic framework for modeling metabolic systems because of its focus on describing regulatory processes based on cybernetic arguments and hence has the capacity to describe both external and internal fluxes. In this article, we explore the alternative of developing hybrid models combining cybernetic models for the external fluxes with the flux balance approach for estimation of the internal fluxes. The approach has the merit of the simplicity of the early cybernetic models and hence computationally facile while also providing detailed information on intracellular fluxes. The hybrid model of this article is based on elementary mode decomposition of the metabolic network. The uptake rates for the various elementary modes are combined using global cybernetic variables based on maximizing substrate uptake rates. Estimation of intracellular metabolism is based on its stoichiometric coupling with the external fluxes under the assumption of (pseudo-) steady state conditions. The set of parameters of the hybrid model was estimated with the aid of nonlinear optimization routine, by fitting simulations with dynamic experimental data on concentrations of biomass, substrate, and fermentation products. The hybrid model estimations were tested with FBA (based on measured substrate uptake rate) for two different metabolic networks (one is a reduced network which fixes ATP contribution to the biomass and maintenance requirement of ATP, and the other network is a more complex network which has a separate reaction for maintenance.) for the same experiment involving anaerobic growth of E. coli GJT001. The hybrid model estimated glucose consumption and all fermentation byproducts to better than 10%. The FBA makes similar estimations of fermentation products, however, with the exception of succinate. The simulation results show that the global cybernetic variables alone can regulate the metabolic reactions obtaining a very satisfactory fit to the measured fermentation byproducts. In view of the hybrid model's ability to predict biomass growth and fermentation byproducts of anaerobic E. coli GJT001, this reduced order model offers a computationally efficient alternative to more detailed models of metabolism and hence useful for the simulation of bioreactors. [source] Effects of topiramate on weight and metabolism in children with epilepsyACTA PAEDIATRICA, Issue 9 2009Hai-feng Li Abstract Aim:, To explore the mechanism of topiramate-induced weight loss in epilepsy children by monitoring metabolism indices. Methods: Children with epilepsy were treated with topiramate at their first clinical visit. Metabolism indices including body mass index (BMI) and its SD scores, leptin, adiponectin, leptin/adiponectin (L/A), lipid profile-insulin and Homeostasis Model Assessments (HOMA) index were collected before and after treatment. Results:, Topiramate treatment significantly reduced L/A (t = 2.156, p = 0.031), and markedly increased the serum level of adiponectin (t = 3.124, p = 0.002). Moreover, there were no relationships between the metabolism indices and dosages of topiramate (p > 0.05). Conclusion:, Our studies find that topiramate treatment in epilepsy children increases energy metabolism, resulting in weight loss. It has been demonstrated that adiponectin play a significant role in metabolic regulations. [source] | ||||||||||||||||