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Sample records for alter glycerolipid metabolism

  1. Chemical modulation of glycerolipid signaling and metabolic pathways

    PubMed Central

    Scott, Sarah A.; Mathews, Thomas P.; Ivanova, Pavlina T.; Lindsley, Craig W.; Brown, H. Alex

    2014-01-01

    Thirty years ago, glycerolipids captured the attention of biochemical researchers as novel cellular signaling entities. We now recognize that these biomolecules occupy signaling nodes critical to a number of physiological and pathological processes. Thus, glycerolipid-metabolizing enzymes present attractive targets for new therapies. A number of fields—ranging from neuroscience and cancer to diabetes and obesity—have elucidated the signaling properties of glycerolipids. The biochemical literature teems with newly emerging small molecule inhibitors capable of manipulating glycerolipid metabolism and signaling. This ever-expanding pool of chemical modulators appears daunting to those interested in exploiting glycerolipid-signaling pathways in their model system of choice. This review distills the current body of literature surrounding glycerolipid metabolism into a more approachable format, facilitating the application of small molecule inhibitors to novel systems. PMID:24440821

  2. Reversing diet-induced metabolic dysregulation by diet switching leads to altered hepatic de novo lipogenesis and glycerolipid synthesis.

    PubMed

    Kowalski, Greg M; Hamley, Steven; Selathurai, Ahrathy; Kloehn, Joachim; De Souza, David P; O'Callaghan, Sean; Nijagal, Brunda; Tull, Dedreia L; McConville, Malcolm J; Bruce, Clinton R

    2016-01-01

    In humans, low-energy diets rapidly reduce hepatic fat and improve/normalise glycemic control. Due to difficulties in obtaining human liver, little is known about changes to the lipid species and pathway fluxes that occur under these conditions. Using a combination of stable isotope, and targeted metabolomic approaches we investigated the acute (7-9 days) hepatic effects of switching high-fat high-sucrose diet (HFD) fed obese mice back to a chow diet. Upon the switch, energy intake was reduced, resulting in reductions of fat mass and hepatic triacyl- and diacylglycerol. However, these parameters were still elevated compared to chow fed mice, thus representing an intermediate phenotype. Nonetheless, glucose intolerance and hyperinsulinemia were completely normalized. The diet reversal resulted in marked reductions in hepatic de novo lipogenesis when compared to the chow and HFD groups. Compared with HFD, glycerolipid synthesis was reduced in the reversal animals, however it remained elevated above that of chow controls, indicating that despite experiencing a net loss in lipid stores, the liver was still actively esterifying available fatty acids at rates higher than that in chow control mice. This effect likely promotes the re-esterification of excess free fatty acids released from the breakdown of adipose depots during the weight loss period. PMID:27273128

  3. Reversing diet-induced metabolic dysregulation by diet switching leads to altered hepatic de novo lipogenesis and glycerolipid synthesis

    PubMed Central

    Kowalski, Greg M.; Hamley, Steven; Selathurai, Ahrathy; Kloehn, Joachim; De Souza, David P.; O’Callaghan, Sean; Nijagal, Brunda; Tull, Dedreia L.; McConville, Malcolm J.; Bruce, Clinton R.

    2016-01-01

    In humans, low-energy diets rapidly reduce hepatic fat and improve/normalise glycemic control. Due to difficulties in obtaining human liver, little is known about changes to the lipid species and pathway fluxes that occur under these conditions. Using a combination of stable isotope, and targeted metabolomic approaches we investigated the acute (7–9 days) hepatic effects of switching high-fat high-sucrose diet (HFD) fed obese mice back to a chow diet. Upon the switch, energy intake was reduced, resulting in reductions of fat mass and hepatic triacyl- and diacylglycerol. However, these parameters were still elevated compared to chow fed mice, thus representing an intermediate phenotype. Nonetheless, glucose intolerance and hyperinsulinemia were completely normalized. The diet reversal resulted in marked reductions in hepatic de novo lipogenesis when compared to the chow and HFD groups. Compared with HFD, glycerolipid synthesis was reduced in the reversal animals, however it remained elevated above that of chow controls, indicating that despite experiencing a net loss in lipid stores, the liver was still actively esterifying available fatty acids at rates higher than that in chow control mice. This effect likely promotes the re-esterification of excess free fatty acids released from the breakdown of adipose depots during the weight loss period. PMID:27273128

  4. Metabolism and Regulation of Glycerolipids in the Yeast Saccharomyces cerevisiae

    PubMed Central

    Henry, Susan A.; Kohlwein, Sepp D.; Carman, George M.

    2012-01-01

    Due to its genetic tractability and increasing wealth of accessible data, the yeast Saccharomyces cerevisiae is a model system of choice for the study of the genetics, biochemistry, and cell biology of eukaryotic lipid metabolism. Glycerolipids (e.g., phospholipids and triacylglycerol) and their precursors are synthesized and metabolized by enzymes associated with the cytosol and membranous organelles, including endoplasmic reticulum, mitochondria, and lipid droplets. Genetic and biochemical analyses have revealed that glycerolipids play important roles in cell signaling, membrane trafficking, and anchoring of membrane proteins in addition to membrane structure. The expression of glycerolipid enzymes is controlled by a variety of conditions including growth stage and nutrient availability. Much of this regulation occurs at the transcriptional level and involves the Ino2–Ino4 activation complex and the Opi1 repressor, which interacts with Ino2 to attenuate transcriptional activation of UASINO-containing glycerolipid biosynthetic genes. Cellular levels of phosphatidic acid, precursor to all membrane phospholipids and the storage lipid triacylglycerol, regulates transcription of UASINO-containing genes by tethering Opi1 to the nuclear/endoplasmic reticulum membrane and controlling its translocation into the nucleus, a mechanism largely controlled by inositol availability. The transcriptional activator Zap1 controls the expression of some phospholipid synthesis genes in response to zinc availability. Regulatory mechanisms also include control of catalytic activity of glycerolipid enzymes by water-soluble precursors, products and lipids, and covalent modification of phosphorylation, while in vivo function of some enzymes is governed by their subcellular location. Genome-wide genetic analysis indicates coordinate regulation between glycerolipid metabolism and a broad spectrum of metabolic pathways. PMID:22345606

  5. Brain Natriuretic Peptide Stimulates Lipid Metabolism through Its Receptor NPR1 and the Glycerolipid Metabolism Pathway in Chicken Adipocytes.

    PubMed

    Huang, H Y; Zhao, G P; Liu, R R; Li, Q H; Zheng, M Q; Li, S F; Liang, Z; Zhao, Z H; Wen, J

    2015-11-01

    Brain natriuretic peptide (BNP) is related to lipid metabolism in mammals, but its effect and the molecular mechanisms underlying it in chickens are incompletely understood. We found that the level of natriuretic peptide precursor B (NPPB, which encodes BNP) mRNA expression in high-abdominal-fat chicken groups was significantly higher than that of low-abdominal-fat groups. Partial correlations indicated that changes in the weight of abdominal fat were positively correlated with NPPB mRNA expression level. In vitro, compared with the control group, preadipocytes with NPPB interference showed reduced levels of proliferation, differentiation, and glycerin in media. Treatments of cells with BNP led to enhanced proliferation and differentiation of cells and glycerin concentration, and mRNA expression of its receptor natriuretic peptide receptor 1 (NPR1) was upregulated significantly. In cells exposed to BNP, 482 differentially expressed genes were identified compared with controls without BNP. Four genes known to be related to lipid metabolism (diacylglycerol kinase; lipase, endothelial; 1-acylglycerol-3-phosphate O-acyltransferase 1; and 1-acylglycerol-3-phosphate O-acyltransferase 2) were enriched in the glycerolipid metabolism pathway and expressed differentially. In conclusion, BNP stimulates the proliferation, differentiation, and lipolysis of preadipocytes through upregulation of the levels of expression of its receptor NPR1 and key genes enriched in the glycerolipid metabolic pathway. PMID:26463554

  6. Obestatin and Nt8U influence glycerolipid metabolism and PPAR gamma signaling in mice.

    PubMed

    Nagaraj, ShreeRanga; Raghavan, Angad V; Rao, Sudha N; Manjappara, Uma V

    2014-08-01

    Obestatin, its N-terminal fragment and the N-terminal fragment analog Nt8U were previously shown to reduce food intake, gain in body weight and triglyceride levels in albino mice. To establish their mode of action, mRNA profiling of the epididymal adipose tissue of mice treated with these peptides were performed. The differential expressions were markedly indicative of their involvement in lipid metabolism. Obestatin showed a significant upregulation of the genes patatin-like phospholipase domain containing 3, diacylglycerol O-acyltransferase 2, monoglyceride lipase, aldo-keto reductase family 1, member 7 which are involved in glycerolipid metabolism. It also upregulated peroxisome proliferator-activated receptor gamma, retinoid X receptor gamma, cluster of differentiation 36, adiponectin, C1Q and collagen domain containing, angiopoietin-like 4, lipoprotein lipase, stearoyl-coenzyme A and desaturase 3 involved in the peroxisome proliferator-activated receptor signaling pathway. Nt8U upregulated genes implicated in the same two pathways but with lesser significance and also upregulated APOL2. The N-terminal fragment though differentially regulated a small subset of the genes differentially regulated by obestatin and Nt8U, no conclusive evidence was obtained as to assign a specific pathway for its mode of action. We hypothesize that reduced food intake brought about by obestatin and Nt8U triggers lipid catabolism. The free fatty acids and lysophosphatidic acid thus produced in turn activates peroxisome proliferator-activated receptor gamma and the genes involved in peroxisome proliferator-activated receptor signaling. All of them together lead to reduction in gain in bodyweight, stored fat and circulating lipids. These results also correlate well with the observed efficacy of the peptides. PMID:24937751

  7. Profiling of promoter occupancy by the SND1 transcriptional coactivator identifies downstream glycerolipid metabolic genes involved in TNFα response in human hepatoma cells

    PubMed Central

    Arretxe, Enara; Armengol, Sandra; Mula, Sarai; Chico, Yolanda; Ochoa, Begoña; Martínez, María José

    2015-01-01

    The NF-κB-inducible Staphylococcal nuclease and tudor domain-containing 1 gene (SND1) encodes a coactivator involved in inflammatory responses and tumorigenesis. While SND1 is known to interact with certain transcription factors and activate client gene expression, no comprehensive mapping of SND1 target genes has been reported. Here, we have approached this question by performing ChIP-chip assays on human hepatoma HepG2 cells and analyzing SND1 binding modulation by proinflammatory TNFα. We show that SND1 binds 645 gene promoters in control cells and 281 additional genes in TNFα-treated cells. Transcription factor binding site analysis of bound probes identified motifs for established partners and for novel transcription factors including HSF, ATF, STAT3, MEIS1/AHOXA9, E2F and p300/CREB. Major target genes were involved in gene expression and RNA metabolism regulation, as well as development and cellular metabolism. We confirmed SND1 binding to 21 previously unrecognized genes, including a set of glycerolipid genes. Knocking-down experiments revealed that SND1 deficiency compromises the glycerolipid gene reprogramming and lipid phenotypic responses to TNFα. Overall, our findings uncover an unexpected large set of potential SND1 target genes and partners and reveal SND1 to be a determinant downstream effector of TNFα that contributes to support glycerophospholipid homeostasis in human hepatocellular carcinoma during inflammation. PMID:26323317

  8. Metabolic alterations accompanying oncogene-induced senescence

    PubMed Central

    Aird, Katherine M; Zhang, Rugang

    2014-01-01

    Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs in normal primary human cells after activation of an oncogene in the absence of other cooperating oncogenic stimuli. OIS is therefore considered a bona fide tumor suppression mechanism in vivo. Indeed, overcoming OIS-associated stable cell growth arrest can lead to tumorigenesis. Although cells that have undergone OIS do not replicate their DNA, they remain metabolically active. A number of recent studies report significant changes in cellular metabolism during OIS, including alterations in nucleotide, glucose, and mitochondrial metabolism and autophagy. These alterations may be necessary for stable senescence-associated cell growth arrest, and overcoming these shifts in metabolism may lead to tumorigenesis. This review highlights what is currently known about alterations in cellular metabolism during OIS and the implication of OIS-associated metabolic changes in cellular transformation and the development of cancer therapeutic strategies. PMID:27308349

  9. Oncometabolites: linking altered metabolism with cancer

    PubMed Central

    Yang, Ming; Soga, Tomoyoshi; Pollard, Patrick J.

    2013-01-01

    The discovery of cancer-associated mutations in genes encoding key metabolic enzymes has provided a direct link between altered metabolism and cancer. Advances in mass spectrometry and nuclear magnetic resonance technologies have facilitated high-resolution metabolite profiling of cells and tumors and identified the accumulation of metabolites associated with specific gene defects. Here we review the potential roles of such “oncometabolites” in tumor evolution and as clinical biomarkers for the detection of cancers characterized by metabolic dysregulation. PMID:23999438

  10. Glycerolipid biosynthesis in isolated pea root plastids

    SciTech Connect

    Xue, Lingru; Sparace, S.A. )

    1990-05-01

    Plastids have been isolated from germinating pea (Pisum sativum L.) roots by differential centrifugation and purified on Percoll gradients. Marker enzymes (NADPH: cytochrome c reductase, fumarase and fatty acid synthesis) indicate that greater than 50% of the plastids are recovered essentially free from mitochondrial and endoplasmic reticulum contamination. Fatty acids synthesized from ({sup 14}C)acetate by Percoll-purified plastids are primarily 16:0, 16:1 and 18:1. ({sup 14}C)Acetate-labelled fatty acids and ({sup 14}C)glycerol-3-phosphate are both readily incorporated into glycerolipid. Approximately 12% of the total activity for glycerolipid biosynthesis from glycerol-3-phosphate is recovered in the purified plastid fraction. Glycerolipids synthesized from these precursors are primarily TAG, DAG, PE, PG, PC, PI and PA. Acyl-CoA's also accumulate when acetate is the precursor.

  11. Metabolic alterations in renal cell carcinoma.

    PubMed

    Massari, Francesco; Ciccarese, Chiara; Santoni, Matteo; Brunelli, Matteo; Piva, Francesco; Modena, Alessandra; Bimbatti, Davide; Fantinel, Emanuela; Santini, Daniele; Cheng, Liang; Cascinu, Stefano; Montironi, Rodolfo; Tortora, Giampaolo

    2015-11-01

    Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways). We analyzed the key metabolic abnormalities underlying RCC carcinogenesis, highlighting those altered pathways that may represent potential targets for the development of more effective therapeutic strategies. PMID:26169313

  12. Altered brain arginine metabolism in schizophrenia.

    PubMed

    Liu, P; Jing, Y; Collie, N D; Dean, B; Bilkey, D K; Zhang, H

    2016-01-01

    Previous research implicates altered metabolism of l-arginine, a versatile amino acid with a number of bioactive metabolites, in the pathogenesis of schizophrenia. The present study, for we believe the first time, systematically compared the metabolic profile of l-arginine in the frontal cortex (Brodmann's area 8) obtained post-mortem from schizophrenic individuals and age- and gender-matched non-psychiatric controls (n=20 per group). The enzyme assays revealed no change in total nitric oxide synthase (NOS) activity, but significantly increased arginase activity in the schizophrenia group. Western blot showed reduced endothelial NOS protein expression and increased arginase II protein level in the disease group. High-performance liquid chromatography and liquid chromatography/mass spectrometric assays confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increased agmatine concentration and glutamate/GABA ratio in the schizophrenia cases. Regression analysis indicated positive correlations between arginase activity and the age of disease onset and between l-ornithine level and the duration of illness. Moreover, cluster analyses revealed that l-arginine and its main metabolites l-citrulline, l-ornithine and agmatine formed distinct groups, which were altered in the schizophrenia group. The present study provides further evidence of altered brain arginine metabolism in schizophrenia, which enhances our understanding of the pathogenesis of schizophrenia and may lead to the future development of novel preventions and/or therapeutics for the disease. PMID:27529679

  13. Alterations of lipid metabolism in Wilson disease

    PubMed Central

    2011-01-01

    Introduction Wilson disease (WD) is an inherited disorder of human copper metabolism, characterised by accumulation of copper predominantly in the liver and brain, leading to severe hepatic and neurological disease. Interesting findings in animal models of WD (Atp7b-/- and LEC rats) showed altered lipid metabolism with a decrease in the amount of triglycerides and cholesterol in the serum. However, serum lipid profile has not been investigated in large human WD patient cohorts to date. Patients and Methods This cohort study involved 251 patients examined at the Heidelberg and Dresden (Germany) University Hospitals. Patients were analysed on routine follow-up examinations for serum lipid profile, including triglycerides, cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL). Data on these parameters at time of diagnosis were retrieved by chart review where available. For statistical testing, patients were subgrouped by sex, manifestation (hepatic, neurological, mixed and asymptomatic) and treatment (D-penicillamine, trientine, zinc or combination). Results A significant difference in total serum cholesterol was found in patients with hepatic symptoms, which diminished under therapy. No alterations were observed for HDL, LDL and triglycerides. Conclusion Contradictory to previous reports using WD animal models (Atp7b-/- and LEC rats), the most obvious alteration in our cohort was a lower serum cholesterol level in hepatic-affected patients, which might be related to liver injury. Our data suggested unimpaired cholesterol metabolism in Wilson disease under therapy, independent of the applied medical treatment. PMID:21595966

  14. Hemostasis alterations in metabolic syndrome (review).

    PubMed

    Palomo, Iván; Alarcón, Marcelo; Moore-Carrasco, Rodrigo; Argilés, Josep M

    2006-11-01

    Metabolic syndrome (MS) is characterized by the presence of at least three of the following alterations: enlargement of the waist diameter, higher levels of arterial pressure, low density lipoprotein cholesterol and glycemia, and reduction of high density lipoprotein cholesterol. The prevalence of MS reaches 23% in young adults, a percentage that increases with age. People with MS have a greater risk of suffering from cardiovascular disease (CVD). The physiopathologic alterations now found to exist in MS are diverse; among them is endothelial dysfunction, which triggers atherogenic lesions and hypercoagulability characterized by alterations of the coagulation factors and the regulatory proteins of fibrinolysis such as the plasminogen activator inhibitor (PAI-1). The increase in oxidative stress and/or the reactive oxygen species in patients with MS is partially related to the oxidation state of the lipoproteins, especially of the low density lipoproteins. This fact favors atherogenesis. Moreover, the oxidative stress produces alterations in the production of adipokines, cytokines secreted by the adipose tissues. The abnormality in the transport of lipoprotein diminishes the catabolism of the very low density lipoprotein (VLDL) and increases the catabolism of the high density lipoprotein (HDL), which creates insulin resistance. This process is associated with a lower concentration of adiponectin that in turn regulates the catabolism of VLDL and HDL; consequently increasing the flow of fatty acids from the adipose tissue to the liver and muscles. The proinflammatory cytokines, among them tumor necrosis factor alpha (TNF-alpha), are of great importance in MS regulating different processes and molecules such as PAI-1. PAI-1 is controlled by the group of transcription factors peroxisome proliferator-activated receptor (PPAR), especially by PPAR gamma and alpha ligands. In summary, MS includes multiple alterations related to insulin resistance at several levels: hepatic

  15. Chemical Genetics in Dissecting Membrane Glycerolipid Functions.

    PubMed

    Chevalier, Florian; Carrera, Laura Cuyàs; Nussaume, Laurent; Maréchal, Eric

    2016-01-01

    Chemical genetics has emerged as a powerful approach to dissect biological processes, based on the utilization of small molecules disturbing the function of specific target proteins. By analogy with classical genetics, 'reverse chemical genetics' refers to the utilization of drugs acting on a known target, enabling its functional characterization at the levels of the cells, tissues and organisms. Likewise, 'direct chemical genetics' refers to the utilization of a drug of unknown mode of action, but triggering a phenotype of interest. In that case, one has to identify the target(s) possibly blocked (or possibly activated) by the small molecule. This chapter illustrates both approaches, like the analysis of the elongation of fatty acids, the biosynthesis of galactoglycerolipids or the catabolism of phosphoglycerolipids by reverse chemical genetics or the study of the membrane glycerolipid remodeling triggered upon phosphate starvation, by direct chemical genetics. PMID:27023235

  16. Metabolic alterations and hepatitis C: From bench to bedside

    PubMed Central

    Chang, Ming-Ling

    2016-01-01

    In addition to causing cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is thought to cause hypolipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, and diabetes. The viral life cycle of HCV depends on cholesterol metabolism in host cells. HCV core protein and nonstructural protein 5A perturb crucial lipid and glucose pathways, such as the sterol regulatory element-binding protein pathway and the protein kinase B/mammalian target of rapamycin/S6 kinase 1 pathway. Although several lines of transgenic mice expressing core or full HCV proteins exhibit hepatic steatosis and/or dyslipidemia, whether they completely reflect the metabolic alterations in humans with HCV infection remains unknown. Many cross-sectional studies have demonstrated increased prevalences of metabolic alterations and cardiovascular events in patients with chronic hepatitis C (CHC); however, conflicting results exist, primarily due to unavoidable individual variations. Utilizing anti-HCV therapy, most longitudinal cohort studies of CHC patients have demonstrated the favorable effects of viral clearance in attenuating metabolic alterations and cardiovascular risks. To determine the risks of HCV-associated metabolic alterations and associated complications in patients with CHC, it is necessary to adjust for crucial confounders, such as HCV genotype and host baseline glucose metabolism, for a long follow-up period after anti-HCV treatment. Adipose tissue is an important endocrine organ due to its release of adipocytokines, which regulate lipid and glucose metabolism. However, most data on HCV infection and adipocytokine alteration are inconclusive. A comprehensive overview of HCV-associated metabolic and adipocytokine alterations, from bench to bedside, is presented in this topic highlight. PMID:26819514

  17. Metabolic alterations and hepatitis C: From bench to bedside.

    PubMed

    Chang, Ming-Ling

    2016-01-28

    In addition to causing cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is thought to cause hypolipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, and diabetes. The viral life cycle of HCV depends on cholesterol metabolism in host cells. HCV core protein and nonstructural protein 5A perturb crucial lipid and glucose pathways, such as the sterol regulatory element-binding protein pathway and the protein kinase B/mammalian target of rapamycin/S6 kinase 1 pathway. Although several lines of transgenic mice expressing core or full HCV proteins exhibit hepatic steatosis and/or dyslipidemia, whether they completely reflect the metabolic alterations in humans with HCV infection remains unknown. Many cross-sectional studies have demonstrated increased prevalences of metabolic alterations and cardiovascular events in patients with chronic hepatitis C (CHC); however, conflicting results exist, primarily due to unavoidable individual variations. Utilizing anti-HCV therapy, most longitudinal cohort studies of CHC patients have demonstrated the favorable effects of viral clearance in attenuating metabolic alterations and cardiovascular risks. To determine the risks of HCV-associated metabolic alterations and associated complications in patients with CHC, it is necessary to adjust for crucial confounders, such as HCV genotype and host baseline glucose metabolism, for a long follow-up period after anti-HCV treatment. Adipose tissue is an important endocrine organ due to its release of adipocytokines, which regulate lipid and glucose metabolism. However, most data on HCV infection and adipocytokine alteration are inconclusive. A comprehensive overview of HCV-associated metabolic and adipocytokine alterations, from bench to bedside, is presented in this topic highlight. PMID:26819514

  18. Metabolic alterations in morbid obesity. Influence on the haemorheological profile.

    PubMed

    Vayá, Amparo; Hernández-Mijares, Antonio; Suescun, Marta; Solá, Eva; Cámara, Rosa; Romagnoli, Marco; Bautista, Daniel; Laiz, Begoña

    2011-01-01

    There are few studies on haemorheological disturbances in morbidly obese patients. The role played by the metabolic syndrome on the rheological profile of morbidly obese subjects has not yet been established, and it is not clear whether morbidly obese, but "metabolically healthy", show rheological alterations. We aimed to determine the whole rheological profile in 136 morbidly obese patients and 136 normo-weight volunteers, along with plasma lipids, inflammatory and insulin resistance parameters. Patients had statistically higher glucose, triglycerides, HbA1c, leptin, insulin, HOMA, CRP, leucocytes, fibrinogen, plasma viscosity (p < 0.001, respectively), erythrocyte aggregation at 3 s-1 (p = 0.011) and lower erythrocyte elongation index 60 Pa (p = 0.015). In the multivariate regression analysis, the anthropometric, lipidic, insulin resistance and inflammatory parameters predicted haemorheological variables (p < 0.001). No differences were observed for the rheological parameters when morbidly obese subjects with (n = 75) and without (n = 61) the metabolic syndrome were compared (p > 0.05), indicating that the altered rheological profile not only related to the metabolic syndrome, but to obesity itself. When further patients were classified as "metabolically healthy" obese (n = 23) and "metabolically unhealthy" obese (n = 113), the latter presented higher insulin resistance (insulin p < 0.01, HOMA p < 0.05, glucose p < 0.001, triglycerides p < 0.05 and HbA1c p < 0.01) than the former, but no differences in the rheological parameters (p > 0.05) were observed. When "metabolically healthy" obese (n = 23) were compared with "metabolically healthy" controls (n = 81), the former still showed higher HOMA (p < 0.001), triglycerides (p < 0.05), CRP (p < 0.001) and HbA1c (p < 0.05), higher fibrinogen (p < 0.001), plasma viscosity (p < 0.001), erythrocyte aggregation at 3 s-1 (p < 0.05), but a lower erythrocyte elongation index 60 Pa (p < 0.05). Morbidly obese subjects present

  19. Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism.

    PubMed

    Abruzzese, Giselle Adriana; Heber, Maria Florencia; Ferreira, Silvana Rocio; Velez, Leandro Martin; Reynoso, Roxana; Pignataro, Omar Pedro; Motta, Alicia Beatriz

    2016-07-01

    Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis. PMID:27179108

  20. Altered glycosaminoglycan metabolism in injured arterial wall

    SciTech Connect

    Salisbury, B.G.; Hajjar, D.P.; Minick, C.R.

    1985-06-01

    Glycosaminoglycans (GAG) are believed to be important in the pathogenesis of atherosclerosis. We have previously demonstrated that areas of injured aorta that have been re-endothelialized accumulate increased amounts of lipid and GAG when compared to areas remaining de-endothelialized. We have now examined the net incorporation of labeled precursors into the individual GAG present in both re-endothelialized and de-endothelialized areas of rabbit aorta. Aortic tissue was examined at 2-3 and 10-14 weeks after a denuding injury by incubating tissue minces with (/sup 3/H)glucosamine and sodium (/sup 35/S)sulfate for 24 hr. Following incubation, the aortic GAG were isolated and assayed for uronic acid concentration and radioactivity. Results indicate that the total GAG concentration was significantly greater in the re-endothelialized as compared to de-endothelialized areas. The concentration in uninjured aorta was 9.01. The difference between the injured tissues was attributable to increased concentrations of sulfated GAG. Hyaluronic acid and chondroitin sulfate were the most metabolically active of the GAG in either uninjured or injured aorta, together accounting for over 75% of the /sup 3/H label. The /sup 3/H specific radioactivities of the four GAG in the short-term, re-endothelialized subgroup were all increased nearly twice that found in uninjured and de-endothelialized tissues. With the exception of heparan sulfate, no significant differences were noted in the /sup 3/H specific radioactivities between the re-endothelialized and de-endothelialized areas in the long-term subgroup. These results indicate that, relative to adjacent areas of de-endothelialization, GAG preferentially accumulate in re-endothelialized areas even as early as 2-3 weeks following a denuding injury.

  1. Drug metabolism alterations in nonalcoholic fatty liver disease

    PubMed Central

    Merrell, Matthew D.; Cherrington, Nathan J.

    2013-01-01

    Drug-metabolizing enzymes play a vital role in the elimination of the majority of therapeutic drugs. The major organ involved in drug metabolism is the liver. Chronic liver diseases have been identified as a potential source of significant interindividual variation in metabolism. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, affecting between 60 and 90 million Americans, yet the vast majority of NAFLD patients are undiagnosed. NAFLD encompasses a spectrum of pathologies, ranging from steatosis to nonalcoholic steatohepatitis and fibrosis. Numerous animal studies have investigated the effects of NAFLD on hepatic gene expression, observing significant alterations in mRNA, protein, and activity levels. Information on the effects of NAFLD in human patients is limited, though several significant investigations have recently been published. Significant alterations in the activity of drug-metabolizing enzymes may affect the clearance of therapeutic drugs, with the potential to result in adverse drug reactions. With the enormous prevalence of NAFLD, it is conceivable that every drug currently on the market is being given to patients with NAFLD. The current review is intended to present the results from both animal models and human patients, summarizing the observed alterations in the expression and activity of the phase I and II drug-metabolizing enzymes. PMID:21612324

  2. Liposomal formulation of a glycerolipidic prodrug for lymphatic delivery of didanosine via oral route.

    PubMed

    Lalanne, M; Andrieux, K; Paci, A; Besnard, M; Ré, M; Bourgaux, C; Ollivon, M; Desmaele, D; Couvreur, P

    2007-11-01

    Didanosine is a polar drug with poor membrane absorption and high hepatic first pass metabolism. This study aimed at developing a lipidic formulation of a glycerolipidic prodrug of didanosine in order to improve its bioavailability. In the course of a preformulation study, the glycerolipidic prodrug of didanosine was characterized by microscopy, DSC and XRDT. In anhydrous conditions, the prodrug displayed a polymorphic behaviour similar to that of triglycerides. Then, we evaluated three types of lipidic formulations (emulsions, mixed micelles and liposomes) in order to encapsulate the prodrug. Solubilities in water - even in the presence of taurocholate micelles - but also in some oils were very low (max 244 microg/mL) as the prodrug was found to be amphiphilic (log P=2). On the contrary, the prodrug was found to be perfectly incorporated in dipalmitoylphosphatidylcholine (DPPC) multilamellar liposomes up to a ratio of 1:5 (mol:mol) prodrug:DPPC as suggested by HPLC-UV and DSC experiments. Moreover, these liposomes could be freeze-dried whereas the chemical integrity of the prodrug was preserved. Then, the freeze-dried liposomal preparation could be formulated as gastro-resistant capsules to prevent didanosine from acidic degradation. Further experiments are on the way to evaluate in vitro the absorption of prodrug incorporated in liposomes by enterocytes. PMID:17616448

  3. Arabidopsis GPAT9 contributes to synthesis of intracellular glycerolipids but not surface lipids

    PubMed Central

    Singer, Stacy D.; Chen, Guanqun; Mietkiewska, Elzbieta; Tomasi, Pernell; Jayawardhane, Kethmi; Dyer, John M.; Weselake, Randall J.

    2016-01-01

    GLYCEROL-3-PHOSPHATE ACYLTRANSFERASE (GPAT) genes encode enzymes involved in glycerolipid biosynthesis in plants. Ten GPAT homologues have been identified in Arabidopsis. GPATs 4–8 have been shown to be involved in the production of extracellular lipid barrier polyesters. Recently, GPAT9 was reported to be essential for triacylglycerol (TAG) biosynthesis in developing Arabidopsis seeds. The enzymatic properties and possible functions of GPAT9 in surface lipid, polar lipid and TAG biosynthesis in non-seed organs, however, have not been investigated. Here we show that Arabidopsis GPAT9 exhibits sn-1 acyltransferase activity with high specificity for acyl-coenzyme A, thus providing further evidence that this GPAT is involved in storage lipid biosynthesis. We also confirm a role for GPAT9 in seed oil biosynthesis and further demonstrate that GPAT9 contributes to the biosynthesis of both polar lipids and TAG in developing leaves, as well as lipid droplet production in developing pollen grains. Conversely, alteration of constitutive GPAT9 expression had no obvious effects on surface lipid biosynthesis. Taken together, these studies expand our understanding of GPAT9 function to include modulation of several different intracellular glycerolipid pools in plant cells. PMID:27325892

  4. Arabidopsis GPAT9 contributes to synthesis of intracellular glycerolipids but not surface lipids.

    PubMed

    Singer, Stacy D; Chen, Guanqun; Mietkiewska, Elzbieta; Tomasi, Pernell; Jayawardhane, Kethmi; Dyer, John M; Weselake, Randall J

    2016-08-01

    GLYCEROL-3-PHOSPHATE ACYLTRANSFERASE (GPAT) genes encode enzymes involved in glycerolipid biosynthesis in plants. Ten GPAT homologues have been identified in Arabidopsis. GPATs 4-8 have been shown to be involved in the production of extracellular lipid barrier polyesters. Recently, GPAT9 was reported to be essential for triacylglycerol (TAG) biosynthesis in developing Arabidopsis seeds. The enzymatic properties and possible functions of GPAT9 in surface lipid, polar lipid and TAG biosynthesis in non-seed organs, however, have not been investigated. Here we show that Arabidopsis GPAT9 exhibits sn-1 acyltransferase activity with high specificity for acyl-coenzyme A, thus providing further evidence that this GPAT is involved in storage lipid biosynthesis. We also confirm a role for GPAT9 in seed oil biosynthesis and further demonstrate that GPAT9 contributes to the biosynthesis of both polar lipids and TAG in developing leaves, as well as lipid droplet production in developing pollen grains. Conversely, alteration of constitutive GPAT9 expression had no obvious effects on surface lipid biosynthesis. Taken together, these studies expand our understanding of GPAT9 function to include modulation of several different intracellular glycerolipid pools in plant cells. PMID:27325892

  5. Choline Metabolism Alteration: A Focus on Ovarian Cancer

    PubMed Central

    Bagnoli, Marina; Granata, Anna; Nicoletti, Roberta; Krishnamachary, Balaji; Bhujwalla, Zaver M.; Canese, Rossella; Podo, Franca; Canevari, Silvana; Iorio, Egidio; Mezzanzanica, Delia

    2016-01-01

    Compared with normal differentiated cells, cancer cells require a metabolic reprograming to support their high proliferation rates and survival. Aberrant choline metabolism is a fairly new metabolic hallmark reflecting the complex reciprocal interactions between oncogenic signaling and cellular metabolism. Alterations of the involved metabolic network may be sustained by changes in activity of several choline transporters as well as of enzymes such as choline kinase-alpha (ChoK-α) and phosphatidylcholine-specific phospholipases C and D. Of note, the net outcome of these enzymatic alterations is an increase of phosphocholine and total choline-containing compounds, a “cholinic phenotype” that can be monitored in cancer by magnetic resonance spectroscopy. This review will highlight the molecular basis for targeting this pathway in epithelial ovarian cancer (EOC), a highly heterogeneous and lethal malignancy characterized by late diagnosis, frequent relapse, and development of chemoresistance. Modulation of ChoK-α expression impairs only EOC but not normal ovarian cells, thus supporting the hypothesis that “cholinic phenotype” is a peculiar feature of transformed cells and indicating ChoK-α targeting as a novel approach to improve efficacy of standard EOC chemotherapeutic treatments. PMID:27446799

  6. Altered lipid metabolism in Drosophila model of Huntington's disease.

    PubMed

    Aditi, Kumari; Shakarad, Mallikarjun N; Agrawal, Namita

    2016-01-01

    Huntington's disease (HD) is late-onset, progressive neurodegenerative disorder caused by expansion of polyglutamine (polyQ) repeat within Huntingtin (Htt) protein. In HD patients, energy-related manifestations such as modulation of weight during entire course of disease with energy deficit at terminal stage have been reported, however, underlying reason remains elusive till date. Lipids, carbohydrate and protein constitute a predominant fraction of body's energy reservoir and perturbation in their homeostasis may influence weight. To discern role of these energy molecules in weight alteration, we quantified them in an in vivo transgenic Drosophila model of HD. We document that diseased flies exhibit change in weight due to an altered lipid metabolism, as evident from considerably high lipid levels at the time of disease onset followed by a pathologic decline at end-stage. An alteration in intracellular lipid droplet size suggested altered cellular lipid turnover. Furthermore, diseased flies displayed substantial changes in carbohydrate and protein content. Interestingly, alteration in weight and lipid levels are independent of the feeding pattern in diseased condition and exhibit weak correlation with insulin-like peptide or adipokinetic hormone producing cells. We propose that therapeutic intervention aimed at restoring lipid levels and associated metabolic pathways may improve longevity and quality of patient's life. PMID:27506601

  7. Radiation Exposure Alters Expression of Metabolic Enzyme Genes In Mice

    NASA Technical Reports Server (NTRS)

    Wotring, Virginia E.; Mangala, L. S.; Zhang, Y.; Wu, H.

    2010-01-01

    Most pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Because of the importance of the liver in drug metabolism it is important to understand the effects of spaceflight on the enzymes of the liver. Exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. This study is an effort to examine the effects of adaptive mechanisms that may be triggered by early exposure to low radiation doses. Using procedures approved by the JSC Animal Care & Use Committee, C57 male mice were exposed to Cs-137 in groups: controls, low dose (50 mGy), high dose (6Gy) and a fourth group that received both radiation doses separated by 24 hours. Animals were anesthetized and sacrificed 4 hours after their last radiation exposure. Livers were removed immediately and flash-frozen in liquid nitrogen. Tissue was homogenized, RNA extracted and purified (Absolutely RNA, Agilent). Quality of RNA samples was evaluated (Agilent Bioanalyzer 2100). Complementary DNA was prepared from high-quality RNA samples, and used to run RT-qPCR screening arrays for DNA Repair and Drug Metabolism (SuperArray, SABiosciences/Qiagen; BioRad Cfx96 qPCR System). Of 91 drug metabolism genes examined, expression of 7 was altered by at least one treatment condition. Genes that had elevated expression include those that metabolize promethazine and steroids (4-8-fold), many that reduce oxidation products, and one that reduces heavy metal exposure (greater than 200-fold). Of the 91 DNA repair and general metabolism genes examined, expression of 14 was altered by at least one treatment condition. These gene expression changes are likely homeostatic and could lead to development of new radioprotective countermeasures.

  8. Soybean cotyledon starch metabolism is sensitive to altered gravity conditions

    NASA Technical Reports Server (NTRS)

    Brown, C. S.; Piastuch, W. C.; Knott, W. M.

    1994-01-01

    We have demonstrated that etiolated soybean seedlings grown under the altered gravity conditions of clinorotation (1 rpm) and centrifugation (5xg) exhibit changes in starch metabolism. Cotyledon starch concentration was lower (-28%) in clinorotated plants and higher (+24%) in centrifuged plants than in vertical control plants. The activity of ADP-glucose pyrophosphorylase in the cotyledons was affected in a similar way, i.e. lower (-37%) in the clinorotated plants and higher (+22%) in the centrifuged plants. Other starch metabolic enzyme activities, starch synthase, starch phosphorylase and total hydrolase were not affected by the altered gravity treatments. We conclude that the observed changes in starch concentrations were primarily due to gravity-mediated differences in ADP-glucose pyrophosphorylase activity.

  9. Alteration of nucleotide metabolism: a new mechanism for mitochondrial disorders.

    PubMed

    Martí, Ramon; Nishigaki, Yutaka; Vilá, Maya R; Hirano, Michio

    2003-07-01

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). TP deficiency alters the metabolism of the nucleosides thymidine and deoxyuridine, which, in turn, produces abnormalities of mitochondrial DNA (mtDNA) including depletion, deletions, and point mutations. MNGIE is the best characterized of the expanding number of mitochondrial disorders caused by alterations in the metabolism of nucleosides/nucleotides. Because mitochondria contain their own machinery for nucleoside and nucleotide metabolism and have physically separate nucleotide pools, it is not surprising that disorders of these pathways cause human diseases. Other diseases in this group include mtDNA depletion syndromes caused by mutations on the nuclear genes encoding the mitochondrial thymidine kinase and deoxyguanosine kinase; autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA due to mutations in the genes encoding the muscle-isoform of mitochondrial ADP/ATP translocator; and mitochondrial DNA depletion due to toxicities of nucleoside analogues. Mutations in the deoxynucleotide carrier, a transporter of deoxynucleoside diphosphates, have been identified as a cause of congenital microcephaly. However, alterations of mtDNA have not yet been established in this disorder. Future studies are likely to reveal additional diseases and provide further insight into this new subject. PMID:12940507

  10. Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

    PubMed Central

    Schuck, Patrícia Fernanda; Malgarin, Fernanda; Cararo, José Henrique; Cardoso, Fabiola; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-01-01

    Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition. PMID:26425393

  11. Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations.

    PubMed

    Schuck, Patrícia Fernanda; Malgarin, Fernanda; Cararo, José Henrique; Cardoso, Fabiola; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-09-01

    Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition. PMID:26425393

  12. Body composition and risk for metabolic alterations in female adolescents

    PubMed Central

    de Faria, Eliane Rodrigues; Gontijo, Cristiana Araújo; Franceschini, Sylvia do Carmo C.; Peluzio, Maria do Carmo G.; Priore, Silvia Eloiza

    2014-01-01

    OBJECTIVE: To study anthropometrical and body composition variables as predictors of risk for metabolic alterations and metabolic syndrome in female adolescents. METHODS: Biochemical, clinical and corporal composition data of 100 adolescents from 14 to 17 years old, who attended public schools in Viçosa, Southeastern Brazil, were collected. RESULTS: Regarding nutritional status, 83, 11 and 6% showed eutrophia, overweight/obesity and low weight, respectively, and 61% presented high body fat percent. Total cholesterol presented the highest percentage of inadequacy (57%), followed by high-density lipoprotein (HDL - 50%), low-density lipoprotein (LDL - 47%) and triacylglycerol (22%). Inadequacy was observed in 11, 9, 3 and 4% in relation to insulin resistance, fasting insulin, blood pressure and glycemia, respectively. The highest values of the fasting insulin and the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) were verified at the highest quartiles of body mass index (BMI), waist perimeter, waist-to-height ratio and body fat percent. Body mass index, waist perimeter, and waist-to-height ratio were the better predictors for high levels of HOMA-IR, blood glucose and fasting insulin. Waist-to-hip ratio was associated to arterial hypertension diagnosis. All body composition variables were effective in metabolic syndrome diagnosis. CONCLUSIONS: Waist perimeter, BMI and waist-to-height ratio showed to be good predictors for metabolic alterations in female adolescents and then should be used together for the nutritional assessment in this age range. PMID:25119752

  13. Retinoid metabolism is altered in human and mouse cicatricial alopecia.

    PubMed

    Everts, Helen B; Silva, Kathleen A; Montgomery, Shalise; Suo, Liye; Menser, Monica; Valet, Amy S; King, Lloyd E; Ong, David E; Sundberg, John P

    2013-02-01

    C57BL/6 mice develop dermatitis and scarring alopecia resembling human cicatricial alopecias (CAs), particularly the central centrifugal CA (CCCA) type. To evaluate the role of retinoids in CA, the expression of retinoid metabolism components were examined in these mice with mild, moderate, or severe CA compared with hair cycle-matched mice with no disease. Two feeding studies were conducted with dams fed either NIH 31 diet (study 1) or AIN93G diet (study 2). Adult mice were fed AIN93M diet with 4 (recommended), 28, or 56 IU vitamin A g(-1) diet. Feeding the AIN93M diet to adults increased CA frequency over NIH 31 fed mice. Increased follicular dystrophy was seen in study 1 and increased dermal scars in study 2 in mice fed the 28 IU diet. These results indicate that retinoid metabolism is altered in CA in C57BL/6J mice that require precise levels of dietary vitamin A. Human patients with CCCA, pseudopelade (end-stage scarring), and controls with no alopecia were also studied. Many retinoid metabolism proteins were increased in mild CCCA, but were undetectable in pseudopelade. Studies to determine whether these dietary alterations in retinoid metabolism seen in C57BL/6J mice are also involved in different types of human CA are needed. PMID:23096705

  14. Metabolic alterations to the mucosal microbiota in inflammatory bowel disease

    PubMed Central

    Davenport, Michael; Poles, Jordan; Leung, Jacqueline M.; Wolff, Martin J.; Abidi, Wasif M.; Ullman, Thomas; Mayer, Lloyd; Cho, Ilseung; Loke, P'ng

    2014-01-01

    Background Inflammation during inflammatory bowel disease (IBD) may alter nutrient availability to adherent mucosal bacteria and impact their metabolic function. Microbial metabolites may regulate intestinal CD4+ T cell homeostasis. We investigated the relationship between inflammation and microbial function by inferred metagenomics of the mucosal microbiota from colonic pinch biopsies of IBD patients. Methods Paired pinch biopsy samples of known inflammation states were analyzed from UC (23), CD (21) and controls (24) by 16S ribosomal sequencing, histopathology and flow cytometry. PICRUSt was used to generate metagenomic data, and derive relative Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway abundance information. Leukocytes were isolated from paired biopsy samples and analyzed by multi-color flow cytometry. Active inflammation was defined by neutrophil infiltration into the epithelium Results Carriage of metabolic pathways in the mucosal microbiota was relatively stable among IBD patients despite large variations in individual bacterial community structures. However, microbial function was significantly altered in inflamed tissue of UC patients, with a reduction in carbohydrate and nucleotide metabolism in favor of increased lipid and amino acid metabolism. These differences were not observed in samples from CD patients. In CD, microbial lipid, carbohydrate, and amino acid metabolism was tightly correlated with frequency of CD4+Foxp3+ Tregs, whereas in UC these pathways were correlated with frequency of CD4+IL-22+ (TH22) cells. Conclusions Metabolic pathways of the mucosal microbiota in CD do not vary as much as UC with inflammation state, indicating a more systemic perturbation of host-bacteria interactions in CD compared to more localized dysfunction in UC. PMID:24583479

  15. Understanding Acyl Chain and Glycerolipid Metabolism in Plants

    SciTech Connect

    Ohlrogge, John B.

    2013-11-05

    Progress is reported in these areas: acyl-editing in initial eukaryotic lipid assembly in soybean seeds; identification and characterization of two Arabidopsis thaliana lysophosphatidyl acyltransferases with preference for lysophosphatidylethanolamine; and characterization and subcellular distribution of lysolipid acyl transferase activity of pea leaves.

  16. Modelling chronotaxicity of cellular energy metabolism to facilitate the identification of altered metabolic states.

    PubMed

    Lancaster, Gemma; Suprunenko, Yevhen F; Jenkins, Kirsten; Stefanovska, Aneta

    2016-01-01

    Altered cellular energy metabolism is a hallmark of many diseases, one notable example being cancer. Here, we focus on the identification of the transition from healthy to abnormal metabolic states. To do this, we study the dynamics of energy production in a cell. Due to the thermodynamic openness of a living cell, the inability to instantaneously match fluctuating supply and demand in energy metabolism results in nonautonomous time-varying oscillatory dynamics. However, such oscillatory dynamics is often neglected and treated as stochastic. Based on experimental evidence of metabolic oscillations, we show that changes in metabolic state can be described robustly by alterations in the chronotaxicity of the corresponding metabolic oscillations, i.e. the ability of an oscillator to resist external perturbations. We also present a method for the identification of chronotaxicity, applicable to general oscillatory signals and, importantly, apply this to real experimental data. Evidence of chronotaxicity was found in glycolytic oscillations in real yeast cells, verifying that chronotaxicity could be used to study transitions between metabolic states. PMID:27483987

  17. Modelling chronotaxicity of cellular energy metabolism to facilitate the identification of altered metabolic states

    PubMed Central

    Lancaster, Gemma; Suprunenko, Yevhen F.; Jenkins, Kirsten; Stefanovska, Aneta

    2016-01-01

    Altered cellular energy metabolism is a hallmark of many diseases, one notable example being cancer. Here, we focus on the identification of the transition from healthy to abnormal metabolic states. To do this, we study the dynamics of energy production in a cell. Due to the thermodynamic openness of a living cell, the inability to instantaneously match fluctuating supply and demand in energy metabolism results in nonautonomous time-varying oscillatory dynamics. However, such oscillatory dynamics is often neglected and treated as stochastic. Based on experimental evidence of metabolic oscillations, we show that changes in metabolic state can be described robustly by alterations in the chronotaxicity of the corresponding metabolic oscillations, i.e. the ability of an oscillator to resist external perturbations. We also present a method for the identification of chronotaxicity, applicable to general oscillatory signals and, importantly, apply this to real experimental data. Evidence of chronotaxicity was found in glycolytic oscillations in real yeast cells, verifying that chronotaxicity could be used to study transitions between metabolic states. PMID:27483987

  18. Alterations in protein metabolism during space flight and inactivity.

    PubMed

    Ferrando, Arny A; Paddon-Jones, Doug; Wolfe, Robert R

    2002-10-01

    Space flight and the accompanying diminished muscular activity lead to a loss of body nitrogen and muscle function. These losses may affect crew capabilities and health in long-duration missions. Space flight alters protein metabolism such that the body is unable to maintain protein synthetic rates. A concomitant hypocaloric intake and altered anabolic/catabolic hormonal profiles may contribute to or exacerbate this problem. The inactivity associated with bedrest also reduces muscle and whole-body protein synthesis. For this reason, bedrest provides a good model for the investigation of potential exercise and nutritional countermeasures to restore muscle protein synthesis. We have demonstrated that minimal resistance exercise preserves muscle protein synthesis throughout bedrest. In addition, ongoing work indicates that an essential amino acid and carbohydrate supplement may ameliorate the loss of lean body mass and muscle strength associated with 28 d of bedrest. The investigation of inactivity-induced alterations in protein metabolism, during space flight or prolonged bedrest, is applicable to clinical populations and, in a more general sense, to the problems associated with the decreased activity that occur with aging. PMID:12361775

  19. Alterations in protein metabolism during space flight and inactivity

    NASA Technical Reports Server (NTRS)

    Ferrando, Arny A.; Paddon-Jones, Doug; Wolfe, Robert R.

    2002-01-01

    Space flight and the accompanying diminished muscular activity lead to a loss of body nitrogen and muscle function. These losses may affect crew capabilities and health in long-duration missions. Space flight alters protein metabolism such that the body is unable to maintain protein synthetic rates. A concomitant hypocaloric intake and altered anabolic/catabolic hormonal profiles may contribute to or exacerbate this problem. The inactivity associated with bedrest also reduces muscle and whole-body protein synthesis. For this reason, bedrest provides a good model for the investigation of potential exercise and nutritional countermeasures to restore muscle protein synthesis. We have demonstrated that minimal resistance exercise preserves muscle protein synthesis throughout bedrest. In addition, ongoing work indicates that an essential amino acid and carbohydrate supplement may ameliorate the loss of lean body mass and muscle strength associated with 28 d of bedrest. The investigation of inactivity-induced alterations in protein metabolism, during space flight or prolonged bedrest, is applicable to clinical populations and, in a more general sense, to the problems associated with the decreased activity that occur with aging.

  20. Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor

    PubMed Central

    Chaudhri, Virendra K.; Salzler, Gregory G.; Dick, Salihah A.; Buckman, Melanie S.; Sordella, Raffaella; Karoly, Edward D.; Mohney, Robert; Stiles, Brendon M.; Elemento, Olivier; Altorki, Nasser K.; McGraw, Timothy E.

    2013-01-01

    SUMMARY Cancer cells undergo a metabolic reprogramming but little is known about metabolic alterations of other cells within tumors. We use mass spectrometry-based profiling and a metabolic pathway-based systems analysis to compare 21 primary human lung tumor cancer-associated fibroblast lines (CAFs) to “normal” fibroblast lines (NFs) generated from adjacent non-neoplastic lung tissue. CAFs are pro-tumorigenic, although the mechanisms by which CAFs support tumors have not been elucidated. We have identified several pathways whose metabolite abundance globally distinguished CAFs from NFs, suggesting that metabolic alterations are not limited to cancer cells. In addition, we found metabolic differences between CAFs from high and low glycolytic tumors that might reflect distinct roles of CAFs related to the tumor’s glycolytic capacity. One such change was an increase of dipeptides in CAFs. Dipeptides primarily arise from the breakdown of proteins. We found in CAFs an increase in basal macroautophagy which likely accounts for the increase in dipeptides. Furthermore, we demonstrate a difference between CAFs and NFs in the induction of autophagy promoted by reduced glucose. In sum, our data suggest increased autophagy may account for metabolic differences between CAFs and NFs and may play additional as yet undetermined roles in lung cancer. PMID:23475953

  1. Do altered energy metabolism or spontaneous locomotion 'mediate' decelerated senescence?

    PubMed

    Arum, Oge; Dawson, John Alexander; Smith, Daniel Larry; Kopchick, John J; Allison, David B; Bartke, Andrzej

    2015-06-01

    That one or multiple measures of metabolic rate may be robustly associated with, or possibly even causative of, the progression of aging-resultant phenotypes such as lifespan is a long-standing, well-known mechanistic hypothesis. To broach this hypothesis, we assessed metabolic function and spontaneous locomotion in two genetic and one dietary mouse models for retarded aging, and subjected the data to mediation analyses to determine whether any metabolic or locomotor trait could be identified as a mediator of the effect of any of the interventions on senescence. We do not test the hypothesis of causality (which would require some experiments), but instead test whether the correlation structure of certain variables is consistent with one possible pathway model in which a proposed mediating variable has a causal role. Results for metabolic measures, including oxygen consumption and respiratory quotient, failed to support this hypothesis; similar negative results were obtained for three behavioral motion metrics. Therefore, our mediation analyses did not find support that any of these correlates of decelerated senescence was a substantial mediator of the effect of either of these genetic alterations (with or without caloric restriction) on longevity. Further studies are needed to relate the examined phenotypic characteristics to mechanisms of aging and control of longevity. PMID:25720347

  2. Lipoxygenase- and cyclooxygenase-reaction products and incorporation into glycerolipids or radiolabeled arachidonic acid in the bovine retina

    SciTech Connect

    Birkle, D.L.; Bazan, N.G.

    1984-02-01

    The metabolism of radiolabeled arachidonic acid (AA) by the intact bovine retina in vitro has been studied. Synthesis of prostaglandins (PGs) and hydroxyeicosatetraenoic acids (HETEs), and incorporation of AA into glycerolipids has been measured by reverse-phase and straight-phase high performance liquid chromatography with flow scintillation detection, and by thin-layer chromatography. AA was actively acylated into glycerolipids, particularly triglycerides, phosphatidylcholine and phosphatidylinositol. AA was also converted to the major PGs, PGF2 alpha, PGE2, PGD2, 6-keto-PGF1 alpha and TXB2, and to the lipoxygenase reaction products, 12-HETE, 5-HETE, and other monohydroxy isomers. Approximately 6% of the radiolabeled AA was converted to eicosanoids. The synthesis of HETEs was inhibited in a concentration-dependent manner (IC50 . 8.3 nM) by nordihydroguaiaretic acid (NDGA). PG synthesis was inhibited by aspirin (10 microM), indomethacin (1 microM) and NDGA (IC50 . 380 nM). Metabolism of AA via lipoxygenase, cyclooxygenase and activation-acylation was inhibited by boiling retinal tissue prior to incubation. These studies demonstrate an active system for the uptake and utilization of AA in the bovine retina, and provide the first evidence of lipoxygenase-mediated metabolism of AA, resulting in the synthesis of mono-hydroxyeicosatetraenoic acids, in the retina.

  3. [The hormonal metabolic alterations in patients in critical state].

    PubMed

    Selivanova, A V

    2012-11-01

    It is established that in patients in critical state occur significant alterations of hormone metabolic parameters. In severe cases, hypermetabolism-hyperkatabolism syndrome is developed. Under this syndrome, the resistance to exogenous introduction of nutrients occurs. The syndrome plays a key role in in pathogenesis of critical state and its course in many respects determine outcome of disease. The article describes in detail the pathogenesis of all cascades of pathologic reactions in severe ill patients subject to pathogenic mechanism of development. The possible approaches to resolve this complicated issue are presented. PMID:23305009

  4. Membrane Glycerolipid Remodeling Triggered by Nitrogen and Phosphorus Starvation in Phaeodactylum tricornutum1

    PubMed Central

    Abida, Heni; Dolch, Lina-Juana; Meï, Coline; Villanova, Valeria; Conte, Melissa; Block, Maryse A.; Finazzi, Giovanni; Bastien, Olivier; Tirichine, Leïla; Bowler, Chris; Rébeillé, Fabrice; Petroutsos, Dimitris; Jouhet, Juliette; Maréchal, Eric

    2015-01-01

    Diatoms constitute a major phylum of phytoplankton biodiversity in ocean water and freshwater ecosystems. They are known to respond to some chemical variations of the environment by the accumulation of triacylglycerol, but the relative changes occurring in membrane glycerolipids have not yet been studied. Our goal was first to define a reference for the glycerolipidome of the marine model diatom Phaeodactylum tricornutum, a necessary prerequisite to characterize and dissect the lipid metabolic routes that are orchestrated and regulated to build up each subcellular membrane compartment. By combining multiple analytical techniques, we determined the glycerolipid profile of P. tricornutum grown with various levels of nitrogen or phosphorus supplies. In different P. tricornutum accessions collected worldwide, a deprivation of either nutrient triggered an accumulation of triacylglycerol, but with different time scales and magnitudes. We investigated in depth the effect of nutrient starvation on the Pt1 strain (Culture Collection of Algae and Protozoa no. 1055/3). Nitrogen deprivation was the more severe stress, triggering thylakoid senescence and growth arrest. By contrast, phosphorus deprivation induced a stepwise adaptive response. The time scale of the glycerolipidome changes and the comparison with large-scale transcriptome studies were consistent with an exhaustion of unknown primary phosphorus-storage molecules (possibly polyphosphate) and a transcriptional control of some genes coding for specific lipid synthesis enzymes. We propose that phospholipids are secondary phosphorus-storage molecules broken down upon phosphorus deprivation, while nonphosphorus lipids are synthesized consistently with a phosphatidylglycerol-to-sulfolipid and a phosphatidycholine-to-betaine lipid replacement followed by a late accumulation of triacylglycerol. PMID:25489020

  5. Metabolic Alterations Associated to Brain Dysfunction in Diabetes

    PubMed Central

    Duarte, João M. N

    2015-01-01

    From epidemiological studies it is known that diabetes patients display increased risk of developing dementia. Moreover, cognitive impairment and Alzheimer’s disease (AD) are also accompanied by impaired glucose homeostasis and insulin signalling. Although there is plenty of evidence for a connection between insulin-resistant diabetes and AD, definitive linking mechanisms remain elusive. Cerebrovascular complications of diabetes, alterations in glucose homeostasis and insulin signalling, as well as recurrent hypoglycaemia are the factors that most likely affect brain function and structure. While difficult to study in patients, the mechanisms by which diabetes leads to brain dysfunction have been investigated in experimental models that display phenotypes of the disease. The present article reviews the impact of diabetes and AD on brain structure and function, and discusses recent findings from translational studies in animal models that link insulin resistance to metabolic alterations that underlie brain dysfunction. Such modifications of brain metabolism are likely to occur at early stages of neurodegeneration and impact regional neurochemical profiles and constitute non-invasive biomarkers detectable by magnetic resonance spectroscopy (MRS). PMID:26425386

  6. Unpredictable Chronic Stress Alters Adenosine Metabolism in Zebrafish Brain.

    PubMed

    Zimmermann, F F; Altenhofen, S; Kist, L W; Leite, C E; Bogo, M R; Cognato, G P; Bonan, C D

    2016-05-01

    Stress is considered a risk factor for several human disorders. Despite the broad knowledge of stress responses in mammals, data on the relationship between unpredictable chronic stress (UCS) and its effects on purinergic signaling are limited. ATP hydrolysis by ectonucleotidases is an important source of adenosine, and adenosine deaminase (ADA) contributes to the control of the nucleoside concentrations. Considering that some stress models could affect signaling systems, the objective of this study was to investigate whether UCS alters ectonucleotidase and ADA pathway in zebrafish brain. Additionally, we analyzed ATP metabolism as well as ada1, ada2.1, ada2.2, adaL, and adaasi gene expression in zebrafish brain. Our results have demonstrated that UCS did not alter ectonucleotidase and soluble ADA activities. However, ecto-ADA activity was significantly decreased (26.8%) in brain membranes of animals exposed to UCS when compared to the control group. Quantitative reverse transcription PCR (RT-PCR) analysis did not show significant changes on ADA gene expression after the UCS exposure. The brain ATP metabolism showed a marked increase in adenosine levels (ADO) in animals exposed to UCS. These data suggest an increase on extracellular adenosine levels in zebrafish brain. Since this nucleoside has neuromodulatory and anxiolytic effects, changes in adenosine levels could play a role in counteracting the stress, which could be related to a compensatory mechanism in order to restore the homeostasis. PMID:26081145

  7. Bile Acid Alters Male Mouse Fertility in Metabolic Syndrome Context

    PubMed Central

    Baptissart, Marine; De Haze, Angélique; Vaz, Frederic; Kulik, Wim; Damon-Soubeyrand, Christelle; Baron, Silvère; Caira, Françoise; Volle, David H.

    2015-01-01

    Bile acids have recently been demonstrated as molecules with endocrine activities controlling several physiological functions such as immunity and glucose homeostases. They act mainly through two receptors, the nuclear receptor Farnesol-X-Receptor alpha (FXRα) and the G-protein coupled receptor (TGR5). These recent studies have led to the idea that molecules derived from bile acids (BAs) and targeting their receptors must be good targets for treatment of metabolic diseases such as obesity or diabetes. Thus it might be important to decipher the potential long term impact of such treatment on different physiological functions. Indeed, BAs have recently been demonstrated to alter male fertility. Here we demonstrate that in mice with overweight induced by high fat diet, BA exposure leads to increased rate of male infertility. This is associated with the altered germ cell proliferation, default of testicular endocrine function and abnormalities in cell-cell interaction within the seminiferous epithelium. Even if the identification of the exact molecular mechanisms will need more studies, the present results suggest that both FXRα and TGR5 might be involved. We believed that this work is of particular interest regarding the potential consequences on future approaches for the treatment of metabolic diseases. PMID:26439743

  8. Traumatic Brain Injury Alters Methionine Metabolism: Implications for Pathophysiology

    PubMed Central

    Dash, Pramod K.; Hergenroeder, Georgene W.; Jeter, Cameron B.; Choi, H. Alex; Kobori, Nobuhide; Moore, Anthony N.

    2016-01-01

    Methionine is an essential proteinogenic amino acid that is obtained from the diet. In addition to its requirement for protein biosynthesis, methionine is metabolized to generate metabolites that play key roles in a number of cellular functions. Metabolism of methionine via the transmethylation pathway generates S-adenosylmethionine (SAM) that serves as the principal methyl (−CH3) donor for DNA and histone methyltransferases (MTs) to regulate epigenetic changes in gene expression. SAM is also required for methylation of other cellular proteins that serve various functions and phosphatidylcholine synthesis that participate in cellular signaling. Under conditions of oxidative stress, homocysteine (which is derived from SAM) enters the transsulfuration pathway to generate glutathione, an important cytoprotective molecule against oxidative damage. As both experimental and clinical studies have shown that traumatic brain injury (TBI) alters DNA and histone methylation and causes oxidative stress, we examined if TBI alters the plasma levels of methionine and its metabolites in human patients. Blood samples were collected from healthy volunteers (HV; n = 20) and patients with mild TBI (mTBI; GCS > 12; n = 20) or severe TBI (sTBI; GCS < 8; n = 20) within the first 24 h of injury. The levels of methionine and its metabolites in the plasma samples were analyzed by either liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry (LC-MS or GC-MS). sTBI decreased the levels of methionine, SAM, betaine and 2-methylglycine as compared to HV, indicating a decrease in metabolism through the transmethylation cycle. In addition, precursors for the generation of glutathione, cysteine and glycine were also found to be decreased as were intermediate metabolites of the gamma-glutamyl cycle (gamma-glutamyl amino acids and 5-oxoproline). mTBI also decreased the levels of methionine, α-ketobutyrate, 2 hydroxybutyrate and glycine, albeit to lesser degrees than

  9. Traumatic Brain Injury Alters Methionine Metabolism: Implications for Pathophysiology.

    PubMed

    Dash, Pramod K; Hergenroeder, Georgene W; Jeter, Cameron B; Choi, H Alex; Kobori, Nobuhide; Moore, Anthony N

    2016-01-01

    Methionine is an essential proteinogenic amino acid that is obtained from the diet. In addition to its requirement for protein biosynthesis, methionine is metabolized to generate metabolites that play key roles in a number of cellular functions. Metabolism of methionine via the transmethylation pathway generates S-adenosylmethionine (SAM) that serves as the principal methyl (-CH3) donor for DNA and histone methyltransferases (MTs) to regulate epigenetic changes in gene expression. SAM is also required for methylation of other cellular proteins that serve various functions and phosphatidylcholine synthesis that participate in cellular signaling. Under conditions of oxidative stress, homocysteine (which is derived from SAM) enters the transsulfuration pathway to generate glutathione, an important cytoprotective molecule against oxidative damage. As both experimental and clinical studies have shown that traumatic brain injury (TBI) alters DNA and histone methylation and causes oxidative stress, we examined if TBI alters the plasma levels of methionine and its metabolites in human patients. Blood samples were collected from healthy volunteers (HV; n = 20) and patients with mild TBI (mTBI; GCS > 12; n = 20) or severe TBI (sTBI; GCS < 8; n = 20) within the first 24 h of injury. The levels of methionine and its metabolites in the plasma samples were analyzed by either liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry (LC-MS or GC-MS). sTBI decreased the levels of methionine, SAM, betaine and 2-methylglycine as compared to HV, indicating a decrease in metabolism through the transmethylation cycle. In addition, precursors for the generation of glutathione, cysteine and glycine were also found to be decreased as were intermediate metabolites of the gamma-glutamyl cycle (gamma-glutamyl amino acids and 5-oxoproline). mTBI also decreased the levels of methionine, α-ketobutyrate, 2 hydroxybutyrate and glycine, albeit to lesser degrees than detected

  10. Molecular links between early energy metabolism alterations and Alzheimer's disease.

    PubMed

    Pedros, Ignacio; Patraca, Ivan; Martinez, Nohora; Petrov, Dmitry; Sureda, Francesc X; Auladell, Carme; Beas-Zarate, Carlos; Folch, Jaume

    2016-01-01

    Recent studies suggest that the neurobiology of Alzheimer's disease (AD) pathology could not be explained solely by an increase in beta-amyloid levels. In fact, success with potential therapeutic drugs that inhibit the generation of beta amyloid has been low. Therefore, due to therapeutic failure in recent years, the scientists are looking for alternative hypotheses to explain the causes of the disease and the cognitive loss. Accordingly, alternative hypothesis propose a link between AD and peripheral metabolic alteration. Then, we review in depth changes related to insulin signalling and energy metabolism in the context of the APPSwe/PS1dE9 (APP/PS1) mice model of AD. We show an integrated view of the changes that occur in the early stages of the amyloidogenic process in the APP/PS1 double transgenic mice model. These early changes affect several key metabolic processes related to glucose uptake and insulin signalling, cellular energy homeostasis, mitochondrial biogenesis and increased Tau phosphorylation by kinase molecules like mTOR and Cdk5. PMID:26709757

  11. Alteration of drug metabolizing enzymes in sulphite oxidase deficiency

    PubMed Central

    Tutuncu, Begum; Kuçukatay, Vural; Arslan, Sevki; Sahin, Barbaros; Semiz, Asli; Sen, Alaattin

    2012-01-01

    The aim of this study was to investigate the possible effects of sulphite oxidase (SOX, E.C. 1.8.3.1) deficiency on xenobiotic metabolism. For this purpose, SOX deficiency was produced in rats by the administration of a low molybdenum diet with concurrent addition of 200 ppm tungsten to their drinking water. First, hepatic SOX activity in deficient groups was measured to confirm SOX deficiency. Then, aminopyrine N-demethylase, aniline 4-hydroxylase, aromatase, caffeine N-demethylase, cytochrome b5 reductase, erythromycin N-demethylase, ethoxyresorufin O-deethylase, glutathione S-transferase, N-nitrosodimethylamine N-demethylase and penthoxyresorufin O-deethylase activities were determined to follow changes in the activity of drug metabolizing enzymes in SOX-deficient rats. Our results clearly demonstrated that SOX deficiency significantly elevated A4H, caffeine N-demethylase, erythromycin N-demethylase and N-nitrosodimethylamine N-demethylase activities while decreasing ethoxyresorufin O-deethylase and aromatase activities. These alterations in drug metabolizing enzymes can contribute to the varying susceptibility and response of sulphite-sensitive individuals to different drugs and/or therapeutics used for treatments. PMID:22798713

  12. Alterations in Lipid and Inositol Metabolisms in Two Dopaminergic Disorders

    PubMed Central

    Berger, Hannah S.; Do, Kieu Trinh; Kastenmüller, Gabi; Wahl, Simone; Adamski, Jerzy; Peters, Annette; Krumsiek, Jan; Suhre, Karsten; Haslinger, Bernhard; Ceballos-Baumann, Andres; Gieger, Christian; Winkelmann, Juliane

    2016-01-01

    Background Serum metabolite profiling can be used to identify pathways involved in the pathogenesis of and potential biomarkers for a given disease. Both restless legs syndrome (RLS) and Parkinson`s disease (PD) represent movement disorders for which currently no blood-based biomarkers are available and whose pathogenesis has not been uncovered conclusively. We performed unbiased serum metabolite profiling in search of signature metabolic changes for both diseases. Methods 456 metabolites were quantified in serum samples of 1272 general population controls belonging to the KORA cohort, 82 PD cases and 95 RLS cases by liquid-phase chromatography and gas chromatography separation coupled with tandem mass spectrometry. Genetically determined metabotypes were calculated using genome-wide genotyping data for the 1272 general population controls. Results After stringent quality control, we identified decreased levels of long-chain (polyunsaturated) fatty acids of individuals with PD compared to both RLS (PD vs. RLS: p = 0.0001 to 5.80x10-9) and general population controls (PD vs. KORA: p = 6.09x10-5 to 3.45x10-32). In RLS, inositol metabolites were increased specifically (RLS vs. KORA: p = 1.35x10-6 to 3.96x10-7). The impact of dopaminergic drugs was reflected in changes in the phenylalanine/tyrosine/dopamine metabolism observed in both individuals with RLS and PD. Conclusions A first discovery approach using serum metabolite profiling in two dopamine-related movement disorders compared to a large general population sample identified significant alterations in the polyunsaturated fatty acid metabolism in PD and implicated the inositol metabolism in RLS. These results provide a starting point for further studies investigating new perspectives on factors involved in the pathogenesis of the two diseases as well as possible points of therapeutic intervention. PMID:26808974

  13. Metabolic profiling reveals altered sugar and secondary metabolism in response to UGPase overexpression in Populus

    DOE PAGESBeta

    Payyavula, Raja S.; Tschaplinski, Timothy J.; Jawdy, Sara; Sykes, Robert; Tuskan, Gerald A.; Kalluri, Udaya C.

    2014-10-07

    Background: UDP-glucose pyrophopharylase (UGPase) is a sugar metabolizing enzyme (E.C. 2.7.7.9) that catalyzes a reversible reaction of UDP-glucose and pyrophosphate from glucose-1-phosphate and uridine triphosphate glucose. UDP-glucose is a key intermediate sugar that is channeled to multiple metabolic pathways. The functional role of UGPase in woody plants such as Populus is poorly understood. Results: We characterized the functional role of UGPase in Populus deltoides by overexpressing a native gene. Overexpression of the native gene resulted in increased leaf area and leaf-to-shoot biomass ratio but decreased shoot and root growth. Metabolomic analyses showed that manipulation of UGPase results in perturbations inmore » primary as well as secondary metabolism resulting in reduced sugar and starch levels and increased phenolics such as caffeoyl- and feruloyl conjugates. While cellulose and lignin levels in the cell walls were not significantly altered, the syringyl-to-guaiacyl ratio was significantly reduced. Conclusions: These results demonstrate that UGPase plays a key role in the tightly coupled primary and secondary metabolic pathways and perturbation in its function results in pronounced effects on growth and metabolism outside of cell wall biosynthesis of Populus.« less

  14. Metabolic profiling reveals altered sugar and secondary metabolism in response to UGPase overexpression in Populus

    SciTech Connect

    Payyavula, Raja S.; Tschaplinski, Timothy J.; Jawdy, Sara; Sykes, Robert; Tuskan, Gerald A.; Kalluri, Udaya C.

    2014-10-07

    Background: UDP-glucose pyrophopharylase (UGPase) is a sugar metabolizing enzyme (E.C. 2.7.7.9) that catalyzes a reversible reaction of UDP-glucose and pyrophosphate from glucose-1-phosphate and uridine triphosphate glucose. UDP-glucose is a key intermediate sugar that is channeled to multiple metabolic pathways. The functional role of UGPase in woody plants such as Populus is poorly understood. Results: We characterized the functional role of UGPase in Populus deltoides by overexpressing a native gene. Overexpression of the native gene resulted in increased leaf area and leaf-to-shoot biomass ratio but decreased shoot and root growth. Metabolomic analyses showed that manipulation of UGPase results in perturbations in primary as well as secondary metabolism resulting in reduced sugar and starch levels and increased phenolics such as caffeoyl- and feruloyl conjugates. While cellulose and lignin levels in the cell walls were not significantly altered, the syringyl-to-guaiacyl ratio was significantly reduced. Conclusions: These results demonstrate that UGPase plays a key role in the tightly coupled primary and secondary metabolic pathways and perturbation in its function results in pronounced effects on growth and metabolism outside of cell wall biosynthesis of Populus.

  15. Metabolic engineering of CHO cells to alter lactate metabolism during fed-batch cultures.

    PubMed

    Toussaint, Cécile; Henry, Olivier; Durocher, Yves

    2016-01-10

    Recombinant yeast pyruvate carboxylase (PYC2) expression was previously shown to be an effective metabolic engineering strategy for reducing lactate formation in a number of relevant mammalian cell lines, but, in the case of CHO cells, did not consistently lead to significant improvement in terms of cell growth, product titer and energy metabolism efficiency. In the present study, we report on the establishment of a PYC2-expressing CHO cell line producing a monoclonal antibody and displaying a significantly altered lactate metabolism compared to its parental line. All clones exhibiting strong PYC2 expression were shown to experience a significant and systematic metabolic shift toward lactate consumption, as well as a prolonged exponential growth phase leading to an increased maximum cell concentration and volumetric product titer. Of salient interest, PYC2-expressing CHO cells were shown to maintain a highly efficient metabolism in fed-batch cultures, even when exposed to high glucose levels, thereby alleviating the need of controlling nutrient at low levels and the potential negative impact of such strategy on product glycosylation. In bioreactor operated in fed-batch mode, the higher maximum cell density achieved with the PYC2 clone led to a net gain (20%) in final volumetric productivity. PMID:26603123

  16. Ultraviolet radiation alters choline phospholipid metabolism in human keratinocytes

    SciTech Connect

    DeLeo, V.; Scheide, S.; Meshulam, J.; Hanson, D.; Cardullo, A.

    1988-10-01

    Ultraviolet radiation B (UVB-290-320 nm) induces inflammation and hyperproliferation in human epidermis. This response is associated with the recovery from irradiated skin of inflammatory mediators derived from membrane phospholipids. We have previously reported that UVB stimulates the production of such mediators by human keratinocytes (HK) in culture. In these studies we examined the effect of UVB on the metabolism of choline containing phospholipids in HK prelabeled with (/sup 3/H) choline. UVB (400-1600J/m2) stimulated a dose dependent release of (/sup 3/H) choline from HK within minutes of irradiation. Examination of media extracts by paper chromatography revealed that the released (/sup 3/H) choline was predominately in the form of glycerophosphorylcholine. Examination of label remaining in membranes of cells after irradiation by acid precipitation and HPLC revealed that the origin of the released (/sup 3/H) choline was the membrane phosphatidylcholine/lysophosphatidylcholine. These data support a concept of UVB stimulation of both a phospholipase A (1 or 2) and a lysophospholipase. These UVB induced alterations of HK membrane phospholipid metabolism likely have profound effects on UVB-induced inflammation and control of cell growth in human skin.

  17. Altered arachidonic acid metabolism and platelet size in atopic subjects

    SciTech Connect

    Audera, C.; Rocklin, R.; Vaillancourt, R.; Jakubowski, J.A.; Deykin, D.

    1988-03-01

    The release and metabolism of endogenous arachidonic acid (AA) in physiologically activated platelets obtained from 11 atopic patients with allergic rhinitis and/or asthma was compared to that of sex- and age-matched nonatopic controls. Prelabeled (/sup 3/H)AA platelets were stimulated with thrombin or collagen and the amount of free (/sup 3/H)AA and radiolabeled metabolites released were measured by high-performance liquid chromatography. The results obtained indicate that although the incorporation of (/sup 3/H)AA into platelet phospholipids and total release of /sup 3/H-radioactivity upon stimulation were comparable in the two groups, the percentage of /sup 3/H-radioactivity released from platelets as free AA was significantly lower (P less than 0.01) in the atopic group. The reduction in free (/sup 3/H)AA was accompanied by an increase (P less than 0.01) in the percentage of /sup 3/H-radioactivity released as cyclooxygenase products in atopic platelets (compared to nonatopic cells) after stimulation with 10 and 25 micrograms/ml collagen. The amount of platelet lipoxygenase product released was comparable between the two groups. Although the blood platelet counts were similar, the mean platelet volume was statistically higher (P less than 0.01) in the atopic group. These results indicate that arachidonic acid metabolism in atopic platelets is altered, the pathophysiological significance of which remains to be clarified.

  18. Aflatoxicosis alters avian renal function, calcium, and vitamin D metabolism.

    PubMed

    Glahn, R P; Beers, K W; Bottje, W G; Wideman, R F; Huff, W E; Thomas, W

    1991-11-01

    Experiments were designed to determine the effects of aflatoxicosis on avian renal function, calcium (CA), inorganic phosphorous (Pi), and vitamin D metabolism, and to determine if the effects of aflatoxin are reversible upon discontinuation of toxin administration. Three-week-old male broiler chickens (n = 12 per treatment) received aflatoxin (AF; 2 mg/kg po) or an equal volume of corn oil, the AF carrier vehicle, for 10 consecutive days. After 10 d of treatment, half of the birds from each treatment group were anesthetized and prepared for renal function analysis, which included a 2-h phosphate loading period. Ten days after discontinuation of AF treatment, the remaining birds in each treatment group were anesthetized and prepared for renal function analysis. AF decreased plasma 25-hydroxy vitamin D [25(OH)D] and 1,25-dihydroxy vitamin D [1,25(OH)2D] levels after 5 d of treatment. After 10 d of treatment, urine flow rate (V), fractional sodium excretion (FENa), and fractional potassium excretion (FEK) were lower in AF-treated birds. In addition, total plasma Ca tended to be lower (p = .10) and fractional Ca excretion (FECa) tended to be higher (p = .10) in the AF-treated birds. Intravenous phosphate loading produced a sharp increase in urine hydrogen ion concentration ([H+]) in the AF-treated birds. Glomerular filtration rate (GFR) was reduced and plasma osmolality was increased in AF-treated birds 10 d after discontinuation of toxin administration. The results indicate that AF directly or indirectly affects Ca and Pi metabolism in avians. At the present time, the effects may be related to altered vitamin D and parathyroid hormone (PTH) metabolism. Aflatoxicosis may decrease endogenous PTH synthesis and the renal sensitivity to PTH. The AF-related increase in urine [H+] during phosphate loading is probably due to increased Na+/H+ counterport, suggesting that AF stimulates sodium reabsorption. Also, the decrease in GFR exhibited 10 d after toxin removal indicates

  19. Nitric oxide alters metabolism in isolated alveolar type II cells.

    PubMed

    Miles, P R; Bowman, L; Huffman, L

    1996-07-01

    Alveolar type II cells may be exposed to nitric oxide (.NO) from external sources, and these cells can also generate .NO. Therefore we studied the effects of altering .NO levels on various type II cell metabolic processes. Incubation of cells with the .NO generator, S-nitroso-N-acetylpenicillamine (SNAP; 1 mM), leads to reductions of 60-70% in the synthesis of disaturated phosphatidylcholines (DSPC) and cell ATP levels. Cellular oxygen consumption, an indirect measure of cell ATP synthesis, is also reduced by SNAP. There is no direct effect of SNAP on lung mitochondrial ATP synthesis, suggesting that .NO does not directly inhibit this process. On the other hand, incubation of cells with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), the enzyme responsible for .NO synthesis, results in increases in DSPC synthesis, cell ATP content, and cellular oxygen consumption. The L-NAME effects are reversed by addition of L-arginine, the substrate for NOS. Production of .NO by type II cells is inhibited by L-NAME, a better inhibitor of constitutive NOS (cNOS) than inducible NOS (iNOS), and is reduced in the absence of external calcium. Aminoguanidine, a specific inhibitor of iNOS, has no effect on cell ATP content or on .NO production. These results indicate that alveolar type II cell lipid and energy metabolism can be affected by .NO and suggest that there may be cNOS activity in these cells. PMID:8760128

  20. Metabolic alterations in bladder cancer: applications for cancer imaging.

    PubMed

    Whyard, Terry; Waltzer, Wayne C; Waltzer, Douglas; Romanov, Victor

    2016-02-01

    Treatment planning, outcome and prognosis are strongly related to the adequate tumor staging for bladder cancer (BC). Unfortunately, a large discrepancy exists between the preoperative clinical and final pathologic staging. Therefore, an advanced imaging-based technique is crucial for adequate staging. Although Magnetic Resonance Imaging (MRI) is currently the best in vivo imaging technique for BC staging because of its excellent soft-tissue contrast and absence of ionizing radiation it lacks cancer-specificity. Tumor-specific positron emission tomography (PET), which is based on the Warburg effect (preferential uptake of glucose by cancer cells), exploits the radioactively-labeled glucose analogs, i.e., FDG. Although FDG-PET is highly cancer specific, it lacks resolution and contrast quality comparable with MRI. Chemical Exchange Saturation Transfer (CEST) MRI enables the detection of low concentrations of metabolites containing protons. BC is an attractive target for glucose CEST MRI because, in addition to the typical systemic administration, glucose might also be directly applied into the bladder to reduce toxicity-related complications. As a first stage of the development of a contrast-specific BC imaging technique we have studied glucose uptake by bladder epithelial cells and have observed that glucose is, indeed, consumed by BC cells with higher intensity than by non-transformed urothelial cells. This effect might be partly explained by increased expression of glucose transporters GLUT1 and GLUT3 in transformed cells as compared to normal urothelium. We also detected higher lactate production by BC cells which is another cancer-specific manifestation of the Warburg effect. In addition, we have observed other metabolic alterations in BC cells as compared to non-transformed cells: in particular, increased pyruvate synthesis. When glucose was substituted by glutamine in culture media, preferential uptake of glutamine by BC cells was observed. The preferential

  1. Remodeling of Leaf Cellular Glycerolipid Composition under Drought and Re-hydration Conditions in Grasses from the Lolium-Festuca Complex

    PubMed Central

    Perlikowski, Dawid; Kierszniowska, Sylwia; Sawikowska, Aneta; Krajewski, Paweł; Rapacz, Marcin; Eckhardt, Änne; Kosmala, Arkadiusz

    2016-01-01

    Drought tolerant plant genotypes are able to maintain stability and integrity of cellular membranes in unfavorable conditions, and to regenerate damaged membranes after stress cessation. The profiling of cellular glycerolipids during drought stress performed on model species such as Arabidopsis thaliana does not fully cover the picture of lipidome in monocots, including grasses. Herein, two closely related introgression genotypes of Lolium multiflorum (Italian ryegrass) × Festuca arundinacea (tall fescue) were used as a model for other grass species to describe lipid rearrangements during drought and re-hydration. The genotypes differed in their level of photosynthetic capacity during drought, and in their capacity for membrane regeneration after stress cessation. A total of 120 lipids, comprising the classes of monogalactosyldiacyloglycerol, digalactosyldiacyloglycerol, sulfoquinovosyldiacylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, diacylglicerol, and triacylglicerol, were analyzed. The results clearly showed that water deficit had a significant impact on lipid metabolism in studied forage grasses. It was revealed that structural and metabolic lipid species changed their abundance during drought and re-watering periods and some crucial genotype-dependent differences were also observed. The introgression genotype characterized by an ability to regenerate membranes after re-hydration demonstrated a higher accumulation level of most chloroplast and numerous extra-chloroplast membrane lipid species at the beginning of drought. Furthermore, this genotype also revealed a significant reduction in the accumulation of most chloroplast lipids after re-hydration, compared with the other introgression genotype without the capacity for membrane regeneration. The potential influence of observed lipidomic alterations on a cellular membrane stability and photosynthetic capacity, are discussed

  2. Remodeling of Leaf Cellular Glycerolipid Composition under Drought and Re-hydration Conditions in Grasses from the Lolium-Festuca Complex.

    PubMed

    Perlikowski, Dawid; Kierszniowska, Sylwia; Sawikowska, Aneta; Krajewski, Paweł; Rapacz, Marcin; Eckhardt, Änne; Kosmala, Arkadiusz

    2016-01-01

    Drought tolerant plant genotypes are able to maintain stability and integrity of cellular membranes in unfavorable conditions, and to regenerate damaged membranes after stress cessation. The profiling of cellular glycerolipids during drought stress performed on model species such as Arabidopsis thaliana does not fully cover the picture of lipidome in monocots, including grasses. Herein, two closely related introgression genotypes of Lolium multiflorum (Italian ryegrass) × Festuca arundinacea (tall fescue) were used as a model for other grass species to describe lipid rearrangements during drought and re-hydration. The genotypes differed in their level of photosynthetic capacity during drought, and in their capacity for membrane regeneration after stress cessation. A total of 120 lipids, comprising the classes of monogalactosyldiacyloglycerol, digalactosyldiacyloglycerol, sulfoquinovosyldiacylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, diacylglicerol, and triacylglicerol, were analyzed. The results clearly showed that water deficit had a significant impact on lipid metabolism in studied forage grasses. It was revealed that structural and metabolic lipid species changed their abundance during drought and re-watering periods and some crucial genotype-dependent differences were also observed. The introgression genotype characterized by an ability to regenerate membranes after re-hydration demonstrated a higher accumulation level of most chloroplast and numerous extra-chloroplast membrane lipid species at the beginning of drought. Furthermore, this genotype also revealed a significant reduction in the accumulation of most chloroplast lipids after re-hydration, compared with the other introgression genotype without the capacity for membrane regeneration. The potential influence of observed lipidomic alterations on a cellular membrane stability and photosynthetic capacity, are discussed

  3. Regional metabolic alterations in the hypothalamus of restricted rats

    SciTech Connect

    Beverly, J.L.; Martin, R.J.

    1986-01-01

    Alterations of intermediary and neurotransmitter metabolism in the hypothalamus of rats on restricted intakes have been documented. The rates of fatty acid oxidation (FAO) and glutamic acid decarboxylase (GAD) were measured in hypothalamic sites of restricted or ad libitum fed rats. Female Sprague-Dawley rats (230 g) receiving a semi-purified diet received either ad lib (AL), 3/7 of ad lib as a single meal at 1700 h (R), 3/7 of ad lib by intubation as three equally spaced meals (TF) or ad lib for 3 d followed by 4 d of starvation (S). Rats were sacrificed at 0800 h and the brains quickly removed. FAO: Two 1.0 mm slices were dissected from the hypothalamus and areas corresponding to the VMN, PVN, and DMN removed with a 20 gauge punch. An 18 gauge punch was used to remove MFB/LHA. Bilateral punches were incubated at 37 C for 2 h in Krebs-bicarb. media containing (1-/sup 14/C) palmitate (0.1 ..mu..Ci)/..mu..mole). GAD: The VMN and MFB-LHA were dissected as above. GAD activity was measured in homogenates using L-(/sup 14/C) glutamate (1 /sup +/Ci/..mu..mole) as described by Tappaz et al. (1976). Restriction significantly reduced FAO rates in the MFB/LHA. FAO rate in the VMN was not altered when restriction occurred as a single meal per day (R) but was reduced with restriction as three small meals per day (TF) or a 4 d starvation (S). No differences were noted in PVN or DMN FAO rates. GAD activity did not differ with restriction except in response to starvation in the VMN.

  4. Altered Lipid Metabolism in Brain Injury and Disorders

    PubMed Central

    Adibhatla, Rao Muralikrishna; Hatcher, J. F.

    2008-01-01

    Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-α and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-α and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice

  5. Alcohol alters low density lipoprotein composition and metabolism

    SciTech Connect

    Hoinacki, J.; Brown, J.; Dawson, M.; Deschenes, R.; Mulligan, J. )

    1991-03-11

    Two separate studies were conducted to examine the effect of ethanol (EtOH) dose on atherogenic low density lipoprotein (LDL) subfractions and LDL metabolism in vivo. In the first study, male, atherosclerosis-susceptible squirrel monkeys were divided in three treatments: controls fed liquid diet, and low and high alcohol groups given liquid diet with vodka substituted for carbohydrate at 12% and 24% of calories, respectively. After 6 months, LDL subclasses (LDL{sub 1a}, LDL{sub 1b} and LDL{sub 2}) were isolated by density gradient ultracentrifugation and polyacrylamide gradient gel electrophoresis, and their lipid and protein composition was determined. Low dose EtOH had no effect on LDL subfraction distribution while 24% EtOH resulted in an increase in the larger (LDL{sub 1a} and LDL{sub 1b}), buoyant subspecies without affecting the level of the more atherogenic, smaller, denser LDL{sub 2} particles. In the second study, {sup 125}I-LDL apolipoprotein B (apo B) was injected intravenously into Control and High EtOH monkeys and kinetic analyses were performed. Although the absolute catabolic rate (LDL production) was not altered, High EtOH primates showed a reduction in the fractional catabolic rate and a longer LDL apoB residence time.

  6. Altered chloride metabolism in cultured cystic fibrosis skin fibroblasts

    SciTech Connect

    Mattes, P.M.; Maloney, P.C.; Littlefield, J.W.

    1987-05-01

    An abnormal regulation of chloride permeability has been described for epithelial cells from patients with cystic fibrosis (CF). To learn more about the biochemical basis of this inherited disease, the authors have studied chloride metabolism in cultured CF fibroblasts by comparing the efflux of /sup 36/Cl/sup -/ from matched pairs of CF and normal fibroblasts. The rate constants describing /sup 36/Cl/sup -/ efflux did not differ between the two cell types, but in each of the four pairs tested the amount of /sup 36/Cl/sup -/ contained within CF cells was consistently reduced, by 25-30%, relative to normal cells. Comparisons of cell water content and /sup 22/Na/sup +/ efflux showed no differences between the two cell types, suggesting that overall intracellular chloride concentration is lower than normal in CF fibroblasts. Such data suggest that the CF gene defect is expressed in skin fibroblasts and that this defect may alter the regulation of intracellular Cl/sup -/ concentration, perhaps through changes in Cl/sup -/ permeability.

  7. Serum Metabolic Profiling Reveals Altered Metabolic Pathways in Patients with Post-traumatic Cognitive Impairments

    PubMed Central

    Yi, Lunzhao; Shi, Shuting; Wang, Yang; Huang, Wei; Xia, Zi-an; Xing, Zhihua; Peng, Weijun; Wang, Zhe

    2016-01-01

    Cognitive impairment, the leading cause of traumatic brain injury (TBI)-related disability, adversely affects the quality of life of TBI patients, and exacts a personal and economic cost that is difficult to quantify. The underlying pathophysiological mechanism is currently unknown, and an effective treatment of the disease has not yet been identified. This study aimed to advance our understanding of the mechanism of disease pathogenesis; thus, metabolomics based on gas chromatography/mass spectrometry (GC-MS), coupled with multivariate and univariate statistical methods were used to identify potential biomarkers and the associated metabolic pathways of post-TBI cognitive impairment. A biomarker panel consisting of nine serum metabolites (serine, pyroglutamic acid, phenylalanine, galactose, palmitic acid, arachidonic acid, linoleic acid, citric acid, and 2,3,4-trihydroxybutyrate) was identified to be able to discriminate between TBI patients with cognitive impairment, TBI patients without cognitive impairment and healthy controls. Furthermore, associations between these metabolite markers and the metabolism of amino acids, lipids and carbohydrates were identified. In conclusion, our study is the first to identify several serum metabolite markers and investigate the altered metabolic pathway that is associated with post-TBI cognitive impairment. These markers appear to be suitable for further investigation of the disease mechanisms of post-TBI cognitive impairment. PMID:26883691

  8. Peroxisome proliferators alter the expression of estrogen-metabolizing enzymes.

    PubMed

    Corton, J C; Bocos, C; Moreno, E S; Merritt, A; Cattley, R C; Gustafsson, J A

    1997-01-01

    Exposure to some peroxisome proliferator chemicals (PPC) leads to toxic effects on sex organ function possibly by alterations of steroid hormone metabolism. A systematic search for genes whose mRNA levels are modulated by the PPC WY-14643 (WY) was carried out in rat liver, a site of steroid hormone metabolism. The sequence of one up-regulated cDNA (2480 bp) was predicted to encode a protein of 735 amino acids with 82% identity to the porcine 17 beta-hydroxysteroid dehydrogenase type IV (HSD IV) originally isolated as a 17 beta-estradiol dehydrogenase. The rat HSD IV was localized to peroxisomes and was regulated by diverse PPC by two distinct mechanisms. Induction of HSD IV and acyl-CoA oxidase (ACO) proteins in rat liver at different treatment times and concentrations of gemfibrozil (GEM) and di-n-butyl phthalate (DBP) were almost identical, suggesting that HSD IV mRNA induction involves the peroxisome proliferator-activated receptor alpha, a regulator of ACO. In contrast, HSD IV protein levels were only weakly induced by WY, a strong inducer of ACO protein, even though the levels of both HSD IV and ACO mRNA were strongly stimulated by WY. Thus HSD IV protein levels were uniquely regulated pretranslationally by WY. In addition to HSD IV we also identified the male-specific alpha 2u-globulin as a PPC down-regulated gene. This prompted us to examine the expression of another male-specific gene, CYP2C11, that catalyzes the hydroxylations of estradiol at the 2 and 16 alpha positions. Cyp2C11 protein expression in rat liver was either decreased or completely abolished after a 3-week treatment by GEM or WY, respectively. Decreased expression of enzymes which inactivate estradiol including Cyp2C11, and the reported increased expression of aromatase may explain why male rats exposed to diverse PPC have higher serum estradiol levels. These higher estradiol levels in male rats have been thought to be mechanistically linked to Leydig cell hyperplasia and adenomas. Increased

  9. Amino acid supplementation alters bone metabolism during simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Zwart, S. R.; Davis-Street, J. E.; Paddon-Jones, D.; Ferrando, A. A.; Wolfe, R. R.; Smith, S. M.

    2005-01-01

    High-protein and acidogenic diets induce hypercalciuria. Foods or supplements with excess sulfur-containing amino acids increase endogenous sulfuric acid production and therefore have the potential to increase calcium excretion and alter bone metabolism. In this study, effects of an amino acid/carbohydrate supplement on bone resorption were examined during bed rest. Thirteen subjects were divided at random into two groups: a control group (Con, n = 6) and an amino acid-supplemented group (AA, n = 7) who consumed an extra 49.5 g essential amino acids and 90 g carbohydrate per day for 28 days. Urine was collected for n-telopeptide (NTX), deoxypyridinoline (DPD), calcium, and pH determinations. Bone mineral content was determined and potential renal acid load was calculated. Bone-specific alkaline phosphatase was measured in serum samples collected on day 1 (immediately before bed rest) and on day 28. Potential renal acid load was higher in the AA group than in the Con group during bed rest (P < 0.05). For all subjects, during bed rest urinary NTX and DPD concentrations were greater than pre-bed rest levels (P < 0.05). Urinary NTX and DPD tended to be higher in the AA group (P = 0.073 and P = 0.056, respectively). During bed rest, urinary calcium was greater than baseline levels (P < 0.05) in the AA group but not the Con group. Total bone mineral content was lower after bed rest than before bed rest in the AA group but not the Con group (P < 0.05). During bed rest, urinary pH decreased (P < 0.05), and it was lower in the AA group than the Con group. These data suggest that bone resorption increased, without changes in bone formation, in the AA group.

  10. Retinal Remodeling and Metabolic Alterations in Human AMD

    PubMed Central

    Jones, Bryan W.; Pfeiffer, Rebecca L.; Ferrell, William D.; Watt, Carl B.; Tucker, James; Marc, Robert E.

    2016-01-01

    Age-related macular degeneration (AMD) is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression. The pathways and mechanisms through which genetic and non-genetic risk factors modulate development of AMD pathogenesis remain largely unexplored. Moreover, current treatment for AMD is palliative and limited to wet/exudative forms. Retina is a complex, heterocellular tissue and most retinal cell classes are impacted or altered in AMD. Defining disease and stage-specific cytoarchitectural and metabolic responses in AMD is critical for highlighting targets for intervention. The goal of this article is to illustrate cell types impacted in AMD and demonstrate the implications of those changes, likely beginning in the retinal pigment epithelium (RPE), for remodeling of the the neural retina. Tracking heterocellular responses in disease progression is best achieved with computational molecular phenotyping (CMP), a tool that enables acquisition of a small molecule fingerprint for every cell in the retina. CMP uncovered critical cellular and molecular pathologies (remodeling and reprogramming) in progressive retinal degenerations such as retinitis pigmentosa (RP). We now applied these approaches to normal human and AMD tissues mapping progression of cellular and molecular changes in AMD retinas, including late-stage forms of the disease. PMID:27199657

  11. Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

    PubMed Central

    Vuong, Chau; Xie, Lisa H.; Potter, Brittney M. J.; Zhang, Jing; Zhang, Ping; Duan, Dehui; Nolan, Christina K.; Sciotti, Richard J.; Zottig, Victor E.; Nanayakkara, N. P. Dhammika; Tekwani, Babu L.; Walker, Larry A.; Smith, Philip L.; Paris, Robert M.; Read, Lisa T.; Li, Qigui; Pybus, Brandon S.; Sousa, Jason C.; Reichard, Gregory A.; Smith, Bryan

    2015-01-01

    Cytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for Plasmodium vivax radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYPmouse 2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-ortho-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-ortho-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations. PMID:25870069

  12. Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

    PubMed Central

    Romero, Freddy; Shah, Dilip; Duong, Michelle; Stafstrom, William; Hoek, Jan B.; Kallen, Caleb B.; Lang, Charles H.

    2014-01-01

    Chronic alcoholism impairs pulmonary immune homeostasis and predisposes to inflammatory lung diseases, including infectious pneumonia and acute respiratory distress syndrome. Although alcoholism has been shown to alter hepatic metabolism, leading to lipid accumulation, hepatitis, and, eventually, cirrhosis, the effects of alcohol on pulmonary metabolism remain largely unknown. Because both the lung and the liver actively engage in lipid synthesis, we hypothesized that chronic alcoholism would impair pulmonary metabolic homeostasis in ways similar to its effects in the liver. We reasoned that perturbations in lipid metabolism might contribute to the impaired pulmonary immunity observed in people who chronically consume alcohol. We studied the metabolic consequences of chronic alcohol consumption in rat lungs in vivo and in alveolar epithelial type II cells and alveolar macrophages (AMs) in vitro. We found that chronic alcohol ingestion significantly alters lung metabolic homeostasis, inhibiting AMP-activated protein kinase, increasing lipid synthesis, and suppressing the expression of genes essential to metabolizing fatty acids (FAs). Furthermore, we show that these metabolic alterations promoted a lung phenotype that is reminiscent of alcoholic fatty liver and is characterized by marked accumulation of triglycerides and free FAs within distal airspaces, AMs, and, to a lesser extent, alveolar epithelial type II cells. We provide evidence that the metabolic alterations in alcohol-exposed rats are mechanistically linked to immune impairments in the alcoholic lung: the elevations in FAs alter AM phenotypes and suppress both phagocytic functions and agonist-induced inflammatory responses. In summary, our work demonstrates that chronic alcohol ingestion impairs lung metabolic homeostasis and promotes pulmonary immune dysfunction. These findings suggest that therapies aimed at reversing alcohol-related metabolic alterations might be effective for preventing and

  13. Trichogramma parasitoids alter the metabolic physiology of Manduca eggs.

    PubMed

    Potter, Kristen A; Woods, H Arthur

    2012-09-01

    Egg parasitoids face unique developmental constraints. First, they have exceptionally limited resources to support themselves and their siblings through three life stages. Second, they develop within the physiological system of another species, which they modify to their own ends. We examined how these constraints affect the metabolic physiology of egg parasitism, and whether parasitoids retool their host eggshell to account for their different metabolic demands. Higher-conductance eggshells allow more oxygen to reach the developing parasitoids, but also allow more water to leave the egg. We used Manduca sexta (Lepidoptera: Sphingidae) eggs and Trichogramma (Hymenoptera: Trichogrammatidae) parasitoids from southeastern AZ, USA. Compared with unparasitized Manduca eggs, eggs parasitized by Trichogramma had lower peak metabolic rates and approximately 50 per cent lower metabolic efficiency. However, developing Trichogramma were far more efficient than typical transfer efficiencies between tropic levels (approx. 10%). Even within a few hours of parasitization, eggs containing more Trichogramma had lower per-parasitoid metabolic rates, suggesting that parasitoid larvae have mechanisms for rapidly adjusting their metabolic rates based on number of siblings. Parasitoids also appear to control the conductance of their host eggshell: their different metabolic demands were mirrored by shifts in rates of water loss. PMID:22719035

  14. Differential CYP 2D6 Metabolism Alters Primaquine Pharmacokinetics

    PubMed Central

    Potter, Brittney M. J.; Xie, Lisa H.; Vuong, Chau; Zhang, Jing; Zhang, Ping; Duan, Dehui; Luong, Thu-Lan T.; Bandara Herath, H. M. T.; Dhammika Nanayakkara, N. P.; Tekwani, Babu L.; Walker, Larry A.; Nolan, Christina K.; Sciotti, Richard J.; Zottig, Victor E.; Smith, Philip L.; Paris, Robert M.; Read, Lisa T.; Li, Qigui; Pybus, Brandon S.; Sousa, Jason C.; Reichard, Gregory A.

    2015-01-01

    Primaquine (PQ) metabolism by the cytochrome P450 (CYP) 2D family of enzymes is required for antimalarial activity in both humans (2D6) and mice (2D). Human CYP 2D6 is highly polymorphic, and decreased CYP 2D6 enzyme activity has been linked to decreased PQ antimalarial activity. Despite the importance of CYP 2D metabolism in PQ efficacy, the exact role that these enzymes play in PQ metabolism and pharmacokinetics has not been extensively studied in vivo. In this study, a series of PQ pharmacokinetic experiments were conducted in mice with differential CYP 2D metabolism characteristics, including wild-type (WT), CYP 2D knockout (KO), and humanized CYP 2D6 (KO/knock-in [KO/KI]) mice. Plasma and liver pharmacokinetic profiles from a single PQ dose (20 mg/kg of body weight) differed significantly among the strains for PQ and carboxy-PQ. Additionally, due to the suspected role of phenolic metabolites in PQ efficacy, these were probed using reference standards. Levels of phenolic metabolites were highest in mice capable of metabolizing CYP 2D6 substrates (WT and KO/KI 2D6 mice). PQ phenolic metabolites were present in different quantities in the two strains, illustrating species-specific differences in PQ metabolism between the human and mouse enzymes. Taking the data together, this report furthers understanding of PQ pharmacokinetics in the context of differential CYP 2D metabolism and has important implications for PQ administration in humans with different levels of CYP 2D6 enzyme activity. PMID:25645856

  15. Modulating the gut flora alters amino acid metabolism in neonatal pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Intestinal microbes consume and produce amino acids (AA). This may impact intestinal threonine (THR) metabolism necessary for adequate gut function. We hypothesized that modulating the gut flora results in an alteration of intestinal THR utilization and hence whole body AA metabolism. Neonatal pigs ...

  16. Characterization of the Glycerolipid Composition and Biosynthetic Capacity of Pea Root Plastids.

    PubMed Central

    Xue, L.; McCune, L. M.; Kleppinger-Sparace, K. F.; Brown, M. J.; Pomeroy, M. K.; Sparace, S. A.

    1997-01-01

    The glycerolipid composition of pea (Pisum sativum L.) root plastids and their capacity to synthesize glycerolipids from [UL-14C]glycerol-3-phosphate were determined. Pea root plastids primarily consist of monogalactosyldiacylglycerol, triacylglycerol, phosphatidylcholine, digalactosyldiacylglycerol, and diacylglycerol. Maximum rates of total glycerolipid biosynthesis were obtained in the presence of 2.4 mM glycerol-3-phosphate, 15 mM KHCO3, 0.2 mM sodium-acetate, 0.5 mM each of NADH and NADPH, 0.05 mM coenzyme A, 2 mM MgCl2, 1 mM ATP, 0.1 M Bis-Tris propane (pH 7.5), and 0.31 M sorbitol. Glycerolipid biosynthesis was completely dependent on exogenously supplied ATP, coenzyme A, and a divalent cation, whereas the remaining cofactors improved their activity from 1.3- to 2.4-fold. Radioactivity from glycerol-3-phosphate was recovered predominantly in phosphatidic acid, phosphatidylglycerol, diacylglycerol, and triacylglycerol with lesser amounts in phosphatidylcholine and monoacylglycerol. The proportions of the various radiolabeled lipids that accumulated were dependent on the pH and the concentration of ATP and glycerol-3-phosphate. The data presented indicate that pea root plastids can synthesize almost all of their component glycerolipids and that glycerolipid biosynthesis is tightly coupled to de novo fatty acid biosynthesis. pH and the availability of ATP may have important roles in the regulation of lipid biosynthesis at the levels of phosphatidic acid phosphatase and in the reactions that are involved in phosphatidylglycerol and triacylglycerol biosynthesis. PMID:12223625

  17. Radiation Exposure Alters Expression of Metabolic Enzyme Genes in Mice

    NASA Technical Reports Server (NTRS)

    Wotring, V. E.; Mangala, L. S.; Zhang, Y.; Wu, H.

    2011-01-01

    Most administered pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand the effects of spaceflight on the enzymes of the liver and exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. Additionally, it has been previous noted that pre-exposure to small radiation doses seems to confer protection against later and larger radiation doses. This protective power of pre-exposure has been called a priming effect or radioadaptation. This study is an effort to examine the drug metabolizing effects of radioadaptation mechanisms that may be triggered by early exposure to low radiation doses.

  18. Diabetes-Induced Decrease in Renal Oxygen Tension: Effects of an Altered Metabolism

    NASA Astrophysics Data System (ADS)

    Palm, Fredrik; Carlsson, Per-Ola; Fasching, Angelica; Hansell, Peter; Liss, Per

    During conditions with experimental diabetes mellitus, it is evident that several alterations in renal oxygen metabolism occur, including increased mitochondrial respiration and increased lactate accumulation in the renal tissue. Consequently, these alterations will contribute to decrease the interstitial pO2, preferentially in the renal medulla of animals with sustained long-term hyperglycemia.

  19. Antidepressants Alter Cerebrovascular Permeability and Metabolic Rate in Primates

    NASA Astrophysics Data System (ADS)

    Preskorn, Sheldon H.; Raichle, Marcus E.; Hartman, Boyd K.

    1982-07-01

    External detection of the annihilation radiation produced by water labeled with oxygen-15 was used to measure cerebrovascular permeability and cerebral blood flow in six rhesus monkeys. Use of oxygen-15 also permitted assessment of cerebral metabolic rate in two of the monkeys. Amitriptyline produced a dose-dependent, reversible increase in permeability at plasma drug concentrations which are therapeutic for depressed patients. At the same concentrations the drug also produced a 20 to 30 percent reduction in cerebral metabolic rate. At higher doses normal autoregulation of cerebral blood flow was suspended, but responsivity to arterial carbon dioxide was normal.

  20. Metabolism alteration in follicular niche: The nexus among intermediary metabolism, mitochondrial function, and classic polycystic ovary syndrome.

    PubMed

    Zhao, Hongcui; Zhao, Yue; Li, Tianjie; Li, Min; Li, Junsheng; Li, Rong; Liu, Ping; Yu, Yang; Qiao, Jie

    2015-09-01

    Classic polycystic ovary syndrome (PCOS) is a high-risk phenotype accompanied by increased risks of reproductive and metabolic abnormalities; however, the local metabolism characteristics of the ovaries and their effects on germ cell development are unclear. The present study used targeted metabolomics to detect alterations in the intermediate metabolites of follicular fluid from classic PCOS patients, and the results indicated that hyperandrogenism but not obesity induced the changed intermediate metabolites in classic PCOS patients. Regarding the direct contact, we identified mitochondrial function, redox potential, and oxidative stress in cumulus cells which were necessary to support oocyte growth before fertilization, and suggested dysfunction of mitochondria, imbalanced redox potential, and increased oxidative stress in cumulus cells of classic PCOS patients. Follicular fluid intermediary metabolic profiles provide signatures of classic PCOS ovary local metabolism and establish a close link with mitochondria dysfunction of cumulus cells, highlighting the role of metabolic signal and mitochondrial cross talk involved in the pathogenesis of classic PCOS. PMID:26057937

  1. Altered glucose metabolism in mouse and humans conceived by IVF.

    PubMed

    Chen, Miaoxin; Wu, Linda; Zhao, Junli; Wu, Fang; Davies, Michael J; Wittert, Gary A; Norman, Robert J; Robker, Rebecca L; Heilbronn, Leonie K

    2014-10-01

    In vitro fertilization (IVF) may influence the metabolic health of children. However, in humans, it is difficult to separate out the relative contributions of genetics, environment, or the process of IVF, which includes ovarian stimulation (OS) and embryo culture. Therefore, we examined glucose metabolism in young adult humans and in adult male C57BL/6J mice conceived by IVF versus natural birth under energy-balanced and high-fat-overfeeding conditions. In humans, peripheral insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (80 mU/m(2)/min), was lower in IVF patients (n = 14) versus control subjects (n = 20) after 3 days of an energy-balanced diet (30% fat). In response to 3 days of overfeeding (+1,250 kcal/day, 45% fat), there was a greater increase in systolic blood pressure in IVF versus controls (P = 0.02). Mice conceived after either OS alone or IVF weighed significantly less at birth versus controls (P < 0.01). However, only mice conceived by IVF displayed increased fasting glucose levels, impaired glucose tolerance, and reduced insulin-stimulated Akt phosphorylation in the liver after 8 weeks of consuming either a chow or high-fat diet (60% fat). Thus, OS impaired fetal growth in the mouse, but only embryo culture resulted in changes in glucose metabolism that may increase the risk of the development of metabolic diseases later in life, in both mice and humans. PMID:24760136

  2. ALTERED METHIONINE METABOLISM IN LONG LIVING AMES DWARF MICE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ames dwarf mice (df/df) are deficient in growth hormone, prolactin, and thyroid-stimulating hormone and live significantly longer than their normal siblings. In the current study, we found that the hormone deficiencies affect methionine metabolism. We previously reported that the dwarf mice exhibit ...

  3. Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD+ oscillation

    PubMed Central

    Sahar, Saurabh; Nin, Veronica; Barbosa, Maria Thereza; Chini, Eduardo Nunes; Sassone-Corsi, Paolo

    2011-01-01

    The Intracellular levels of nicotinamide adenine dinucleotide (NAD+) are rhythmic and controlled by the circadian clock. However, whether NAD+ oscillation in turn contributes to circadian physiology is not fully understood. To address this question we analyzed mice mutated for the NAD+ hydrolase CD38. We found that rhythmicity of NAD+ was altered in the CD38-deficient mice. The high, chronic levels of NAD+ results in several anomalies in circadian behavior and metabolism. CD38-null mice display a shortened period length of locomotor activity and alteration in the rest-activity rhythm. Several clock genes and, interestingly, genes involved in amino acid metabolism were deregulated in CD38-null livers. Metabolomic analysis identified alterations in the circadian levels of several amino acids, specifically tryptophan levels were reduced in the CD38-null mice at a circadian time paralleling with elevated NAD+ levels. Thus, CD38 contributes to behavioral and metabolic circadian rhythms and altered NAD+ levels influence the circadian clock. PMID:21937766

  4. Degeneration of Dopaminergic Neurons Due to Metabolic Alterations and Parkinson’s Disease

    PubMed Central

    Song, Juhyun; Kim, Jongpil

    2016-01-01

    The rates of metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, and cardiovascular disease (CVD), markedly increase with age. In recent years, studies have reported an association between metabolic changes and various pathophysiological mechanisms in the central nervous system (CNS) in patients with metabolic diseases. Oxidative stress and hyperglycemia in metabolic diseases lead to adverse neurophysiological phenomena, including neuronal loss, synaptic dysfunction, and improper insulin signaling, resulting in Parkinson’s disease (PD). In addition, several lines of evidence suggest that alterations of CNS environments by metabolic changes influence the dopamine neuronal loss, eventually affecting the pathogenesis of PD. Thus, we reviewed recent findings relating to degeneration of dopaminergic neurons during metabolic diseases. We highlight the fact that using a metabolic approach to manipulate degeneration of dopaminergic neurons can serve as a therapeutic strategy to attenuate pathology of PD. PMID:27065205

  5. Altered Circadian Rhythm and Metabolic Gene Profile in Rats Subjected to Advanced Light Phase Shifts

    PubMed Central

    Herrero, Laura; Valcarcel, Lorea; da Silva, Crhistiane Andressa; Albert, Nerea; Diez-Noguera, Antoni; Cambras, Trinitat; Serra, Dolors

    2015-01-01

    The circadian clock regulates metabolic homeostasis and its disruption predisposes to obesity and other metabolic diseases. However, the effect of phase shifts on metabolism is not completely understood. We examined whether alterations in the circadian rhythm caused by phase shifts induce metabolic changes in crucial genes that would predispose to obesity. Three-month-old rats were maintained on a standard diet under lighting conditions with chronic phase shifts consisting of advances, delays or advances plus delays. Serum leptin, insulin and glucose levels decreased only in rats subjected to advances. The expression of the clock gene Bmal 1 increased in the hypothalamus, white adipose tissue (WAT), brown adipose tissue (BAT) and liver of the advanced group compared to control rats. The advanced group showed an increase in hypothalamic AgRP and NPY mRNA, and their lipid metabolism gene profile was altered in liver, WAT and BAT. WAT showed an increase in inflammation and ER stress and brown adipocytes suffered a brown-to-white transformation and decreased UCP-1 expression. Our results indicate that chronic phase advances lead to significant changes in neuropeptides, lipid metabolism, inflammation and ER stress gene profile in metabolically relevant tissues such as the hypothalamus, liver, WAT and BAT. This highlights a link between alteration of the circadian rhythm and metabolism at the transcriptional level. PMID:25837425

  6. Arabidopsis GPAT9 contributes to synthesis of intracellular glycerolipids but not surface lipids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    GLYCEROL-3-PHOSPHATE ACYLTRANSFERASE (GPAT) genes encode enzymes involved in glycerolipid biosynthesis in plants. Ten GPAT homologues have been identified in Arabidopsis thaliana (Arabidopsis). GPATs 4-8 have been shown to be involved in the production of extracellular lipid barrier polyesters. Rece...

  7. Experimental ocean acidification alters the allocation of metabolic energy

    PubMed Central

    Pan, T.-C. Francis; Applebaum, Scott L.; Manahan, Donal T.

    2015-01-01

    Energy is required to maintain physiological homeostasis in response to environmental change. Although responses to environmental stressors frequently are assumed to involve high metabolic costs, the biochemical bases of actual energy demands are rarely quantified. We studied the impact of a near-future scenario of ocean acidification [800 µatm partial pressure of CO2 (pCO2)] during the development and growth of an important model organism in developmental and environmental biology, the sea urchin Strongylocentrotus purpuratus. Size, metabolic rate, biochemical content, and gene expression were not different in larvae growing under control and seawater acidification treatments. Measurements limited to those levels of biological analysis did not reveal the biochemical mechanisms of response to ocean acidification that occurred at the cellular level. In vivo rates of protein synthesis and ion transport increased ∼50% under acidification. Importantly, the in vivo physiological increases in ion transport were not predicted from total enzyme activity or gene expression. Under acidification, the increased rates of protein synthesis and ion transport that were sustained in growing larvae collectively accounted for the majority of available ATP (84%). In contrast, embryos and prefeeding and unfed larvae in control treatments allocated on average only 40% of ATP to these same two processes. Understanding the biochemical strategies for accommodating increases in metabolic energy demand and their biological limitations can serve as a quantitative basis for assessing sublethal effects of global change. Variation in the ability to allocate ATP differentially among essential functions may be a key basis of resilience to ocean acidification and other compounding environmental stressors. PMID:25825763

  8. Altered asymmetric dimethyl arginine metabolism in allergically inflamed mouse lungs.

    PubMed

    Ahmad, Tanveer; Mabalirajan, Ulaganathan; Ghosh, Balaram; Agrawal, Anurag

    2010-01-01

    Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), causes uncoupling of NOS leading to generation of reactive nitrogen species, such as peroxynitrite. The lung generates a significant amount of ADMA, potentially contributing to plasma ADMA levels that have been related to endothelial dysfunction. ADMA infusion causes increased collagen deposition in lungs, suggesting that it could influence the development of chronic lung diseases such as fibrosis, chronic obstructive pulmonary disease, and asthma. To explore the link between endogenous ADMA and asthma, we determined the levels of ADMA, enzymes implicated in its metabolism, and peroxynitrite in murine models of allergic airway inflammation (AAI) resembling asthma. ADMA levels and nitrosative stress were found to be positively correlated in cytosol and mitochondria during AAI. This was associated with increased expression of protein-arginine methyltransferase-2, an ADMA-synthesizing enzyme, and reduced expression of dimethylarginine dimethylaminohydrolase-2, an ADMA-degrading enzyme, in bronchial epithelia. Increased nitrotyrosine similarly localized to the bronchial epithelium, as well as in infiltrated inflammatory cells. Administration of L-arginine, which was expected to compete with ADMA and reverse the uncoupling/inhibition of NOS, restored normal ADMA metabolism, along with the expected reduction of nitrosative stress in lung. Because dimethylarginine dimethylaminohydrolase-2 function is known to be negatively related to oxidative stress, this may represent a feed-forward loop effect. We conclude that a delicate balance between ADMA-metabolizing enzymes is disturbed in bronchial epithelium during AAI, potentially causing increased nitrosative stress in a self-propagating cycle. This represents a potential therapeutic target in asthma. PMID:19648472

  9. Experimental ocean acidification alters the allocation of metabolic energy.

    PubMed

    Pan, T-C Francis; Applebaum, Scott L; Manahan, Donal T

    2015-04-14

    Energy is required to maintain physiological homeostasis in response to environmental change. Although responses to environmental stressors frequently are assumed to involve high metabolic costs, the biochemical bases of actual energy demands are rarely quantified. We studied the impact of a near-future scenario of ocean acidification [800 µatm partial pressure of CO2 (pCO2)] during the development and growth of an important model organism in developmental and environmental biology, the sea urchin Strongylocentrotus purpuratus. Size, metabolic rate, biochemical content, and gene expression were not different in larvae growing under control and seawater acidification treatments. Measurements limited to those levels of biological analysis did not reveal the biochemical mechanisms of response to ocean acidification that occurred at the cellular level. In vivo rates of protein synthesis and ion transport increased ∼50% under acidification. Importantly, the in vivo physiological increases in ion transport were not predicted from total enzyme activity or gene expression. Under acidification, the increased rates of protein synthesis and ion transport that were sustained in growing larvae collectively accounted for the majority of available ATP (84%). In contrast, embryos and prefeeding and unfed larvae in control treatments allocated on average only 40% of ATP to these same two processes. Understanding the biochemical strategies for accommodating increases in metabolic energy demand and their biological limitations can serve as a quantitative basis for assessing sublethal effects of global change. Variation in the ability to allocate ATP differentially among essential functions may be a key basis of resilience to ocean acidification and other compounding environmental stressors. PMID:25825763

  10. IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism

    PubMed Central

    Grassian, Alexandra R.; Parker, Seth J.; Davidson, Shawn M.; Divakarun, Ajit S.; Green, Courtney R.; Zhang, Xiamei; Slocum, Kelly L.; Pu, Minying; Lin, Fallon; Vickers, Chad; Joud-Caldwell, Carol; Chung, Franklin; Yin, Hong; Handly, Erika D.; Straub, Christopher; Growney, Joseph D.; Vander Heiden, Matthew G.; Murphy, Anne N.; Pagliarini, Raymond; Metallo, Christian M.

    2016-01-01

    Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed 13C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation. PMID:24755473

  11. Altered phosphate metabolism in myocardial infarction: P-31 MR spectroscopy

    SciTech Connect

    Bottomley, P.A.; Herfkens, R.J.; Smith, L.S.; Bashore, T.M.

    1987-12-01

    The high-energy myocardial phosphate metabolism of four patients with acute anterior myocardial infarction after coronary angioplasty and drug therapy was evaluated with cardiac-gated phosphorus magnetic resonance (MR) depth-resolved surface coil spectroscopy (DRESS) 5-9 days after the onset of symptoms. Significant reductions (about threefold) in the phosphocreatine (PCr) to inorganic phosphate (Pi) ratio and elevations in the Pi to adenosine triphosphate (ATP) ratio were observed in endocardially or transmurally derived MR spectra when compared with values from epicardially displaced spectra and values from seven healthy volunteers (P less than .05). High-energy phosphate metabolites and Pi ratios did not vary significantly during the cardiac cycle in healthy volunteers. However, contamination of Pi resonances by phosphomonoester components, including blood 2,3-diphosphoglycerate, precluded accurate spectral quantification of Pi and pH. The results indicate that localized P-31 MR spectroscopy may be used to directly assess cellular energy reserve in clinical myocardial infarction and to evaluate metabolic response to interventions.

  12. Adding biotic complexity alters the metabolic benefits of mutualism.

    PubMed

    Harcombe, William R; Betts, Alex; Shapiro, Jason W; Marx, Christopher J

    2016-08-01

    Mutualism is ubiquitous in nature and plays an integral role in most communities. To predict the eco-evolutionary dynamics of mutualism it is critical to extend classic pair-wise analysis to include additional species. We investigated the effect of adding a third species to a pair-wise mutualism in a spatially structured environment. We tested the hypotheses that selection for costly excretions in a focal population (i) decreases when an exploiter is added (ii) increases when a third mutualist is added relative to the pair-wise scenario. We assayed the selection acting on Salmonella enterica when it exchanges methionine for carbon in an obligate mutualism with an auxotrophic Escherichia coli. A third bacterium, Methylobacterium extorquens, was then added and acted either as an exploiter of the carbon or third obligate mutualist depending on the nitrogen source. In the tripartite mutualism M. extorquens provided nitrogen to the other species. Contrary to our expectations, adding an exploiter increased selection for methionine excretion in S. enterica. Conversely, selection for cooperation was lower in the tripartite mutualism relative to the pair-wise system. Genome-scale metabolic models helped identify the mechanisms underlying these changes in selection. Our results highlight the utility of connecting metabolic mechanisms and eco-evolutionary dynamics. PMID:27272242

  13. Metabolic alterations in different developmental stages of Pilocarpus microphyllus.

    PubMed

    Abreu, Ilka N; Choi, Young H; Sawaya, Alexandra C H F; Eberlin, Marcos N; Mazzafera, Paulo; Verpoorte, Robert

    2011-02-01

    Pilocarpine is an imidazole alkaloid that has been used for more than a century in glaucoma treatment. It is present in several species of the Pilocarpus genus (jaborandi), with its highest concentrations in P. microphyllus. In addition to pilocarpine, pilosine--an imidazole alkaloid without pharmacological use--is produced in high concentrations in mature plants. A metabolomic study was carried out on juvenile and mature plants to obtain information about pilocarpine metabolism at different developmental stages. Methanol-water and alkaloid extracts were analyzed by ¹H NMR and ESI-MS. Metabolic profiles from both techniques showed clear differences between various developmental stages. Intense signals in the aromatic region of the ¹H NMR spectrum and ions from pilosine and related alkaloids by ESI/MS were found only in extracts from mature plant. Two new imidazole alkaloids were identified by MS(n). Our results suggest that pilosine is produced exclusively in mature developmental stage, and juvenile plant material seems to be appropriate for further studies on pilocarpine biosynthesis. PMID:20845264

  14. Antagonist of prostaglandin E2 receptor 4 induces metabolic alterations in liver of mice.

    PubMed

    Li, Ning; Zhang, Limin; An, Yanpeng; Zhang, Lulu; Song, Yipeng; Wang, Yulan; Tang, Huiru

    2015-03-01

    Prostaglandin E2 receptor 4 (EP4) is one of the receptors for prostaglandin E2 and plays important roles in various biological functions. EP4 antagonists have been used as anti-inflammatory drugs. To investigate the effects of an EP4 antagonist (L-161982) on the endogenous metabolism in a holistic manner, we employed a mouse model, and obtained metabolic and transcriptomic profiles of multiple biological matrixes, including serum, liver, and urine of mice with and without EP4 antagonist (L-161982) exposure. We found that this EP4 antagonist caused significant changes in fatty acid metabolism, choline metabolism, and nucleotide metabolism. EP4 antagonist exposure also induced oxidative stress to mice. Our research is the first of its kind to report information on the alteration of metabolism associated with an EP4 antagonist. This information could further our understanding of current and new biological functions of EP4. PMID:25669961

  15. Metabolic alterations in children with environmental enteric dysfunction.

    PubMed

    Semba, Richard D; Shardell, Michelle; Trehan, Indi; Moaddel, Ruin; Maleta, Kenneth M; Ordiz, M Isabel; Kraemer, Klaus; Khadeer, Mohammed; Ferrucci, Luigi; Manary, Mark J

    2016-01-01

    Environmental enteric dysfunction, an asymptomatic condition characterized by inflammation of the small bowel mucosa, villous atrophy, malabsorption, and increased intestinal permeability, is a major contributor to childhood stunting in low-income countries. Here we report the relationship of increased intestinal permeability with serum metabolites in 315 children without acute malnutrition, aged 12-59 months, in rural Malawi. Increased gut permeability was associated with significant differences in circulating metabolites that included lower serum phosphatidylcholines, sphingomyelins, tryptophan, ornithine, and citrulline, and elevated serum glutamate, taurine, and serotonin. Our findings suggest that environmental enteric dysfunction is characterized by alterations in important metabolites involved in growth and differentiation and gut function and integrity. PMID:27294788

  16. Metabolic alterations in children with environmental enteric dysfunction

    PubMed Central

    Semba, Richard D.; Shardell, Michelle; Trehan, Indi; Moaddel, Ruin; Maleta, Kenneth M.; Ordiz, M. Isabel; Kraemer, Klaus; Khadeer, Mohammed; Ferrucci, Luigi; Manary, Mark J.

    2016-01-01

    Environmental enteric dysfunction, an asymptomatic condition characterized by inflammation of the small bowel mucosa, villous atrophy, malabsorption, and increased intestinal permeability, is a major contributor to childhood stunting in low-income countries. Here we report the relationship of increased intestinal permeability with serum metabolites in 315 children without acute malnutrition, aged 12–59 months, in rural Malawi. Increased gut permeability was associated with significant differences in circulating metabolites that included lower serum phosphatidylcholines, sphingomyelins, tryptophan, ornithine, and citrulline, and elevated serum glutamate, taurine, and serotonin. Our findings suggest that environmental enteric dysfunction is characterized by alterations in important metabolites involved in growth and differentiation and gut function and integrity. PMID:27294788

  17. [Study on the altered nitric oxide metabolism in experimental diabetes].

    PubMed

    Tábi, Tamási; Soltész, Zsuzsa; Magyar, Kálmán; Szöko, Eva

    2006-01-01

    Decreased biological action of nitric oxide (NO) and increased oxidative stress are established to be involved in the development of endothelium dysfunction, early sign of diabetic angiopathy. In the present study, increased nitric oxide synthase (NOS) enzyme activity in the aorta and decreased activity in the kidney tissue of streptozotocin-induced diabetic rats has been found in the early phase of the disease. Augmentation of oxidative transformation of NO in the kidney and heart of the diabetic animals has been demonstrated by the measurement of the stable end-products of NO and other reactive nitrogen species. Insulin treatment was found effective to reduce the intensified oxidative metabolism of NO without increasing its production. Reduced biological effects of NO observed in endothelial dysfunction, is thus probably the consequence of its increased oxidative inactivation. PMID:17094672

  18. Altered Sulfide (H2S) Metabolism in Ethylmalonic Encephalopathy

    PubMed Central

    Tiranti, Valeria; Zeviani, Massimo

    2013-01-01

    Hydrogen sulfide (sulfide, H2S) is a colorless, water-soluble gas with a typical smell of rotten eggs. In the past, it has been investigated for its role as a potent toxic gas emanating from sewers and swamps or as a by-product of industrial processes. At high concentrations, H2S is a powerful inhibitor of cytochrome c oxidase; in trace amounts, it is an important signaling molecule, like nitric oxide (NO) and carbon monoxide (CO), together termed “gasotransmitters.” This review will cover the physiological role and the pathogenic effects of H2S, focusing on ethylmalonic encephalopathy, a human mitochondrial disorder caused by genetic abnormalities of sulfide metabolism. We will also discuss the options that are now conceivable for preventing genetically driven chronic H2S toxicity, taking into account that a complete understanding of the physiopathology of H2S has still to be achieved. PMID:23284046

  19. A computational model of skeletal muscle metabolism linking cellular adaptations induced by altered loading states to metabolic responses during exercise

    PubMed Central

    Dash, Ranjan K; DiBella, John A; Cabrera, Marco E

    2007-01-01

    Background The alterations in skeletal muscle structure and function after prolonged periods of unloading are initiated by the chronic lack of mechanical stimulus of sufficient intensity, which is the result of a series of biochemical and metabolic interactions spanning from cellular to tissue/organ level. Reduced activation of skeletal muscle alters the gene expression of myosin heavy chain isoforms to meet the functional demands of reduced mechanical load, which results in muscle atrophy and reduced capacity to process fatty acids. In contrast, chronic loading results in the opposite pattern of adaptations. Methods To quantify interactions among cellular and skeletal muscle metabolic adaptations, and to predict metabolic responses to exercise after periods of altered loading states, we develop a computational model of skeletal muscle metabolism. The governing model equations – with parameters characterizing chronic loading/unloading states- were solved numerically to simulate metabolic responses to moderate intensity exercise (WR ≤ 40% VO2 max). Results Model simulations showed that carbohydrate oxidation was 8.5% greater in chronically unloaded muscle compared with the loaded muscle (0.69 vs. 0.63 mmol/min), while fat oxidation was 7% higher in chronically loaded muscle (0.14 vs. 0.13 mmol/min), during exercise. Muscle oxygen uptake (VO2) and blood flow (Q) response times were 29% and 44% shorter in chronically loaded muscle (0.4 vs. 0.56 min for VO2 and 0.25 vs. 0.45 min for Q). Conclusion The present model can be applied to test complex hypotheses during exercise involving the integration and control of metabolic processes at various organizational levels (cellular to tissue) in individuals who have undergone periods of chronic loading or unloading. PMID:17448235

  20. Does acute caffeine ingestion alter brain metabolism in young adults?

    PubMed

    Xu, Feng; Liu, Peiying; Pekar, James J; Lu, Hanzhang

    2015-04-15

    Caffeine, as the most commonly used stimulant drug, improves vigilance and, in some cases, cognition. However, the exact effect of caffeine on brain activity has not been fully elucidated. Because caffeine has a pronounced vascular effect which is independent of any neural effects, many hemodynamics-based methods such as fMRI cannot be readily applied without a proper calibration. The scope of the present work is two-fold. In Study 1, we used a recently developed MRI technique to examine the time-dependent changes in whole-brain cerebral metabolic rate of oxygen (CMRO2) following the ingestion of 200mg caffeine. It was found that, despite a pronounced decrease in CBF (p<0.001), global CMRO2 did not change significantly. Instead, the oxygen extraction fraction (OEF) was significantly elevated (p=0.002) to fully compensate for the reduced blood supply. Using the whole-brain finding as a reference, we aim to investigate whether there are any regional differences in the brain's response to caffeine. Therefore, in Study 2, we examined regional heterogeneities in CBF changes following the same amount of caffeine ingestion. We found that posterior brain regions such as posterior cingulate cortex and superior temporal regions manifested a slower CBF reduction, whereas anterior brain regions including dorsolateral prefrontal cortex and medial frontal cortex showed a faster rate of decline. These findings have a few possible explanations. One is that caffeine may result in a region-dependent increase or decrease in brain activity, resulting in an unaltered average brain metabolic rate. The other is that caffeine's effect on vasculature may be region-specific. Plausibility of these explanations is discussed in the context of spatial distribution of the adenosine receptors. PMID:25644657

  1. Does acute caffeine ingestion alter brain metabolism in young adults?

    PubMed Central

    Xu, Feng; Liu, Peiying; Pekar, James J.; Lu, Hanzhang

    2015-01-01

    Caffeine, as the most commonly used stimulant drug, improves vigilance and, in some cases, cognition. However, the exact effect of caffeine on brain activity has not been fully elucidated. Because caffeine has a pronounced vascular effect which is independent of any neural effects, many hemodynamics-based methods such as fMRI cannot be readily applied without a proper calibration. The scope of the present work is two-fold. In Study 1, we used a recently developed MRI technique to examine the time-dependent changes in whole-brain cerebral metabolic rate of oxygen (CMRO2) following the ingestion of 200mg caffeine. It was found that, despite a pronounced decrease in CBF (p<0.001), global CMRO2 did not change significantly. Instead, the oxygen extraction fraction (OEF) was significantly elevated (p=0.002) to fully compensate for the reduced blood supply. Using the whole-brain finding as a reference, we aim to investigate whether there are any regional differences in the brain’s response to caffeine. Therefore, in Study 2, we examined regional heterogeneities in CBF changes following the same amount of caffeine ingestion. We found that posterior brain regions such as posterior cingulate cortex and superior temporal regions manifested a slower CBF reduction, whereas anterior brain regions including dorsolateral prefrontal cortex and medial frontal cortex showed a faster rate of decline. These findings have a few possible explanations. One is that caffeine may result in a region-dependent increase or decrease in brain activity, resulting in an unaltered average brain metabolic rate. The other is that caffeine’s effect on vasculature may be region-specific. Plausibility of these explanations is discussed in the context of spatial distribution of the adenosine receptors. PMID:25644657

  2. Speeding up Growth: Selection for Mass-Independent Maximal Metabolic Rate Alters Growth Rates.

    PubMed

    Downs, Cynthia J; Brown, Jessi L; Wone, Bernard W M; Donovan, Edward R; Hayes, Jack P

    2016-03-01

    Investigations into relationships between life-history traits, such as growth rate and energy metabolism, typically focus on basal metabolic rate (BMR). In contrast, investigators rarely examine maximal metabolic rate (MMR) as a relevant metric of energy metabolism, even though it indicates the maximal capacity to metabolize energy aerobically, and hence it might also be important in trade-offs. We studied the relationship between energy metabolism and growth in mice (Mus musculus domesticus Linnaeus) selected for high mass-independent metabolic rates. Selection for high mass-independent MMR increased maximal growth rate, increased body mass at 20 weeks of age, and generally altered growth patterns in both male and female mice. In contrast, there was little evidence that the correlated response in mass-adjusted BMR altered growth patterns. The relationship between mass-adjusted MMR and growth rate indicates that MMR is an important mediator of life histories. Studies investigating associations between energy metabolism and life histories should consider MMR because it is potentially as important in understanding life history as BMR. PMID:26913943

  3. Tumor Necrosis Factor, but Not Neutrophils, Alters the Metabolic Profile in Acute Experimental Arthritis

    PubMed Central

    Oliveira, Marina C.; Tavares, Luciana P.; Vago, Juliana P.; Batista, Nathália V.; Queiroz-Junior, Celso M.; Vieira, Angelica T.; Menezes, Gustavo B.; Sousa, Lirlândia P.; van de Loo, Fons A. J.; Teixeira, Mauro M.; Amaral, Flávio A.; Ferreira, Adaliene V. M.

    2016-01-01

    Metabolic alterations are associated with arthritis apart from obesity. However, it is still unclear which is the underlying process behind these metabolic changes. Here, we investigate the role of tumor necrosis factor (TNF) in this process in an acute model of antigen-induced arthritis (AIA). Immunized male BALB/c mice received an intra-articular injection of PBS (control) or methylated bovine serum albumin (mBSA) into their knees, and were also pre-treated with different drugs: Etanercept, an anti-TNF drug, DF2156A, a CXCR1/2 receptor antagonist, or a monoclonal antibody RB6-8C5 to deplete neutrophils. Local challenge with mBSA evoked an acute neutrophil influx into the knee joint, and enhanced the joint nociception, along with a transient systemic metabolic alteration (higher levels of glucose and lipids, and altered adipocytokines). Pre-treatment with the conventional biological Etanercept, an inhibitor of TNF action, ameliorated the nociception and the acute joint inflammation dominated by neutrophils, and markedly improved many of the altered systemic metabolites (glucose and lipids), adipocytokines and PTX3. However, the lessening of metabolic changes was not due to diminished accumulation of neutrophils in the joint by Etanercept. Reduction of neutrophil recruitment by pre-treating AIA mice with DF2156A, or even the depletion of these cells by using RB6-8C5 reduced all of the inflammatory parameters and hypernociception developed after AIA challenge, but could not prevent the metabolic changes. Therefore, the induction of joint inflammation provoked acute metabolic alterations which were involved with TNF. We suggest that the role of TNF in arthritis-associated metabolic changes is not due to local neutrophils, which are the major cells present in this model, but rather due to cytokines. PMID:26742100

  4. Tumor Necrosis Factor, but Not Neutrophils, Alters the Metabolic Profile in Acute Experimental Arthritis.

    PubMed

    Oliveira, Marina C; Tavares, Luciana P; Vago, Juliana P; Batista, Nathália V; Queiroz-Junior, Celso M; Vieira, Angelica T; Menezes, Gustavo B; Sousa, Lirlândia P; van de Loo, Fons A J; Teixeira, Mauro M; Amaral, Flávio A; Ferreira, Adaliene V M

    2016-01-01

    Metabolic alterations are associated with arthritis apart from obesity. However, it is still unclear which is the underlying process behind these metabolic changes. Here, we investigate the role of tumor necrosis factor (TNF) in this process in an acute model of antigen-induced arthritis (AIA). Immunized male BALB/c mice received an intra-articular injection of PBS (control) or methylated bovine serum albumin (mBSA) into their knees, and were also pre-treated with different drugs: Etanercept, an anti-TNF drug, DF2156A, a CXCR1/2 receptor antagonist, or a monoclonal antibody RB6-8C5 to deplete neutrophils. Local challenge with mBSA evoked an acute neutrophil influx into the knee joint, and enhanced the joint nociception, along with a transient systemic metabolic alteration (higher levels of glucose and lipids, and altered adipocytokines). Pre-treatment with the conventional biological Etanercept, an inhibitor of TNF action, ameliorated the nociception and the acute joint inflammation dominated by neutrophils, and markedly improved many of the altered systemic metabolites (glucose and lipids), adipocytokines and PTX3. However, the lessening of metabolic changes was not due to diminished accumulation of neutrophils in the joint by Etanercept. Reduction of neutrophil recruitment by pre-treating AIA mice with DF2156A, or even the depletion of these cells by using RB6-8C5 reduced all of the inflammatory parameters and hypernociception developed after AIA challenge, but could not prevent the metabolic changes. Therefore, the induction of joint inflammation provoked acute metabolic alterations which were involved with TNF. We suggest that the role of TNF in arthritis-associated metabolic changes is not due to local neutrophils, which are the major cells present in this model, but rather due to cytokines. PMID:26742100

  5. Alterations in cancer cell metabolism: the Warburg effect and metabolic adaptation.

    PubMed

    Asgari, Yazdan; Zabihinpour, Zahra; Salehzadeh-Yazdi, Ali; Schreiber, Falk; Masoudi-Nejad, Ali

    2015-05-01

    The Warburg effect means higher glucose uptake of cancer cells compared to normal tissues, whereas a smaller fraction of this glucose is employed for oxidative phosphorylation. With the advent of high throughput technologies and computational systems biology, cancer cell metabolism has been reinvestigated over the last decades toward identifying various events underlying "how" and "why" a cancer cell employs aerobic glycolysis. Significant progress has been shaped to revise the Warburg effect. In this study, we have integrated the gene expression of 13 different cancer cells with the genome-scale metabolic network of human (Recon1) based on the E-Flux method, and analyzed them based on constraint-based modeling. Results show that regardless of significant up- and down-regulated metabolic genes, the distribution of metabolic changes is similar in different cancer types. These findings support the theory that the Warburg effect is a consequence of metabolic adaptation in cancer cells. PMID:25773945

  6. Alcohol Deranges Hepatic Lipid Metabolism via Altered Transcriptional Regulation.

    PubMed Central

    Crabb, David W.

    2004-01-01

    Alcohol has classically been thought to cause fatty liver by way of altered redox potential in the liver, which inhibits fatty acid oxidation. Additional effects appear to play a role both in impairing fat oxidation and stimulating lipogenesis. Alcohol reduces the DNA binding and transcription-activating properties of peroxisome proliferator-activated receptor alpha (PPARalpha), both in cultured cells and in mice fed alcohol. Treatment of alcohol-fed mice with a PPARalpha agonist reverses fatty liver despite continued alcohol consumption. Alcohol also activates sterol response element- binding protein 1 (SREBP-1), inducing a battery of lipogenic enzymes. This effect may be due in part to inhibition of AMP-dependent protein kinase. This understanding of alcohol effects provides new therapeutic targets to reverse alcoholic fatty liver. Images Fig. 4 Fig. 6 PMID:17060973

  7. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences

    PubMed Central

    Cox, Laura M.; Yamanishi, Shingo; Sohn, Jiho; Alekseyenko, Alexander V.; Leung, Jacqueline M.; Cho, Ilseung; Kim, Sungheon; Li, Huilin; Gao, Zhan; Mahana, Douglas; Rodriguez, Jorge G. Zárate; Rogers, Arlin B.; Robine, Nicolas; Loke, P'ng; Blaser, Martin J.

    2014-01-01

    SUMMARY Acquisition of the intestinal microbiota begins at birth and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction, and identify several taxa consistently linked with metabolic alterations. PMID:25126780

  8. Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding

    PubMed Central

    Purushotham, Aparna; Xu, Qing; Li, Xiaoling

    2012-01-01

    SIRT1 is a highly-conserved NAD+-dependent protein deacetylase that plays essential roles in the regulation of energy metabolism, genomic stability, and stress response. Although the functions of SIRT1 in many organs have been extensively studied in tissue-specific knockout mouse models, the systemic role of SIRT1 is still largely unknown as a result of severe developmental defects that result from whole-body knockout in mice. Here, we investigated the systemic functions of SIRT1 in metabolic homeostasis by utilizing a whole-body SIRT1 heterozygous mouse model. These mice are phenotypically normal under standard feeding conditions. However, when chronically challenged with a 40% fat diet, they become obese and insulin resistant, display increased serum cytokine levels, and develop hepatomegaly. Hepatic metabolomic analyses revealed that SIRT1 heterozygous mice have elevated gluconeogenesis and oxidative stress. Surprisingly, they are depleted of glycerolipid metabolites and free fatty acids, yet accumulate lysolipids. Moreover, high-fat feeding induces elevation of serum testosterone levels and enlargement of seminal vesicles in SIRT1 heterozygous males. Microarray analysis of liver mRNA indicates that they have altered expression of genes involved in steroid metabolism and glycerolipid metabolism. Taken together, our findings indicate that SIRT1 plays a vital role in the regulation of systemic energy and steroid hormone homeostasis.—Purushotham, A., Xu, Q., Li, X. Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding. PMID:22006157

  9. Altered cholesterol metabolism in APP695-transfected neuroblastoma cells.

    PubMed

    Wirths, Oliver; Thelen, Karin M; Lütjohann, Dieter; Falkai, Peter; Bayer, Thomas A

    2007-06-01

    Cholesterol has been implicated to play an important role in the generation of Abeta peptides, which are the main component of beta-amyloid plaques in the brains of patients suffering from Alzheimer's disease (AD). Epidemiological data implicate that lowering cholesterol levels has beneficial effects on the extent of beta-amyloid pathology. Thus therapeutic intervention using cholesterol lowering drugs like statins seems to be a promising approach. A couple of studies, in vitro or in vivo by the use of AD transgenic mouse models, focused on the manipulation of cholesterol levels and the resulting effects on Abeta generation. In contrast, there is not much known about the effect of the amyloid precursor protein (APP) on cholesterol levels. In the present report, we transfected human neuroblastoma cells with human APP695 and compared cellular cholesterol levels with the respective levels in Mock-transfected control cells. Furthermore, we determined the levels of diverse cholesterol precursors and metabolites using gas chromatography-mass spectrometry (GC-MS). Significant differences in the levels of the respective cholesterol precursors were observed, whereas inhibition of gamma-secretase activity by the gamma-secretase inhibitor DAPT did not have a significant effect on cellular cholesterol metabolism. PMID:17428449

  10. Mechanisms linking obesity to altered metabolism in mice colon carcinogenesis.

    PubMed

    Nimri, Lili; Saadi, Janan; Peri, Irena; Yehuda-Shnaidman, Einav; Schwartz, Betty

    2015-11-10

    There are an increasing number of reports on obesity being a key risk factor for the development of colon cancer. Our goal in this study was to explore the metabolic networks and molecular signaling pathways linking obesity, adipose tissue and colon cancer. Using in-vivo experiments, we found that mice fed a high-fat diet (HFD) and injected with MC38 colon cancer cells develop significantly larger tumors than their counterparts fed a control diet. In ex-vivo experiments, MC38 and CT26 colon cancer cells exposed to conditioned media (CM) from the adipose tissue of HFD-fed mice demonstrated significantly lower oxygen consumption rate as well as lower maximal oxygen consumption rate after carbonyl cyanide-4-trifluoromethoxy-phenylhydrazone treatment. In addition, in-vitro assays showed downregulated expression of mitochondrial genes in colon cancer cells exposed to CM prepared from the visceral fat of HFD-fed mice or to leptin. Interestingly, leptin levels detected in the media of adipose tissue explants co-cultured with MC38 cancer cells were higher than in adipose tissue explants cultures, indicating cross talk between the adipose tissue and the cancer cells. Salient findings of the present study demonstrate that this crosstalk is mediated at least partially by the JNK/STAT3-signaling pathway. PMID:26472027

  11. Mechanisms linking obesity to altered metabolism in mice colon carcinogenesis

    PubMed Central

    Nimri, Lili; Saadi, Janan; Peri, Irena; Yehuda-Shnaidman, Einav; Schwartz, Betty

    2015-01-01

    There are an increasing number of reports on obesity being a key risk factor for the development of colon cancer. Our goal in this study was to explore the metabolic networks and molecular signaling pathways linking obesity, adipose tissue and colon cancer. Using in-vivo experiments, we found that mice fed a high-fat diet (HFD) and injected with MC38 colon cancer cells develop significantly larger tumors than their counterparts fed a control diet. In ex-vivo experiments, MC38 and CT26 colon cancer cells exposed to conditioned media (CM) from the adipose tissue of HFD-fed mice demonstrated significantly lower oxygen consumption rate as well as lower maximal oxygen consumption rate after carbonyl cyanide-4-trifluoromethoxy-phenylhydrazone treatment. In addition, in-vitro assays showed downregulated expression of mitochondrial genes in colon cancer cells exposed to CM prepared from the visceral fat of HFD-fed mice or to leptin. Interestingly, leptin levels detected in the media of adipose tissue explants co-cultured with MC38 cancer cells were higher than in adipose tissue explants cultures, indicating cross talk between the adipose tissue and the cancer cells. Salient findings of the present study demonstrate that this crosstalk is mediated at least partially by the JNK/STAT3-signaling pathway. PMID:26472027

  12. JCL roundtable: Lessons from genetic variants altering lipoprotein metabolism.

    PubMed

    Brown, William Virgil; Ference, Brian A; Kathiresan, Sekar

    2016-01-01

    Because the Human Genome Project reached its first major milestone in completing the full sequence of human DNA, many new discoveries have been made relating genetic variants to disease. The new methodology that allows much more rapid and focused analyses of selected genes and the ability to screen the entire exome of any individual has provided tools to examine literally thousands of individuals for a given study. Genetic analysis has become a large-scale epidemiologic tool for examining variants in gene structure and correlating them with phenotypic markers of human disorders. These genome-wide association studies have been quite revealing about the mechanism of disorders of many types. These tools have been applied to the appearance of clinical atherosclerosis and to the chronic metabolic risk factors for this disease process. We are joined by 2 individuals who have made very significant contributions to this area of research: Dr Brian Ference of Wayne State University School of Medicine and Dr Sekar Kathiresan from Massachusetts General Hospital and Harvard Medical School. In our discussion, we are going to focus on genetic variants, which lead to changes in lipoprotein concentrations and those that have an association with earlier onset of clinical vascular disease. This roundtable was recorded during the November 2016 American Heart Association Scientific Sessions in Orlando, Florida. PMID:27206929

  13. Macrophyte disturbance alters aquatic surface microlayer structure, metabolism, and fate.

    PubMed

    Seliskar, Denise M; Gallagher, John L

    2014-03-01

    Macrophytes drive the functioning of many salt marsh ecosystem components. We questioned how temporary clearing of the macrophyte community, during restoration, would impact processes at the scale of the aquatic surface microlayer. Development, deposition, and breakup of the tidal creek surface microlayer were followed over tidal cycles seasonally in a cleared "former" Phragmites marsh and an adjacent restored Spartina marsh. Metabolic and physical processes of the mobile surface microlayers and underlying water were compared, along with distribution of organic and inorganic components onto simulated plant stems. In July and October, chlorophyll-a quantities were less on simulated stems in the cleared site than in the restored site. The aquatic microlayer in the cleared site creek exhibited lower photosynthesis and respiration rates, fewer diatoms and green algae, and less chlorophyll-a. There was a lower concentration (250 times) and reduced diversity of fatty acids in the surface microlayer of the cleared site, reflecting a smaller and less diverse microbial community and reduced food resources. Fiddler crab activity was an order of magnitude higher where macrophytes had been cleared. Their consumption of edaphic algae on the mud surface may account for the reduced algae and other organics in the creek surface microlayer, thus representing a redirection of this food resource from creek consumers. Overall, there were less total particulates in the creek surface microlayer at the cleared site, and they dropped out of the surface microlayer sooner in the tidal cycle, resulting in a lower sediment load available for deposit onto marsh surfaces. PMID:24135995

  14. Chronic cola drinking induces metabolic and cardiac alterations in rats

    PubMed Central

    Milei, José; Losada, Matilde Otero; Llambí, Hernán Gómez; Grana, Daniel R; Suárez, Daniel; Azzato, Francisco; Ambrosio, Giuseppe

    2011-01-01

    AIM: To investigate the effects of chronic drinking of cola beverages on metabolic and echocardiographic parameters in rats. METHODS: Forty-eight male Wistar rats were divided in 3 groups and allowed to drink regular cola (C), diet cola (L), or tap water (W) ad libitum during 6 mo. After this period, 50% of the animals in each group were euthanized. The remaining rats drank tap water ad libitum for an additional 6 mo and were then sacrificed. Rat weight, food, and beverage consumption were measured regularly. Biochemical, echocardiographic and systolic blood pressure data were obtained at baseline, and at 6 mo (treatment) and 12 mo (washout). A complete histopathology study was performed after sacrifice. RESULTS: After 6 mo, C rats had increased body weight (+7%, P < 0.01), increased liquid consumption (+69%, P < 0.001), and decreased food intake (-31%, P < 0.001). C rats showed mild hyperglycemia and hypertriglyceridemia. Normoglycemia (+69%, P < 0.01) and sustained hypertriglyceridemia (+69%, P < 0.01) were observed in C after washout. Both cola beverages induced an increase in left ventricular diastolic diameter (C: +9%, L: +7%, P < 0.05 vs W) and volumes (diastolic C: +26%, L: +22%, P < 0.01 vs W; systolic C: +24%, L: +24%, P < 0.05 vs W) and reduction of relative posterior wall thickness (C: -8%, L: -10%, P < 0.05 vs W). Cardiac output tended to increase (C: +25%, P < 0.05 vs W; L: +17%, not significant vs W). Heart rate was not affected. Pathology findings were scarce, related to aging rather than treatment. CONCLUSION: This experimental model may prove useful to investigate the consequences of high consumption of soft drinks. PMID:21526048

  15. Alterations in Lipid Metabolism and Antioxidant Status in Lichen Planus

    PubMed Central

    Panchal, Falguni H; Ray, Somshukla; Munshi, Renuka P; Bhalerao, Supriya S; Nayak, Chitra S

    2015-01-01

    Background: Lichen planus (LP), a T-cell-mediated inflammatory disorder, wherein inflammation produces lipid metabolism disturbances, is linked to increase in cardiovascular (CV) risk with dyslipidemia. Increased reactive oxygen species and lipid peroxides have also been implicated in its pathogenesis. Aim and Objective: The aim of the study was to evaluate the status on lipid disturbances, oxidative stress, and inflammation in LP patients. Materials and Methods: The study was initiated after obtaining Institutional Ethics Committee permission and written informed consent from participants. The study included 125 patients (74 LP patients and 51 age and sex-matched controls) visiting the outpatient clinic in the dermatology department of our hospital. Variables analyzed included lipid profile, C-reactive protein (CRP), malondialdehyde (MDA), and catalase (CAT) activity. Results: Analysis of lipid parameters revealed significantly higher levels of total cholesterol (TC), triglycerides, and low-density lipoprotein cholesterol (LDL-C) along with decreased levels of high-density lipoprotein cholesterol (HDL-C) in LP patients as compared to their respective controls. LP patients also presented with a significantly higher atherogenic index that is, (TC/HDL-C) and LDL-C/HDL-C ratios than the controls. A significant increase in CRP levels was observed among the LP patients. There was a statistically significant increase in the serum levels of the lipid peroxidation product, MDA and a statistically significant decrease in CAT activity in LP patients as compared to their respective controls. A statistically significant positive correlation (r = 0.96) was observed between serum MDA levels and duration of LP whereas a significantly negative correlation (r = −0.76) was seen between CAT activity and LP duration. Conclusion: Chronic inflammation in patients with LP may explain the association with dyslipidemia and CV risk. Our findings also suggest that an increase in oxidative

  16. Dietary patterns in men and women are simultaneously determinants of altered glucose metabolism and bone metabolism.

    PubMed

    Langsetmo, Lisa; Barr, Susan I; Dasgupta, Kaberi; Berger, Claudie; Kovacs, Christopher S; Josse, Robert G; Adachi, Jonathan D; Hanley, David A; Prior, Jerilynn C; Brown, Jacques P; Morin, Suzanne N; Davison, Kenneth S; Goltzman, David; Kreiger, Nancy

    2016-04-01

    We hypothesized that diet would have direct effects on glucose metabolism with direct and indirect effects on bone metabolism in a cohort of Canadian adults. We assessed dietary patterns (Prudent [fruit, vegetables, whole grains, fish, and legumes] and Western [soft drinks, potato chips, French fries, meats, and desserts]) from a semiquantitative food frequency questionnaire. We used fasting blood samples to measure glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR), 25-hydroxyvitamin D (25OHD), parathyroid hormone, bone-specific alkaline phosphatase (a bone formation marker), and serum C-terminal telopeptide (CTX; a bone resorption marker). We used multivariate regression models adjusted for confounders and including/excluding body mass index. In a secondary analysis, we examined relationships through structural equations models. The Prudent diet was associated with favorable effects on glucose metabolism (lower insulin and HOMA-IR) and bone metabolism (lower CTX in women; higher 25OHD and lower parathyroid hormone in men). The Western diet was associated with deleterious effects on glucose metabolism (higher glucose, insulin, and HOMA-IR) and bone metabolism (higher bone-specific alkaline phosphatase and lower 25OHD in women; higher CTX in men). Body mass index adjustment moved point estimates toward the null, indicating partial mediation. The structural equation model confirmed the hypothesized linkage with strong effects of Prudent and Western diet on metabolic risk, and both direct and indirect effects of a Prudent diet on bone turnover. In summary, a Prudent diet was associated with lower metabolic risk with both primary and mediated effects on bone turnover, suggesting that it is a potential target for reducing fracture risk. PMID:27001278

  17. Prenatal caffeine ingestion induces transgenerational neuroendocrine metabolic programming alteration in second generation rats

    SciTech Connect

    Luo, Hanwen; Deng, Zixin; Liu, Lian; Shen, Lang; Kou, Hao; He, Zheng; Ping, Jie; Xu, Dan; Ma, Lu; Chen, Liaobin; Wang, Hui

    2014-02-01

    Our previous studies have demonstrated that prenatal caffeine ingestion induces an increased susceptibility to metabolic syndrome with alterations of glucose and lipid metabolic phenotypes in adult first generation (F1) of intrauterine growth retardation (IUGR) rats, and the underlying mechanism is originated from a hypothalamic–pituitary–adrenal (HPA) axis-associated neuroendocrine metabolic programming alteration in utero. This study aims to investigate the transgenerational effects of this programming alteration in adult second generation (F2). Pregnant Wistar rats were administered with caffeine (120 mg/kg·d) from gestational day 11 until delivery. Four groups in F2 were set according to the cross-mating between control and caffeine-induced IUGR rats. F2 were subjected to a fortnight ice water swimming stimulus on postnatal month 4, and blood samples were collected before and after stress. Results showed that the majority of the activities of HPA axis and phenotypes of glucose and lipid metabolism were altered in F2. Particularly, comparing with the control group, caffeine groups had an enhanced corticosterone levels after chronic stress. Compared with before stress, the serum glucose levels were increased in some groups whereas the triglyceride levels were decreased. Furthermore, total cholesterol gain rates were enhanced but the high-density lipoprotein-cholesterol gain rates were decreased in most caffeine groups after stress. These transgenerational effects were characterized partially with gender and parental differences. Taken together, these results indicate that the reproductive and developmental toxicities and the neuroendocrine metabolic programming mechanism by prenatal caffeine ingestion have transgenerational effects in rats, which may help to explain the susceptibility to metabolic syndrome and associated diseases in F2. - Highlights: • Caffeine-induced neuroendocrine metabolic programming of HPA has hereditary effect. • Caffeine

  18. Carnosine metabolism in diabetes is altered by reactive metabolites.

    PubMed

    Peters, Verena; Lanthaler, Barbara; Amberger, Albert; Fleming, Thomas; Forsberg, Elisabete; Hecker, Markus; Wagner, Andreas H; Yue, Wyatt W; Hoffmann, Georg F; Nawroth, Peter; Zschocke, Johannes; Schmitt, Claus P

    2015-11-01

    Carnosinase 1 (CN1) contributes to diabetic nephropathy by cleaving histidine-dipeptides which scavenge reactive oxygen and carbonyl species and increase nitric oxide (NO) production. In diabetic mice renal CN1 activity is increased, the regulatory mechanisms are unknown. We therefore analysed the in vitro and in vivo regulation of CN1 activity using recombinant and human CN1, and the db/db mouse model of diabetes. Glucose, leptin and insulin did not modify recombinant and human CN1 activity in vitro, glucose did not alter renal CN1 activity of WT or db/db mice ex vivo. Reactive metabolite methylglyoxal and Fenton reagent carbonylated recombinant CN1 and doubled CN1 efficiency. NO S-nitrosylated CN1 and decreased CN1 efficiency for carnosine by 70 % (p < 0.01), but not for anserine. Both CN1 cysteine residues were nitrosylated, the cysteine at position 102 but not at position 229 regulated CN1 activities. In db/db mice, renal CN1 mRNA and protein levels were similar as in non-diabetic controls, CN1 efficiency 1.9 and 1.6 fold higher for carnosine and anserine. Renal carbonyl stress was strongly increased and NO production halved, CN1 highly carbonylated and less S-nitrosylated compared to WT mice. GSH and NO2/3 concentrations were reduced and inversely related with carnosine degradation rate (r = -0.82/-0.85). Thus, reactive metabolites of diabetes upregulate CN1 activity by post-translational modifications, and thus decrease the availability of reactive metabolite-scavenging histidine dipeptides in the kidney in a positive feedback loop. Interference with this vicious circle may represent a new therapeutic target for mitigation of DN. PMID:26081982

  19. Improved metabolic health alters host metabolism in parallel with changes in systemic xeno-metabolites of gut origin.

    PubMed

    Campbell, Caitlin; Grapov, Dmitry; Fiehn, Oliver; Chandler, Carol J; Burnett, Dustin J; Souza, Elaine C; Casazza, Gretchen A; Gustafson, Mary B; Keim, Nancy L; Newman, John W; Hunter, Gary R; Fernandez, Jose R; Garvey, W Timothy; Harper, Mary-Ellen; Hoppel, Charles L; Meissen, John K; Take, Kohei; Adams, Sean H

    2014-01-01

    Novel plasma metabolite patterns reflective of improved metabolic health (insulin sensitivity, fitness, reduced body weight) were identified before and after a 14-17 wk weight loss and exercise intervention in sedentary, obese insulin-resistant women. To control for potential confounding effects of diet- or microbiome-derived molecules on the systemic metabolome, sampling was during a tightly-controlled feeding test week paradigm. Pairwise and multivariate analysis revealed intervention- and insulin-sensitivity associated: (1) Changes in plasma xeno-metabolites ("non-self" metabolites of dietary or gut microbial origin) following an oral glucose tolerance test (e.g. higher post-OGTT propane-1,2,3-tricarboxylate [tricarballylic acid]) or in the overnight-fasted state (e.g., lower γ-tocopherol); (2) Increased indices of saturated very long chain fatty acid elongation capacity; (3) Increased post-OGTT α-ketoglutaric acid (α-KG), fasting α-KG inversely correlated with Matsuda index, and altered patterns of malate, pyruvate and glutamine hypothesized to stem from improved mitochondrial efficiency and more robust oxidation of glucose. The results support a working model in which improved metabolic health modifies host metabolism in parallel with altering systemic exposure to xeno-metabolites. This highlights that interpretations regarding the origins of peripheral blood or urinary "signatures" of insulin resistance and metabolic health must consider the potentially important contribution of gut-derived metabolites toward the host's metabolome. PMID:24416208

  20. Improved Metabolic Health Alters Host Metabolism in Parallel with Changes in Systemic Xeno-Metabolites of Gut Origin

    PubMed Central

    Fiehn, Oliver; Chandler, Carol J.; Burnett, Dustin J.; Souza, Elaine C.; Casazza, Gretchen A.; Gustafson, Mary B.; Keim, Nancy L.; Newman, John W.; Hunter, Gary R.; Fernandez, Jose R.; Garvey, W. Timothy; Harper, Mary-Ellen; Hoppel, Charles L.; Meissen, John K.; Take, Kohei; Adams, Sean H.

    2014-01-01

    Novel plasma metabolite patterns reflective of improved metabolic health (insulin sensitivity, fitness, reduced body weight) were identified before and after a 14–17 wk weight loss and exercise intervention in sedentary, obese insulin-resistant women. To control for potential confounding effects of diet- or microbiome-derived molecules on the systemic metabolome, sampling was during a tightly-controlled feeding test week paradigm. Pairwise and multivariate analysis revealed intervention- and insulin-sensitivity associated: (1) Changes in plasma xeno-metabolites (“non-self” metabolites of dietary or gut microbial origin) following an oral glucose tolerance test (e.g. higher post-OGTT propane-1,2,3-tricarboxylate [tricarballylic acid]) or in the overnight-fasted state (e.g., lower γ-tocopherol); (2) Increased indices of saturated very long chain fatty acid elongation capacity; (3) Increased post-OGTT α-ketoglutaric acid (α-KG), fasting α-KG inversely correlated with Matsuda index, and altered patterns of malate, pyruvate and glutamine hypothesized to stem from improved mitochondrial efficiency and more robust oxidation of glucose. The results support a working model in which improved metabolic health modifies host metabolism in parallel with altering systemic exposure to xeno-metabolites. This highlights that interpretations regarding the origins of peripheral blood or urinary “signatures” of insulin resistance and metabolic health must consider the potentially important contribution of gut-derived metabolites toward the host's metabolome. PMID:24416208

  1. Metabolic and Signaling Alterations in Dystrophin-Deficient Hearts Precede Overt Cardiomyopathy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The cytoskeletal protein dystrophin has been implicated in hereditary and acquired forms of cardiomyopathy. However, much remains to be learned about the role of dystrophin in the heart. We hypothesized that the dystrophin-deficient heart displays early alterations in energy metabolism that precede ...

  2. Chromium supplementation alters the glucose and lipid metabolism of feedlot cattle during the receiving period

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Crossbreed steers (n = 20; 235 ± 4 kg) were fed 53 d during a receiving period to determine if supplementing chromium (Cr; KemTRACE®brand Chromium Propionate 0.04%, Kemin Industries) would alter the glucose or lipid metabolism of newly received cattle. Chromium premixes were supplemented to add 0 (C...

  3. Chromium supplementation alters both glucose and lipid metabolism in feedlot cattle during the receiving period

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Crossbred steers (n = 20; 235 +/- 4 kg) were fed 53 days during a receiving period to determine if supplementing chromium (Cr; KemTRACE®brandChromium Propionate 0.04%, Kemin Industries) would alter the glucose or lipid metabolism of newly received cattle. Chromium premixes were supplemented to add 0...

  4. Methyl-ß-cyclodextrin alters adipokine gene expression and glucose metabolism in swine adipose tissue

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine if metabolic stress as induced by methyl-ß-cyclodextrin (MCD) can alter cytokine expression in neonatal swine adipose tissue explants. Subcutaneous adipose tissue explants (100 ± 10 mg) were prepared from 21 day old pigs. Explants were incubated in medium 199 s...

  5. Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals.

    PubMed

    Vázquez-Castellanos, J F; Serrano-Villar, S; Latorre, A; Artacho, A; Ferrús, M L; Madrid, N; Vallejo, A; Sainz, T; Martínez-Botas, J; Ferrando-Martínez, S; Vera, M; Dronda, F; Leal, M; Del Romero, J; Moreno, S; Estrada, V; Gosalbes, M J; Moya, A

    2015-07-01

    Altered interplay between gut mucosa and microbiota during treated HIV infection may possibly contribute to increased bacterial translocation and chronic immune activation, both of which are predictors of morbidity and mortality. Although a dysbiotic gut microbiota has recently been reported in HIV+ individuals, the metagenome gene pool associated with HIV infection remains unknown. The aim of this study is to characterize the functional gene content of gut microbiota in HIV+ patients and to define the metabolic pathways of this bacterial community, which is potentially associated with immune dysfunction. We determined systemic markers of innate and adaptive immunity in a cohort of HIV-infected individuals on successful antiretroviral therapy without comorbidities and in healthy non-HIV-infected subjects. Metagenome sequencing revealed an altered functional profile, with enrichment of the genes involved in various pathogenic processes, lipopolysaccharide biosynthesis, bacterial translocation, and other inflammatory pathways. In contrast, we observed depletion of genes involved in amino acid metabolism and energy processes. Bayesian networks showed significant interactions between the bacterial community, their altered metabolic pathways, and systemic markers of immune dysfunction. This study reveals altered metabolic activity of microbiota and provides novel insight into the potential host-microbiota interactions driving the sustained inflammatory state in successfully treated HIV-infected patients. PMID:25407519

  6. Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers

    PubMed Central

    Perkins, Michelle; Wolf, Andrew B.; Chavira, Bernardo; Shonebarger, Daniel; Meckel, J.P.; Leung, Lana; Ballina, Lauren; Ly, Sarah; Saini, Aman; Jones, T. Bucky; Vallejo, Johana; Jentarra, Garilyn; Valla, Jon

    2016-01-01

    The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer’s disease (AD). Apolipoprotein E ɛ4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD. PMID:27128370

  7. Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers.

    PubMed

    Perkins, Michelle; Wolf, Andrew B; Chavira, Bernardo; Shonebarger, Daniel; Meckel, J P; Leung, Lana; Ballina, Lauren; Ly, Sarah; Saini, Aman; Jones, T Bucky; Vallejo, Johana; Jentarra, Garilyn; Valla, Jon

    2016-04-23

    The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer's disease (AD). Apolipoprotein E ɛ4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD. PMID:27128370

  8. Metabolic alterations and neurodevelopmental outcome of infants with transposition of the great arteries.

    PubMed

    Park, I Sook; Yoon, S Young; Min, J Yeon; Kim, Y Hwue; Ko, J Kok; Kim, K Soo; Seo, D Man; Lee, J Hee

    2006-01-01

    Abnormal neurodevelopment has been reported for infants who were born with transposition of the great arteries (TGA) and underwent arterial switch operation (ASO). This study evaluates the cerebral metabolism of TGA infants at birth and before ASO and neurodevelopment 1 year after ASO. Proton magnetic resonance spectroscopy (1H-MRS) was performed on 16 full-term TGA brains before ASO within 3-6 days after birth. The brain metabolite ratios of [NAA/Cr], [Cho/Cr], and [mI/Cr] evaluated measured. Ten infants were evaluated at 1 year using the Bayley Scales of Infants Development II (BSED II). Cerebral metabolism of infants with TGA was altered in parietal white matter (PWM) and occipital gray matter (OGM) at birth before ASO. One year after ASO, [Cho/Cr] in PWM remained altered, but all metabolic ratios in OGM were normal. The results of BSID II at 1 year showed delayed mental and psychomotor development. This delayed neurodevelopmental outcome may reflect consequences of the altered cerebral metabolism in PWM measured by 1H-MRS. It is speculated that the abnormal hemodynamics due to TGA in utero may be responsible for the impaired cerebral metabolism and the subsequent neurodevelopmental deficit. PMID:16897317

  9. Preweaning cocaine exposure alters brain glucose metabolic rates following repeated amphetamine administration in the adult rat.

    PubMed

    Melnick, Susan M; Torres-Reveron, Annelyn; Dow-Edwards, Diana L

    2004-10-15

    Developmental cocaine exposure produces long-term alterations in function of many neuronal circuits. This study examined glucose metabolic rates following repeated amphetamine administration in adult male and female rats pretreated with cocaine during postnatal days (PND) 11-20. PND11-20 cocaine increased the response to amphetamine in many components of the motor system and the dorsal caudate-putamen, in particular, and decreased the metabolic response in the hypothalamus. While amphetamine alone produced widespread increases in metabolism, there were no cocaine-related effects in the mesolimbic, limbic or sensory structures. These data suggest that a brief cocaine exposure during development can alter ontogeny and result in abnormal neuronal responses to repeated psychostimulant administration in adulthood. PMID:15464226

  10. Metabolic alterations induced in cultured skeletal muscle by stretch-relaxation activity

    NASA Technical Reports Server (NTRS)

    Hatfaludy, Sophia; Shansky, Janet; Vandenburgh, Herman H.

    1989-01-01

    Muscle cells differentiated in vitro are repetitively stretched and relaxed in order to determine the presence of short- and long-term alterations occurring in glucose uptake and lactate efflux that are similar to the metabolic alterations occurring in stimulated organ-cultured muscle and in vivo skeletal muscle during the active state. It is observed that whereas mechanical stimulation increases these metabolic parameters within 4-6 h of starting activity, unstimulated basal rates in control cultures also increase during this period of time, and by 8 h, their rates have reached or exceeded the rates in continuously stimulated cells. Measurements of these parameters in media of different compositions show that activity-induced long-term alterations in the parameters occur independently of growth factors in serium and embryo extracts.

  11. Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer

    PubMed Central

    2014-01-01

    Background Loss of the endosulfatase HSulf-1 is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis. However, metabolic differences between isogenic cells with and without HSulf-1 have not been characterized upon HSulf-1 suppression in vitro. Since growth factor signaling is closely tied to metabolic alterations, we determined the extent to which HSulf-1 loss affects cancer cell metabolism. Results Ingenuity pathway analysis of gene expression in HSulf-1 shRNA-silenced cells (Sh1 and Sh2 cells) compared to non-targeted control shRNA cells (NTC cells) and subsequent Kyoto Encyclopedia of Genes and Genomics (KEGG) database analysis showed altered metabolic pathways with changes in the lipid metabolism as one of the major pathways altered inSh1 and 2 cells. Untargeted global metabolomic profiling in these isogenic cell lines identified approximately 338 metabolites using GC/MS and LC/MS/MS platforms. Knockdown of HSulf-1 in OV202 cells induced significant changes in 156 metabolites associated with several metabolic pathways including amino acid, lipids, and nucleotides. Loss of HSulf-1 promoted overall fatty acid synthesis leading to enhance the metabolite levels of long chain, branched, and essential fatty acids along with sphingolipids. Furthermore, HSulf-1 loss induced the expression of lipogenic genes including FASN, SREBF1, PPARγ, and PLA2G3 stimulated lipid droplet accumulation. Conversely, re-expression of HSulf-1 in Sh1 cells reduced the lipid droplet formation. Additionally, HSulf-1 also enhanced CPT1A and fatty acid oxidation and augmented the protein expression of key lipolytic enzymes such as MAGL, DAGLA, HSL, and ASCL1. Overall, these findings suggest that loss of HSulf-1 by concomitantly enhancing fatty acid synthesis and oxidation confers a lipogenic phenotype leading to the metabolic alterations associated with the progression of ovarian cancer. Conclusions Taken together, these

  12. Interactions of Non-Phosphorous Glycerolipids with DNA: Energetics, Molecular Docking and Topoisomerase I Attenuation.

    PubMed

    Grinberg, Valery Y; Tsvetkov, Vladimir B; Markova, Alina A; Dezhenkova, Lyubov G; Burova, Tatiana V; Grinberg, Natalia V; Dubovik, Alexander S; Plyavnik, Natalia V; Shtil, Alexander A

    2016-01-01

    The phosphorus-containing glycerolipid based antitumor drugs (edelfosine as a prototype) are currently in clinical trials. To avoid the use of potentially harmful phosphoric reagents in the preparation of biologically active glycerolipids, and to obtain the compounds without the phosphoester bond cleavable inside the cells, we developed the synthesis of non-phosphorous glycerolipids (NPGLs) with neutral or cationic polar 'heads'. In this study, we analyzed the ability of novel NPGLs L1-L5 to interact with duplex DNA and interfere with the DNA modifying enzyme topoisomerase I (topo I). In cell-free systems, NPGLs formed highly affine complexes with DNA. Molecular docking revealed that NPGLs fitted very well into the DNA minor groove. Compounds L2 (with two long hydrophobic 'tails') and L4 (with ethylimidazolium cationic group), the most affine DNA binders, showed the best calculated energies of complex formation with DNA and topo I. The models demonstrated the binding of NPGLs to the topo I site known for interaction with conventional inhibitors. Each NPGL attenuated the topo I mediated unwinding of supercoiled DNA. Again, L2 and, to a lesser extent, L4 were the most potent topo I inhibitors. Thus, NPGLs with polar 'heads' emerge as a new class of DNA ligands and interfacial topo I antagonists. PMID:26416535

  13. Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis.

    PubMed

    Lv, Long-Xian; Fang, Dai-Qiong; Shi, Ding; Chen, De-Ying; Yan, Ren; Zhu, Yi-Xin; Chen, Yan-Fei; Shao, Li; Guo, Fei-Fei; Wu, Wen-Rui; Li, Ang; Shi, Hai-Yan; Jiang, Xia-Wei; Jiang, Hui-Yong; Xiao, Yong-Hong; Zheng, Shu-Sen; Li, Lan-Juan

    2016-07-01

    We selected 42 early-stage primary biliary cirrhosis (PBC) patients and 30 healthy controls (HC). Metagenomic sequencing of the 16S rRNA gene was used to characterize the fecal microbiome. UPLC-MS/MS assaying of small molecules was used to characterize the metabolomes of the serum, urine and feces. Liquid chip assaying of serum cytokines was used to characterize the immune profiles. The gut of PBC patients were depleted of some potentially beneficial bacteria, such as Acidobacteria, Lachnobacterium sp., Bacteroides eggerthii and Ruminococcus bromii, but were enriched in some bacterial taxa containing opportunistic pathogens, such as γ-Proteobacteria, Enterobacteriaceae, Neisseriaceae, Spirochaetaceae, Veillonella, Streptococcus, Klebsiella, Actinobacillus pleuropneumoniae, Anaeroglobus geminatus, Enterobacter asburiae, Haemophilus parainfluenzae, Megasphaera micronuciformis and Paraprevotella clara. Several altered gut bacterial taxa exhibited potential interactions with PBC through their associations with altered metabolism, immunity and liver function indicators, such as those of Klebsiella with IL-2A and Neisseriaceae with urinary indoleacrylate. Many gut bacteria, such as some members of Bacteroides, were altered in their associations with the immunity and metabolism of PBC patients, although their relative abundances were unchanged. Consequently, the gut microbiome is altered and may be critical for the onset or development of PBC by interacting with metabolism and immunity. PMID:27243236

  14. An integrated multi-omics study revealed metabolic alterations underlying the effects of coffee consumption.

    PubMed

    Takahashi, Shoko; Saito, Kenji; Jia, Huijuan; Kato, Hisanori

    2014-01-01

    Many epidemiological studies have indicated that coffee consumption may reduce the risks of developing obesity and diabetes, but the underlying mechanisms of these effects are poorly understood. Our previous study revealed the changes on gene expression profiles in the livers of C57BL/6J mice fed a high-fat diet containing three types of coffee (caffeinated, decaffeinated and green unroasted coffee), using DNA microarrays. The results revealed remarkable alterations in lipid metabolism-related molecules which may be involved in the anti-obesity effects of coffee. We conducted the present study to further elucidate the metabolic alterations underlying the effects of coffee consumption through comprehensive proteomic and metabolomic analyses. Proteomics revealed an up-regulation of isocitrate dehydrogenase (a key enzyme in the TCA cycle) and its related proteins, suggesting increased energy generation. The metabolomics showed an up-regulation of metabolites involved in the urea cycle, with which the transcriptome data were highly consistent, indicating accelerated energy expenditure. The TCA cycle and the urea cycle are likely be accelerated in a concerted manner, since they are directly connected by mutually providing each other's intermediates. The up-regulation of these pathways might result in a metabolic shift causing increased ATP turnover, which is related to the alterations of lipid metabolism. This mechanism may play an important part in the suppressive effects of coffee consumption on obesity, inflammation, and hepatosteatosis. This study newly revealed global metabolic alterations induced by coffee intake, providing significant insights into the association between coffee intake and the prevention of type 2 diabetes, utilizing the benefits of multi-omics analyses. PMID:24618914

  15. Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism.

    PubMed

    Meiser, J; Delcambre, S; Wegner, A; Jäger, C; Ghelfi, J; d'Herouel, A Fouquier; Dong, X; Weindl, D; Stautner, C; Nonnenmacher, Y; Michelucci, A; Popp, O; Giesert, F; Schildknecht, S; Krämer, L; Schneider, J G; Woitalla, D; Wurst, W; Skupin, A; Weisenhorn, D M Vogt; Krüger, R; Leist, M; Hiller, K

    2016-05-01

    The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an important function in cellular antioxidant responses, but its role in central metabolism of neurons is still elusive. We applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1 and show that DJ-1 deficient neuronal cells exhibit decreased glutamine influx and reduced serine biosynthesis. By providing precursors for GSH synthesis, these two metabolic pathways are important contributors to cellular antioxidant response. Down-regulation of these pathways, as a result of loss of DJ-1 leads to an impaired antioxidant response. Furthermore, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered central metabolism and constitutive activation of glia cells raise the susceptibility of dopaminergic neurons towards degeneration in patients harboring mutated DJ-1. Our work reveals metabolic alterations leading to increased cellular instability and identifies potential new intervention points that can further be studied in the light of novel translational medicine approaches. PMID:26836693

  16. Alterations of hippocampal glucose metabolism by even versus uneven medium chain triglycerides

    PubMed Central

    McDonald, Tanya S; Tan, Kah Ni; Hodson, Mark P; Borges, Karin

    2014-01-01

    Medium chain triglycerides (MCTs) are used to treat neurologic disorders with metabolic impairments, including childhood epilepsy and early Alzheimer's disease. However, the metabolic effects of MCTs in the brain are still unclear. Here, we studied the effects of feeding even and uneven MCTs on brain glucose metabolism in the mouse. Adult mice were fed 35% (calories) of trioctanoin or triheptanoin (the triglycerides of octanoate or heptanoate, respectively) or a matching control diet for 3 weeks. Enzymatic assays and targeted metabolomics by liquid chromatography tandem mass spectrometry were used to quantify metabolites in extracts from the hippocampal formations (HFs). Both oils increased the levels of β-hydroxybutyrate, but no other significant metabolic alterations were observed after triheptanoin feeding. The levels of glucose 6-phosphate and fructose 6-phosphate were increased in the HF of mice fed trioctanoin, whereas levels of metabolites further downstream in the glycolytic pathway and the pentose phosphate pathway were reduced. This indicates that trioctanoin reduces glucose utilization because of a decrease in phosphofructokinase activity. Trioctanoin and triheptanoin showed similar anticonvulsant effects in the 6 Hz seizure model, but it remains unknown to what extent the anticonvulsant mechanism(s) are shared. In conclusion, triheptanoin unlike trioctanoin appears to not alter glucose metabolism in the healthy brain. PMID:24169853

  17. Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition

    PubMed Central

    Zhu, Zhu; Hua, Bingxuan; Shang, Zhanxian; Yuan, Gongsheng; Xu, Lirong; Li, Ermin; Li, Xiaobo; Yan, Zuoqin; Qian, Ruizhe

    2016-01-01

    Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice. Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice) by altering exposure to light. C57 BL/6J mice (C57 mice) and ApoE-KO mice (ApoE-KO mice) exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1) levels and rhythmicity. Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice. Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation.

  18. Alterations of hippocampal glucose metabolism by even versus uneven medium chain triglycerides.

    PubMed

    McDonald, Tanya S; Tan, Kah Ni; Hodson, Mark P; Borges, Karin

    2014-01-01

    Medium chain triglycerides (MCTs) are used to treat neurologic disorders with metabolic impairments, including childhood epilepsy and early Alzheimer's disease. However, the metabolic effects of MCTs in the brain are still unclear. Here, we studied the effects of feeding even and uneven MCTs on brain glucose metabolism in the mouse. Adult mice were fed 35% (calories) of trioctanoin or triheptanoin (the triglycerides of octanoate or heptanoate, respectively) or a matching control diet for 3 weeks. Enzymatic assays and targeted metabolomics by liquid chromatography tandem mass spectrometry were used to quantify metabolites in extracts from the hippocampal formations (HFs). Both oils increased the levels of β-hydroxybutyrate, but no other significant metabolic alterations were observed after triheptanoin feeding. The levels of glucose 6-phosphate and fructose 6-phosphate were increased in the HF of mice fed trioctanoin, whereas levels of metabolites further downstream in the glycolytic pathway and the pentose phosphate pathway were reduced. This indicates that trioctanoin reduces glucose utilization because of a decrease in phosphofructokinase activity. Trioctanoin and triheptanoin showed similar anticonvulsant effects in the 6 Hz seizure model, but it remains unknown to what extent the anticonvulsant mechanism(s) are shared. In conclusion, triheptanoin unlike trioctanoin appears to not alter glucose metabolism in the healthy brain. PMID:24169853

  19. Metabolic Alterations Induce Oxidative Stress in Diabetic and Failing Hearts: Different Pathways, Same Outcome

    PubMed Central

    Roul, David

    2015-01-01

    Abstract Significance: Several authors have proposed a link between altered cardiac energy substrate metabolism and reactive oxygen species (ROS) generation. A cogent evidence of this association has been found in diabetic cardiomyopathy (dCM); however, experimental findings in animal models of heart failure (HF) and in human myocardium also seem to support the coexistence of the two alterations in HF. Critical Issues: Two important questions remain open: whether pathological changes in metabolism play an important role in enhancing oxidative stress and whether there is a common pathway linking altered substrate utilization and activation of ROS-generating enzymes, independently of the underlying cardiac pathology. In this regard, the comparison between dCM and HF is intriguing, in that these pathological conditions display very different cardiac metabolic phenotypes. Recent Advances: Our literature review on this topic indicates that a vast body of knowledge is now available documenting the relationship between the metabolism of energy substrates and ROS generation in dCM. In some cases, biochemical mechanisms have been identified. On the other hand, only a few and relatively recent studies have explored this phenomenon in HF and their conclusions are not consistent. Future Directions: Better methods of investigation, especially in vivo, will be necessary to test whether the metabolic fate of certain substrates is causally linked to ROS production. If successful, these studies will place a new emphasis on the potential clinical relevance of metabolic modulators, which might indirectly mitigate cardiac oxidative stress in dCM, HF, and, possibly, in other pathological conditions. Antioxid. Redox Signal. 22, 1502–1514. PMID:25836025

  20. Effects of Light Intensity and Nitrogen Starvation on Glycerolipid, Glycerophospholipid, and Carotenoid Composition in Dunaliella tertiolecta Culture

    PubMed Central

    Lee, Seok-Young; Hong, Seong-Joo; Cho, Byung-Kwan; Lee, Hookeun; Lee, Choul-Gyun; Choi, Hyung-Kyoon

    2013-01-01

    Time-course variation of lipid and carotenoid production under high light (300 μE/m2s) and nitrogen starvation conditions was determined in a Dunaliella tertiolecta strain. Nanoelectrospray (nanoESI) chip based direct infusion was used for lipid analysis and ultra-performance liquid chromatography (UPLC) coupled with a photodiode array (PDA) or atmospheric chemical ionization mass spectrometry (APCI-MS) was used for carotenoid analysis. A total of 29 lipids and 7 carotenoids were detected. Alterations to diacylglyceryltrimethylhomoserine (DGTS) and digalactosyldiacylglycerol (DGDG) species were significant observations under stress conditions. Their role in relation to the regulation of photosynthesis under stress condition is discussed in this study. The total carotenoid content was decreased under stress conditions, while ã-carotene was increased under nitrate-deficient cultivation. The highest productivity of carotenoid was attained under high light and nitrate sufficiency (HLNS) condition, which result from the highest level of biomass under HLNS. When stress was induced at stationary phase, the substantial changes to the lipid composition occurred, and the higher carotenoid content and productivity were exhibited. This is the first report to investigate the variation of lipids, including glycerolipid, glycerophospholipid, and carotenoid in D. tertiolecta in response to stress conditions using lipidomics tools. PMID:24039760

  1. Liquid Chromatography-Mass Spectrometry-Based In Vitro Metabolic Profiling Reveals Altered Enzyme Expressions in Eicosanoid Metabolism

    PubMed Central

    Lee, Su Hyeon; Kim, Eung Ju; Lee, Dong-Hyoung; Lee, Won-Yong; Chung, Bong Chul

    2016-01-01

    Background Eicosanoids are metabolites of arachidonic acid that are rapidly biosynthesized and degraded during inflammation, and their metabolic changes reveal altered enzyme expression following drug treatment. We developed an eicosanoid profiling method and evaluated their changes on drug treatment. Methods Simultaneous quantitative profiling of 32 eicosanoids in liver S9 fractions obtained from rabbits with carrageenan-induced inflammation was performed and validated by liquid chromatography-mass spectrometry coupled to anion-exchange solid-phase purification. Results The limit of quantification for the devised method ranged from 0.5 to 20.0 ng/mg protein, and calibration linearity was achieved (R2>0.99). The precision (% CV) and accuracy (% bias) ranged from 4.7 to 10.3% and 88.4 to 110.9%, respectively, and overall recoveries ranged from 58.0 to 105.3%. Our method was then applied and showed that epitestosterone treatment reduced the levels of all eicosanoids that were generated by cyclooxygenases and lipoxygenases. Conclusions Quantitative eicosanoid profiling combined with in vitro metabolic assays may be useful for evaluating metabolic changes affected by drugs during eicosanoid metabolism. PMID:27139607

  2. Altered lipid metabolism in Drosophila model of Huntington’s disease

    PubMed Central

    Aditi, Kumari; Shakarad, Mallikarjun N.; Agrawal, Namita

    2016-01-01

    Huntington’s disease (HD) is late-onset, progressive neurodegenerative disorder caused by expansion of polyglutamine (polyQ) repeat within Huntingtin (Htt) protein. In HD patients, energy-related manifestations such as modulation of weight during entire course of disease with energy deficit at terminal stage have been reported, however, underlying reason remains elusive till date. Lipids, carbohydrate and protein constitute a predominant fraction of body’s energy reservoir and perturbation in their homeostasis may influence weight. To discern role of these energy molecules in weight alteration, we quantified them in an in vivo transgenic Drosophila model of HD. We document that diseased flies exhibit change in weight due to an altered lipid metabolism, as evident from considerably high lipid levels at the time of disease onset followed by a pathologic decline at end-stage. An alteration in intracellular lipid droplet size suggested altered cellular lipid turnover. Furthermore, diseased flies displayed substantial changes in carbohydrate and protein content. Interestingly, alteration in weight and lipid levels are independent of the feeding pattern in diseased condition and exhibit weak correlation with insulin-like peptide or adipokinetic hormone producing cells. We propose that therapeutic intervention aimed at restoring lipid levels and associated metabolic pathways may improve longevity and quality of patient’s life. PMID:27506601

  3. Metabolic alterations following visceral fat removal and expansion: Beyond anatomic location.

    PubMed

    Foster, Michelle T; Pagliassotti, Michael J

    2012-10-01

    Increased visceral adiposity is a risk factor for metabolic disorders such as dyslipidemia, hypertension, insulin resistance and type 2 diabetes, whereas peripheral (subcutaneous) obesity is not. Though the specific mechanisms which contribute to these adipose depot differences are unknown, visceral fat accumulation is proposed to result in metabolic dysregulation because of increased effluent, e.g., fatty acids and/or adipokines/cytokines, to the liver via the hepatic portal vein. Pathological significance of visceral fat accumulation is also attributed to adipose depot/adipocyte-specific characteristics, specifically differences in structural, physiologic and metabolic characteristics compared with subcutaneous fat. Fat manipulations, such as removal or transplantation, have been utilized to identify location dependent or independent factors that play a role in metabolic dysregulation. Obesity-induced alterations in adipose tissue function/intrinsic characteristics, but not mass, appear to be responsible for obesity-induced metabolic dysregulation, thus "quality" is more important than "quantity." This review summarizes the implications of obesity-induced metabolic dysfunction as it relates to anatomic site and inherent adipocyte characteristics. PMID:23700533

  4. Phenotypic characterization of nanshi oral liquid alters metabolic signatures during disease prevention

    PubMed Central

    Zhang, Aihua; Liu, Qi; Zhao, Hongwei; Zhou, Xiaohang; Sun, Hui; Nan, Yang; Zou, Shiyu; Ma, Chung Wah; Wang, Xijun

    2016-01-01

    This paper was designed to investigate the phenotypic characterization of Nanshi Oral Liquid (NOL) alters metabolic signatures of the ‘Kidney Yang Deficiency syndrome’ (KYDS). Urine metabolites were profiled by UPLC-ESI-Q-TOF-HDMS. The significantly changed metabolites such as xanthurenic acid, 4,8-dihydroxyquinoline, 3-methyldioxyindole, 4,6-dihydroxyquinoline, kynurenic acid, hippuric acid, taurine, tyramine, and 3-metanephrine, had been identified, and were related to the disturbance in tyrosine metabolism, steroid hormone biosynthesis, taurine and hypotaurine metabolism, tryptophan metabolism, phenylalanine metabolism and lysine degradation, which were helpful to further understanding the KYDS and intervention mechanism of NOL. The biochemical result showed that NOL can alleviate the kidney impairment induced by KYDS. Metabolomics results indicated the significantly changed metabolites were found to be reasonable in explaining the action mechanism of NOL. Interestingly, the effectiveness of NOL against KYDS was proved using the established metabolomics method and regulated the biomarkers as well as adjusted the metabolic disorder pathways. NOL had potentially pharmacological effect through regulating multiple perturbed pathways to normal state. This work showed that the metabolomics method was a powerful approach for studying the phenotypic characterization of disease’s syndrome during disease prevention and its intervention mechanism. PMID:26785698

  5. Aglycones and sugar moieties alter anthocyanin absorption and metabolism after berry consumption in weanling pigs.

    PubMed

    Wu, Xianli; Pittman, Hoy E; McKay, Steve; Prior, Ronald L

    2005-10-01

    To investigate the absorption and metabolism of anthocyanins (ACNs) with different aglycones and sugar moieties, weanling pigs (11.4 +/- 3.8 kg) were fed, in a single meal, a freeze-dried powder of chokeberry, black currant, or elderberry at a single dose of 229, 140, or 228 mumol total ACN/kg body weight (BW), respectively. These berries provided ACNs with differences in aglycone as well as some unique differences in the sugar moieties. The relative proportions of the different metabolites depended upon concentrations, quantities consumed, and types of glycoside of ACNs in the berry. Delphinidin ACNs were not metabolized to any measurable extent. Cyanidin ACNs were metabolized via methylation and glucuronidation as well as by formation of both derivatives on the same ACN molecule. ACNs with either a di- or trisaccharide attached to them were excreted in the urine primarily as the intact form. Over 80% of the ACN compounds containing rutinose or sambubiose, which were excreted in the urine from black currant, elderberry, or Marion blackberry, were excreted as the intact molecule. The limited metabolism of these ACNs that did occur was via methylation. ACN monoglycosides other than the glucoside were metabolized via methylation and/or glucuronide formation. The monoglucuronide that formed represented a small proportion of the metabolites relative to the methylated or the mixed methylated and glucuronide forms of ACNs. The data clearly demonstrate that the aglycone and the sugar moieties can alter the apparent absorption and metabolism of ACNs. PMID:16177206

  6. Enzymatic passaging of human embryonic stem cells alters central carbon metabolism and glycan abundance

    PubMed Central

    Badur, Mehmet G.; Zhang, Hui; Metallo, Christian M.

    2016-01-01

    To realize the potential of human embryonic stem cells (hESCs) in regenerative medicine and drug discovery applications, large numbers of cells that accurately recapitulate cell and tissue function must be robustly produced. Previous studies have suggested that genetic instability and epigenetic changes occur as a consequence of enzymatic passaging. However, the potential impacts of such passaging methods on the metabolism of hESCs have not been described. Using stable isotope tracing and mass spectrometry-based metabolomics, we have explored how different passaging reagents impact hESC metabolism. Enzymatic passaging caused significant decreases in glucose utilization throughout central carbon metabolism along with attenuated de novo lipogenesis. In addition, we developed and validated a method for rapidly quantifying glycan abundance and isotopic labeling in hydrolyzed biomass. Enzymatic passaging reagents significantly altered levels of glycans immediately after digestion but surprisingly glucose contribution to glycans was not affected. These results demonstrate that there is an immediate effect on hESC metabolism after enzymatic passaging in both central carbon metabolism and biosynthesis. HESCs subjected to enzymatic passaging are routinely placed in a state requiring re-synthesis of biomass components, subtly influencing their metabolic needs in a manner that may impact cell performance in regenerative medicine applications. PMID:26289220

  7. Polychlorinated biphenyl 126 exposure in L6 myotubes alters glucose metabolism: a pilot study.

    PubMed

    Mauger, Jean-François; Nadeau, Lucien; Caron, Audrey; Chapados, Natalie Ann; Aguer, Céline

    2016-04-01

    Polychlorinated biphenyls (PCBs) are increasingly recognized as metabolic disruptors. Due to its mass, skeletal muscle is the major site of glucose disposal. While muscle mitochondrial dysfunction and oxidative stress have been shown to play a central role in metabolic disease development, no studies to date have investigated the effect of PCB exposure on muscle energy metabolism and oxidative stress. In this pilot study, we tested the effect of exposure to PCB126 in L6 myotubes (from 1 to 2500 nM for 24 h) on mitochondrial function, glucose metabolism, and oxidative stress. Exposure to PCB126 had no apparent effect on resting, maximal, and proton leak-dependent oxygen consumption rate in intact L6 myotubes. However, basal glucose uptake and glycolysis were inhibited by 20-30 % in L6 myotubes exposed to PCB126. Exposure to PCB126 did not appear to alter skeletal muscle anti-oxidant defense or oxidative stress. In conclusion, our study shows for the first time that exposure to a dioxin-like PCB adversely affects skeletal muscle glucose metabolism. Given the importance of skeletal muscle in the maintenance of glucose homeostasis, PCB126 could play an important role in the development of metabolic disorders. PMID:26936477

  8. Myocardial Reloading After Extracorporeal Membrane Oxygenation Alters Substrate Metabolism While Promoting Protein Synthesis

    PubMed Central

    Kajimoto, Masaki; O'Kelly Priddy, Colleen M.; Ledee, Dolena R.; Xu, Chun; Isern, Nancy; Olson, Aaron K.; Rosiers, Christine Des; Portman, Michael A.

    2013-01-01

    Background Extracorporeal membrane oxygenation (ECMO) unloads the heart, providing a bridge to recovery in children after myocardial stunning. ECMO also induces stress which can adversely affect the ability to reload or wean the heart from the circuit. Metabolic impairments induced by altered loading and/or stress conditions may impact weaning. However, cardiac substrate and amino acid requirements upon weaning are unknown. We assessed the hypothesis that ventricular reloading with ECMO modulates both substrate entry into the citric acid cycle (CAC) and myocardial protein synthesis. Methods and Results Sixteen immature piglets (7.8 to 15.6 kg) were separated into 2 groups based on ventricular loading status: 8‐hour ECMO (UNLOAD) and postwean from ECMO (RELOAD). We infused into the coronary artery [2‐13C]‐pyruvate as an oxidative substrate and [13C6]‐L‐leucine as an indicator for amino acid oxidation and protein synthesis. Upon RELOAD, each functional parameter, which were decreased substantially by ECMO, recovered to near‐baseline level with the exclusion of minimum dP/dt. Accordingly, myocardial oxygen consumption was also increased, indicating that overall mitochondrial metabolism was reestablished. At the metabolic level, when compared to UNLOAD, RELOAD altered the contribution of various substrates/pathways to tissue pyruvate formation, favoring exogenous pyruvate versus glycolysis, and acetyl‐CoA formation, shifting away from pyruvate decarboxylation to endogenous substrate, presumably fatty acids. Furthermore, there was also a significant increase of tissue concentrations for all CAC intermediates (≈80%), suggesting enhanced anaplerosis, and of fractional protein synthesis rates (>70%). Conclusions RELOAD alters both cytosolic and mitochondrial energy substrate metabolism, while favoring leucine incorporation into protein synthesis rather than oxidation in the CAC. Improved understanding of factors governing these metabolic perturbations may

  9. Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism

    PubMed Central

    Jansen, S. W.; Akintola, A. A.; Roelfsema, F.; van der Spoel, E.; Cobbaert, C. M.; Ballieux, B. E.; Egri, P.; Kvarta-Papp, Z.; Gereben, B.; Fekete, C.; Slagboom, P. E.; van der Grond, J.; Demeneix, B. A.; Pijl, H.; Westendorp, R. G. J.; van Heemst, D.

    2015-01-01

    Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism. PMID:26089239

  10. Phage infection of an environmentally relevant marine bacterium alters host metabolism and lysate composition

    PubMed Central

    Ankrah, Nana Yaw D; May, Amanda L; Middleton, Jesse L; Jones, Daniel R; Hadden, Mary K; Gooding, Jessica R; LeCleir, Gary R; Wilhelm, Steven W; Campagna, Shawn R; Buchan, Alison

    2014-01-01

    Viruses contribute to the mortality of marine microbes, consequentially altering biological species composition and system biogeochemistry. Although it is well established that host cells provide metabolic resources for virus replication, the extent to which infection reshapes host metabolism at a global level and the effect of this alteration on the cellular material released following viral lysis is less understood. To address this knowledge gap, the growth dynamics, metabolism and extracellular lysate of roseophage-infected Sulfitobacter sp. 2047 was studied using a variety of techniques, including liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based metabolomics. Quantitative estimates of the total amount of carbon and nitrogen sequestered into particulate biomass indicate that phage infection redirects ∼75% of nutrients into virions. Intracellular concentrations for 82 metabolites were measured at seven time points over the infection cycle. By the end of this period, 71% of the detected metabolites were significantly elevated in infected populations, and stable isotope-based flux measurements showed that these cells had elevated metabolic activity. In contrast to simple hypothetical models that assume that extracellular compounds increase because of lysis, a profile of metabolites from infected cultures showed that >70% of the 56 quantified compounds had decreased concentrations in the lysate relative to uninfected controls, suggesting that these small, labile nutrients were being utilized by surviving cells. These results indicate that virus-infected cells are physiologically distinct from their uninfected counterparts, which has implications for microbial community ecology and biogeochemistry. PMID:24304672

  11. Effects of independently altering body weight and body mass on the metabolic cost of running.

    PubMed

    Teunissen, Lennart P J; Grabowski, Alena; Kram, Rodger

    2007-12-01

    The metabolic cost of running is substantial, despite the savings from elastic energy storage and return. Previous studies suggest that generating vertical force to support body weight and horizontal forces to brake and propel body mass are the major determinants of the metabolic cost of running. In the present study, we investigated how independently altering body weight and body mass affects the metabolic cost of running. Based on previous studies, we hypothesized that reducing body weight would decrease metabolic rate proportionally, and adding mass and weight would increase metabolic rate proportionally. Further, because previous studies show that adding mass alone does not affect the forces generated on the ground, we hypothesized that adding mass alone would have no substantial effect on metabolic rate. We manipulated the body weight and body mass of 10 recreational human runners and measured their metabolic rates while they ran at 3 m s(-1). We reduced weight using a harness system, increased mass and weight using lead worn about the waist, and increased mass alone using a combination of weight support and added load. We found that net metabolic rate decreased in less than direct proportion to reduced body weight, increased in slightly more than direct proportion to added load (added mass and weight), and was not substantially different from normal running with added mass alone. Adding mass alone was not an effective method for determining the metabolic cost attributable to braking/propelling body mass. Runners loaded with mass alone did not generate greater vertical or horizontal impulses and their metabolic costs did not substantially differ from those of normal running. Our results show that generating force to support body weight is the primary determinant of the metabolic cost of running. Extrapolating our reduced weight data to zero weight suggests that supporting body weight comprises at most 74% of the net cost of running. However, 74% is probably an

  12. Gold nanoparticles alter parameters of oxidative stress and energy metabolism in organs of adult rats.

    PubMed

    Ferreira, Gabriela Kozuchovski; Cardoso, Eria; Vuolo, Francieli Silva; Michels, Monique; Zanoni, Elton Torres; Carvalho-Silva, Milena; Gomes, Lara Mezari; Dal-Pizzol, Felipe; Rezin, Gislaine Tezza; Streck, Emilio L; Paula, Marcos Marques da Silva

    2015-12-01

    This study evaluated the parameters of oxidative stress and energy metabolism after the acute and long-term administration of gold nanoparticles (GNPs, 10 and 30 nm in diameter) in different organs of rats. Adult male Wistar rats received a single intraperitoneal injection or repeated injections (once daily for 28 days) of saline solution, GNPs-10 or GNPs-30. Twenty-four hours after the last administration, the animals were killed, and the liver, kidney, and heart were isolated for biochemical analysis. We demonstrated that acute administration of GNPs-30 increased the TBARS levels, and that GNPs-10 increased the carbonyl protein levels. The long-term administration of GNPs-10 increased the TBARS levels, and the carbonyl protein levels were increased by GNPs-30. Acute administration of GNPs-10 and GNPs-30 increased SOD activity. Long-term administration of GNPs-30 increased SOD activity. Acute administration of GNPs-10 decreased the activity of CAT, whereas long-term administration of GNP-10 and GNP-30 altered CAT activity randomly. Our results also demonstrated that acute GNPs-30 administration decreased energy metabolism, especially in the liver and heart. Long-term GNPs-10 administration increased energy metabolism in the liver and decreased energy metabolism in the kidney and heart, whereas long-term GNPs-30 administration increased energy metabolism in the heart. The results of our study are consistent with other studies conducted in our research group and reinforce the fact that GNPs can lead to oxidative damage, which is responsible for DNA damage and alterations in energy metabolism. PMID:26583437

  13. Insulin sensitivity of muscle protein metabolism is altered in patients with chronic kidney disease and metabolic acidosis

    PubMed Central

    Garibotto, Giacomo; Sofia, Antonella; Russo, Rodolfo; Paoletti, Ernesto; Bonanni, Alice; Parodi, Emanuele L; Viazzi, Francesca; Verzola, Daniela

    2015-01-01

    An emergent hypothesis is that a resistance to the anabolic drive by insulin may contribute to loss of strength and muscle mass in patients with chronic kidney disease (CKD). We tested whether insulin resistance extends to protein metabolism using the forearm perfusion method with arterial insulin infusion in 7 patients with CKD and metabolic acidosis (bicarbonate 19 mmol/l) and 7 control individuals. Forearm glucose balance and protein turnover (2H-phenylalanine kinetics) were measured basally and in response to insulin infused at different rates for 2 h to increase local forearm plasma insulin concentration by approximately 20 and 50 μU/ml. In response to insulin, forearm glucose uptake was significantly increased to a lesser extent (−40%) in patients with CKD than controls. In addition, whereas in the controls net muscle protein balance and protein degradation were decreased by both insulin infusion rates, in patients with CKD net protein balance and protein degradation were sensitive to the high (0.035 mU/kg per min) but not the low (0.01 mU/kg per min) insulin infusion. Besides blunting muscle glucose uptake, CKD and acidosis interfere with the normal suppression of protein degradation in response to a moderate rise in plasma insulin. Thus, alteration of protein metabolism by insulin may lead to changes in body tissue composition which may become clinically evident in conditions characterized by low insulinemia. PMID:26308671

  14. Early environmental factors, alteration of epigenetic marks and metabolic disease susceptibility.

    PubMed

    Portha, B; Fournier, A; Kioon, M D Ah; Mezger, V; Movassat, J

    2014-02-01

    The environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Early-life nutrition and stress are among the best documented examples of such conditions because they influence the adult risk of developing metabolic diseases, such as type 2 diabetes mellitus (T2D) and cardiovascular diseases. It is now becoming increasingly accepted that environmental compounds including nutrients can produce changes in the genome activity that in spite of not altering DNA sequence can produce important, stable and transgenerational alterations in the phenotype. Epigenetic changes, in particular DNA methylation and histone acetylation/methylation, provide a 'memory' of developmental plastic responses to early environment and are central to the generation of phenotypes and their stability throughout the life course. Their effects may only become manifest later in life, e.g. in terms of altered responses to environmental challenges. PMID:24139903

  15. Anti-inflammatory salicylate treatment alters the metabolic adaptations to lactation in dairy cattle

    PubMed Central

    Farney, Jaymelynn K.; Mamedova, Laman K.; Coetzee, Johann F.; KuKanich, Butch; Sordillo, Lorraine M.; Stoakes, Sara K.; Minton, J. Ernest; Hollis, Larry C.

    2013-01-01

    Adapting to the lactating state requires metabolic adjustments in multiple tissues, especially in the dairy cow, which must meet glucose demands that can exceed 5 kg/day in the face of negligible gastrointestinal glucose absorption. These challenges are met through the process of homeorhesis, the alteration of metabolic setpoints to adapt to a shift in physiological state. To investigate the role of inflammation-associated pathways in these homeorhetic adaptations, we treated cows with the nonsteroidal anti-inflammatory drug sodium salicylate (SS) for the first 7 days of lactation. Administration of SS decreased liver TNF-α mRNA and marginally decreased plasma TNF-α concentration, but plasma eicosanoids and liver NF-κB activity were unaltered during treatment. Despite the mild impact on these inflammatory markers, SS clearly altered metabolic function. Plasma glucose concentration was decreased by SS, but this was not explained by a shift in hepatic gluconeogenic gene expression or by altered milk lactose secretion. Insulin concentrations decreased in SS-treated cows on day 7 compared with controls, which was consistent with the decline in plasma glucose concentration. The revised quantitative insulin sensitivity check index (RQUICKI) was then used to assess whether altered insulin sensitivity may have influenced glucose utilization rate with SS. The RQUICKI estimate of insulin sensitivity was significantly elevated by SS on day 7, coincident with the decline in plasma glucose concentration. Salicylate prevented postpartum insulin resistance, likely causing excessive glucose utilization in peripheral tissues and hypoglycemia. These results represent the first evidence that inflammation-associated pathways are involved in homeorhetic adaptations to lactation. PMID:23678026

  16. Energy metabolism in developing chicken lymphocytes is altered during the embryonic to posthatch transition.

    PubMed

    Rudrappa, Shashidhara G; Humphrey, Brooke D

    2007-02-01

    Adequate energy status in lymphocytes is vital for their development. The ability of developing chicken lymphocytes to acquire and metabolize energy substrates was determined during embryonic days (e) and neonatal days (d) of life when primary-energy substrate metabolism is altered at the whole-animal level. In 3 experiments, bursacytes and thymocytes were isolated on e17, e20, d1, d3, d7, or d14 to analyze markers associated with glucose, glutamine, and lipid metabolism. Bursacyte glucose transporter-3 (Glut-3) mRNA abundance increased from d1 to d14 and hexokinase-1 (HK-1) mRNA abundance was maximum on e20 (P<0.05). Thymocyte Glut-1, Glut-3, and HK-1 mRNA abundance increased from e17 to d14 (P<0.05). HK enzyme activity increased from e20 to d3 in bursacytes and d3 to d7 in thymocytes (P<0.05). Glucose uptake by bursacytes and thymocytes was greater on d14 compared to d1 and d7 (P<0.05). Bursacyte and thymocyte sodium coupled neutral amino acid transporter-2 and glutaminase (GA) mRNA abundance increased from e20 to d7 (P<0.05). GA enzyme activity increased from e20 to d7 in bursacytes (P<0.05) and did not change in thymocytes. Carnitine palmitoyl transferase enzyme activity did not change over time in either cell type. These studies suggest that developing B and T lymphocytes adapt their metabolism during the first 2 wk after hatch. Developing lymphocytes increase glucose metabolism with no change in fatty acid metabolism and bursacytes, but not thymocytes, increase glutamine metabolism. Understanding the factors that regulate lymphocyte development in neonatal chicks may help promote their adaptive immune responses to pathogens in early life. PMID:17237322

  17. Short-term fasting alters cytochrome P450-mediated drug metabolism in humans.

    PubMed

    Lammers, Laureen A; Achterbergh, Roos; de Vries, Emmely M; van Nierop, F Samuel; Klümpen, Heinz-Josef; Soeters, Maarten R; Boelen, Anita; Romijn, Johannes A; Mathôt, Ron A A

    2015-06-01

    Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in humans need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36 h) on P450-mediated drug metabolism. In a randomized crossover study design, nine healthy subjects ingested a cocktail consisting of five P450-specific probe drugs [caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and midazolam (CYP3A4)] on two occasions (control study after an overnight fast and after 36 h of fasting). Blood samples were drawn for pharmacokinetic analysis using nonlinear mixed effects modeling. In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of P450 isoforms corresponding with the five studied P450 enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (P = 0.03) and decreased oral S-warfarin clearance by 25% (P < 0.001). In rats, short-term fasting increased mRNA expression of the orthologs of human CYP1A2, CYP2C19, CYP2D6, and CYP3A4 (P < 0.05), and decreased the mRNA expression of the ortholog of CYP2C9 (P < 0.001) compared with the postabsorptive state. These results demonstrate that short-term fasting alters cytochrome P450-mediated drug metabolism in a nonuniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450-mediated drug metabolism in humans. PMID:25795462

  18. Acute administration of l-tyrosine alters energetic metabolism of hippocampus and striatum of infant rats.

    PubMed

    Ramos, Andrea C; Ferreira, Gabriela K; Carvalho-Silva, Milena; Furlanetto, Camila B; Gonçalves, Cinara L; Ferreira, Gustavo C; Schuck, Patrícia F; Streck, Emilio L

    2013-08-01

    Tyrosinemia type II is an inborn error of metabolism caused by mutations in the gene that encodes tyrosine aminotransferase, which leads to increased blood tyrosine levels. Considering that tyrosine levels are highly elevated in fluids of patients with tyrosinemia type II, and that previous studies demonstrated significant alterations in brain energy metabolism of young rats caused by l-tyrosine, the present study aimed to evaluate the effect of acute administration of l-tyrosine on the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase, and mitochondrial respiratory chain complexes I, II, II-III, and IV in posterior cortex, hippocampus, and striatum of infant rats. Wistar rats (10 days old) were killed 1h after a single intraperitoneal injection of tyrosine (500 mg/kg) or saline. The activities of energy metabolism enzymes were evaluated in brain of rats. Our results demonstrated that acute administration of l-tyrosine inhibited the activity of citrate synthase activity in striatum and increased the activities of malate dehydrogenase and succinate dehydrogenase in hippocampus. On the other hand, these enzymes were not affected in posterior cortex. The activities of complex I and complex II were inhibited by acute administration of l-tyrosine in striatum. On the other hand, the acute administration of l-tyrosine increased the activity of activity of complex II-III in hippocampus. Complex IV was not affected by acute administration of l-tyrosine in infant rats. Our results indicate an alteration in the energy metabolism in hippocampus and striatum of infant rats after acute administration of l-tyrosine. If the same effects occur in the brain of the patients, it is possible that energy metabolism impairment may be contribute to possible damage in memory and cognitive processes in patients with tyrosinemia type II. PMID:23602810

  19. Metabolic and feeding behavior alterations provoked by prenatal exposure to aspartame.

    PubMed

    von Poser Toigo, E; Huffell, A P; Mota, C S; Bertolini, D; Pettenuzzo, L F; Dalmaz, C

    2015-04-01

    The use of artificial sweeteners has increased together with the epidemic growth of obesity. In addition to their widespread use in sodas, artificial sweeteners are added to nearly 6000 other products sold in the US, including baby foods, frozen dinners and even yogurts. It has been suggested that the use of nonnutritive sweeteners can lead to body weight gain and an altered metabolic profile. However, very few studies have evaluated the effects of maternal consumption of artificial non-caloric sweeteners on body weight, feeding behavior or the metabolism of offspring in adult life. In this study, we found that animals exposed to aspartame during the prenatal period presented a higher consumption of sweet foods during adulthood and a greater susceptibility to alterations in metabolic parameters, such as increased glucose, LDL and triglycerides. These effects were observed in both males and females, although they were more pronounced in males. Despite the preliminary nature of this study, and the need for further confirmation of these effects, our data suggest that the consumption of sweeteners during gestation may have deleterious long-term effects and should be used with caution. PMID:25543075

  20. DHEA-Mediated Inhibition of the Pentose Phosphate Pathway Alters Oocyte Lipid Metabolism in Mice

    PubMed Central

    Jimenez, Patricia T.; Frolova, Antonina I.; Chi, Maggie M.; Grindler, Natalia M.; Willcockson, Alexandra R.; Reynolds, Kasey A.; Zhao, Quihong

    2013-01-01

    Women with polycystic ovary syndrome (PCOS) and hyperandrogenism have altered hormone levels and suffer from ovarian dysfunction leading to subfertility. We have attempted to generate a model of hyperandrogenism by feeding mice chow supplemented with dehydroepiandrosterone (DHEA), an androgen precursor that is often elevated in women with PCOS. Treated mice had polycystic ovaries, low ovulation rates, disrupted estrous cycles, and altered hormone levels. Because DHEA is an inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway, we tested the hypothesis that oocytes from DHEA-exposed mice would have metabolic disruptions. Citrate levels, glucose-6-phosphate dehydrogenase activity, and lipid content in denuded oocytes from these mice were significantly lower than controls, suggesting abnormal tricarboxylic acid and pentose phosphate pathway metabolism. The lipid and citrate effects were reversible by supplementation with nicotinic acid, a precursor for reduced nicotinamide adenine dinucleotide phosphate. These findings suggest that elevations in systemic DHEA can have a negative impact on oocyte metabolism and may contribute to poor pregnancy outcomes in women with hyperandrogenism and PCOS. PMID:24036000

  1. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption

    PubMed Central

    Xie, Guoxiang; Zhong, Wei; Li, Houkai; Li, Qiong; Qiu, Yunping; Zheng, Xiaojiao; Chen, Huiyuan; Zhao, Xueqing; Zhang, Shucha; Zhou, Zhanxiang; Zeisel, Steven H.; Jia, Wei

    2013-01-01

    Our understanding of the bile acid metabolism is limited by the fact that previous analyses have primarily focused on a selected few circulating bile acids; the bile acid profiles of the liver and gastrointestinal tract pools are rarely investigated. Here, we determined how chronic ethanol consumption altered the bile acids in multiple body compartments (liver, gastrointestinal tract, and serum) of rats. Rats were fed a modified Lieber-DeCarli liquid diet with 38% of calories as ethanol (the amount equivalent of 4–5 drinks in humans). While conjugated bile acids predominated in the liver (98.3%), duodenum (97.8%), and ileum (89.7%), unconjugated bile acids comprised the largest proportion of measured bile acids in serum (81.2%), the cecum (97.7%), and the rectum (97.5%). In particular, taurine-conjugated bile acids were significantly decreased in the liver and gastrointestinal tract of ethanol-treated rats, while unconjugated and glycine-conjugated species increased. Ethanol consumption caused increased expression of genes involved in bile acid biosynthesis, efflux transport, and reduced expression of genes regulating bile acid influx transport in the liver. These results provide an improved understanding of the systemic modulations of bile acid metabolism in mammals through the gut-liver axis.—Xie, G., Zhong, W., Li, H., Li, Q., Qiu, Y., Zheng, X., Chen, H., Zhao, X., Zhang, S., Zhou, Z., Zeisel, S. H., Jia, W. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption. PMID:23709616

  2. Alterations in lung arginine metabolism in lambs with pulmonary hypertension associated with increased pulmonary blood flow

    PubMed Central

    Sharma, Shruti; Kumar, Sanjiv; Sud, Neetu; Wiseman, Dean A.; Tian, Jing; Rehmani, Imran; Datar, Sanjeev; Oishi, Peter; Fratz, Sohrab; Venema, Richard C.; Fineman, Jeffrey R.; Black, Stephen M.

    2010-01-01

    Previous studies demonstrate impaired nitric oxide (NO) signaling in children and animal models with congenital heart defects and increased pulmonary blood flow. However, the molecular mechanisms underlying these alterations remain incompletely understood. The purpose of this study was to determine if early changes in arginine metabolic pathways could play a role in the reduced NO signaling demonstrated in our lamb model of congenital heart disease with increased pulmonary blood flow (Shunt lambs). The activities of the arginine recycling enzymes, argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) were both decreased in lung tissues of Shunt lambs while arginase activity was increased. Associated with these alterations, lung L-arginine levels were decreased. These changes correlated with an increase in NO synthase-derived reactive oxygen species (ROS) generation. This study provides further insights into the molecular mechanisms leading to decreased NO signaling in Shunt lambs and suggests that altered arginine metabolism may play a role in the development of the endothelial dysfunction associated with pulmonary hypertension secondary to increased pulmonary blood flow. PMID:19818875

  3. Weight loss is associated with plasma free amino acid alterations in subjects with metabolic syndrome

    PubMed Central

    Tochikubo, O; Nakamura, H; Jinzu, H; Nagao, K; Yoshida, H; Kageyama, N; Miyano, H

    2016-01-01

    Objectives: The prevalence of metabolic syndrome is increasing worldwide, especially in Asian populations. Early detection and effective intervention are vital. Plasma free amino acid profile is a potential biomarker for the early detection for lifestyle-related diseases. However, little is known about whether the altered plasma free amino acid profiles in subjects with metabolic syndrome are related to the effectiveness of dietary and exercise interventions. Methods: Eighty-five Japanese subjects who fulfilled the Japanese diagnostic criteria for metabolic syndrome were enrolled in a 3-month diet and exercise intervention. The plasma free amino acid concentrations and metabolic variables were measured, and the relationships between plasma free amino acid profiles, metabolic variables and the extent of body weight reduction were investigated. Those who lost more than 3% of body weight were compared with those who lost less than 3%. Results: Baseline levels of most amino acids in the subset that went on to lose <3% body weight were markedly lower compared with the counterpart, although both groups showed similar proportional pattern of plasma amino acid profiles. The weight loss induced by the diet and exercise intervention normalized plasma free amino acid profiles. For those with a high degree of weight loss, those changes were also associated with improvement in blood pressure, triglyceride and hemoglobin A1c levels. Conclusions: These data suggest that among Japanese adults meeting the criteria for metabolic syndrome, baseline plasma free amino acid profiles may differ in ways that predict who will be more vs less beneficially responsive to a standard diet and exercise program. Plasma free amino acid profiles may also be useful as markers for monitoring the risks of developing lifestyle-related diseases and measuring improvement in physiological states. PMID:26926588

  4. Alteration of glial-neuronal metabolic interactions in a mouse model of Alexander disease

    PubMed Central

    Meisingset, Tore Wergeland; Risa, Øystein; Brenner, Michael; Messing, Albee; Sonnewald, Ursula

    2010-01-01

    Alexander disease is a rare and usually fatal neurological disorder characterized by the abundant presence of protein aggregates in astrocytes. Most cases result from dominant missense de novo mutations in the gene encoding glial fibrillary acidic protein (GFAP), but how these mutations lead to aggregate formation and compromise function is not known. A transgenic mouse line (Tg73.7) over-expressing human GFAP produces astrocytic aggregates indistinguishable from those seen in the human disease, making them a model of this disorder. To investigate possible metabolic changes associated with Alexander disease Tg73.7 mice and controls were injected simultaneously with [1-13C]glucose to analyze neuronal metabolism and [1,2-13C]acetate to monitor astrocytic metabolism. Brain extracts were analyzed by 1H magnetic resonance spectroscopy (MRS) to quantify amounts of several key metabolites, and by 13C MRS to analyze amino acid neurotransmitter metabolism. In the cerebral cortex, reduced utilization of [1,2-13C]acetate was observed for synthesis of glutamine, glutamate, and GABA, and the concentration of the marker for neuronal mitochondrial metabolism, N-acetylaspartate (NAA), was decreased. This indicates impaired astrocytic and neuronal metabolism and decreased transfer of glutamine from astrocytes to neurons compared to control mice. In the cerebellum, glutamine and GABA content and labeling from [1-13C]glucose were increased. Evidence for brain edema was found in the increased amount of water and of the osmoregulators myo-inositol and taurine. It can be concluded that astrocyte – neuronal interactions were altered differently in distinct regions. PMID:20544858

  5. Fetal rat metabonome alteration by prenatal caffeine ingestion probably due to the increased circulatory glucocorticoid level and altered peripheral glucose and lipid metabolic pathways

    SciTech Connect

    Liu, Yansong; Xu, Dan; Feng, Jianghua; Kou, Hao; Liang, Gai; Yu, Hong; He, Xiaohua; Zhang, Baifang; Chen, Liaobin; Magdalou, Jacques; Wang, Hui

    2012-07-15

    The aims of this study were to clarify the metabonome alteration in fetal rats after prenatal caffeine ingestion and to explore the underlying mechanism pertaining to the increased fetal circulatory glucocorticoid (GC). Pregnant Wistar rats were daily intragastrically administered with different doses of caffeine (0, 20, 60 and 180 mg/kg) from gestational days (GD) 11 to 20. Metabonome of fetal plasma and amniotic fluid on GD20 were analyzed by {sup 1}H nuclear magnetic resonance-based metabonomics. Gene and protein expressions involved in the GC metabolism, glucose and lipid metabolic pathways in fetal liver and gastrocnemius were measured by real-time RT-PCR and immunohistochemistry. Fetal plasma metabonome were significantly altered by caffeine, which presents as the elevated α- and β‐glucose, reduced multiple lipid contents, varied apolipoprotein contents and increased levels of a number of amino acids. The metabonome of amniotic fluids showed a similar change as that in fetal plasma. Furthermore, the expressions of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD-2) were decreased, while the level of blood GC and the expressions of 11β-HSD-1 and glucocorticoid receptor (GR) were increased in fetal liver and gastrocnemius. Meanwhile, the expressions of insulin-like growth factor 1 (IGF-1), IGF-1 receptor and insulin receptor were decreased, while the expressions of adiponectin receptor 2, leptin receptors and AMP-activated protein kinase α2 were increased after caffeine treatment. Prenatal caffeine ingestion characteristically change the fetal metabonome, which is probably attributed to the alterations of glucose and lipid metabolic pathways induced by increased circulatory GC, activated GC metabolism and enhanced GR expression in peripheral metabolic tissues. -- Highlights: ► Prenatal caffeine ingestion altered the metabonome of IUGR fetal rats. ► Caffeine altered the glucose and lipid metabolic pathways of IUGR fetal rats. ► Prenatal caffeine

  6. Do altered energy metabolism or spontaneous locomotion ‘mediate’ decelerated senescence?

    PubMed Central

    Arum, Oge; Dawson, John Alexander; Smith, Daniel Larry; Kopchick, John J; Allison, David B; Bartke, Andrzej

    2015-01-01

    That one or multiple measures of metabolic rate may be robustly associated with, or possibly even causative of, the progression of aging-resultant phenotypes such as lifespan is a long-standing, well-known mechanistic hypothesis. To broach this hypothesis, we assessed metabolic function and spontaneous locomotion in two genetic and one dietary mouse models for retarded aging, and subjected the data to mediation analyses to determine whether any metabolic or locomotor trait could be identified as a mediator of the effect of any of the interventions on senescence. We do not test the hypothesis of causality (which would require some experiments), but instead test whether the correlation structure of certain variables is consistent with one possible pathway model in which a proposed mediating variable has a causal role. Results for metabolic measures, including oxygen consumption and respiratory quotient, failed to support this hypothesis; similar negative results were obtained for three behavioral motion metrics. Therefore, our mediation analyses did not find support that any of these correlates of decelerated senescence was a substantial mediator of the effect of either of these genetic alterations (with or without caloric restriction) on longevity. Further studies are needed to relate the examined phenotypic characteristics to mechanisms of aging and control of longevity. PMID:25720347

  7. Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression.

    PubMed

    Ioannides, Zara A; Ngo, Shyuan T; Henderson, Robert D; McCombe, Pamela A; Steyn, Frederik J

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research. PMID:27400276

  8. Chronic liquid nutrition intake induces obesity and considerable but reversible metabolic alterations in Wistar rats.

    PubMed

    Mikuska, Livia; Vrabcova, Michaela; Tillinger, Andrej; Balaz, Miroslav; Ukropec, Jozef; Mravec, Boris

    2016-06-01

    We have previously described the development of substantial, but reversible obesity in Wistar rats fed with palatable liquid nutrition (Fresubin). In this study, we investigated changes in serum hormone levels, glycemia, fat mass, adipocyte size, and gene expression of adipokines and inflammatory markers in adipose tissue of Wistar rats fed by Fresubin (i) for 5 months, (ii) up to 90 days of age, or (iii) after 90 days of age to characterize metabolic alterations and their reversibility in rats fed with Fresubin. An intra-peritoneal glucose tolerance test was also performed to determine levels of serum leptin, adiponectin, insulin, and C-peptide in 2- and 4-month-old animals. In addition, mesenteric and epididymal adipose tissue weight, adipocyte diameter, and gene expression of pro- and anti-inflammatory adipokines and other markers were determined at the end of the study. Chronic Fresubin intake significantly increased adipocyte diameter, reduced glucose tolerance, and increased serum leptin, adiponectin, insulin, and C-peptide levels. Moreover, gene expression of leptin, adiponectin, CD68, and nuclear factor kappa B was significantly increased in mesenteric adipose tissue of Fresubin fed rats. Monocyte chemotactic protein 1 messenger RNA (mRNA) levels increased in mesenteric adipose tissue only in the group fed Fresubin during the entire experiment. In epididymal adipose tissue, fatty acid binding protein 4 mRNA levels were significantly increased in rats fed by Fresubin during adulthood. In conclusion, chronic Fresubin intake induced complex metabolic alterations in Wistar rats characteristic of metabolic syndrome. However, transition of rats from Fresubin to standard diet reversed these alterations. PMID:26939586

  9. HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition.

    PubMed

    Kis, Olena; Sankaran-Walters, Sumathi; Hoque, M Tozammel; Walmsley, Sharon L; Dandekar, Satya; Bendayan, Reina

    2016-05-01

    This study investigated the effects of HIV-1 infection and antiretroviral therapy (ART) on the expression of intestinal drug efflux transporters, i.e., P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP), and metabolic enzymes, such as cytochrome P450s (CYPs), in the human upper intestinal tract. Intestinal biopsy specimens were obtained from HIV-negative healthy volunteers, ART-naive HIV-positive (HIV(+)) subjects, and HIV(+) subjects receiving ART (10 in each group). Intestinal tissue expression of drug transporters and metabolic enzymes was examined by microarray, real-time quantitative reverse transcription-PCR (qPCR), and immunohistochemistry analyses. Microarray analysis demonstrated significantly lower expression of CYP3A4 and ABCC2/MRP2 in the HIV(+) ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression of ABCC2/MRP2 in ART-naive subjects than in the control group, while CYP3A4 and ABCG2/BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV(+) naive group than in the control group and was partially restored to baseline levels in HIV(+) subjects receiving ART. In contrast, gene and protein expression of ABCB1/Pgp was significantly increased in HIV(+) subjects on ART relative to HIV(+) ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV(+) subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV(+) subjects. This has clinical implications when using data from healthy volunteers to guide ART. PMID:26902756

  10. Chronic Intake of Japanese Sake Mediates Radiation-Induced Metabolic Alterations in Mouse Liver

    PubMed Central

    Nakajima, Tetsuo; Vares, Guillaume; Wang, Bing; Nenoi, Mitsuru

    2016-01-01

    Sake is a traditional Japanese alcoholic beverage that is gaining popularity worldwide. Although sake is reported to have beneficial health effects, it is not known whether chronic sake consumption modulates health risks due to radiation exposure or other factors. Here, the effects of chronic administration of sake on radiation-induced metabolic alterations in the livers of mice were evaluated. Sake (junmai-shu) was administered daily to female mice (C3H/He) for one month, and the mice were exposed to fractionated doses of X-rays (0.75 Gy/day) for the last four days of the sake administration period. For comparative analysis, a group of mice were administered 15% (v/v) ethanol in water instead of sake. Metabolites in the liver were analyzed by capillary electrophoresis-time-of-flight mass spectrometry one day following the last exposure to radiation. The metabolite profiles of mice chronically administered sake in combination with radiation showed marked changes in purine, pyrimidine, and glutathione (GSH) metabolism, which were only partially altered by radiation or sake administration alone. Notably, the changes in GSH metabolism were not observed in mice treated with radiation following chronic administration of 15% ethanol in water. Changes in several metabolites, including methionine and valine, were induced by radiation alone, but were not detected in the livers of mice who received chronic administration of sake. In addition, the chronic administration of sake increased the level of serum triglycerides, although radiation exposure suppressed this increase. Taken together, the present findings suggest that chronic sake consumption promotes GSH metabolism and anti-oxidative activities in the liver, and thereby may contribute to minimizing the adverse effects associated with radiation. PMID:26752639

  11. Ethanol induced impairment of glucose metabolism involves alterations of GABAergic signaling in pancreatic β-cells.

    PubMed

    Wang, Shuanglian; Luo, Yan; Feng, Allen; Li, Tao; Yang, Xupeng; Nofech-Mozes, Roy; Yu, Meng; Wang, Changhui; Li, Ziwei; Yi, Fan; Liu, Chuanyong; Lu, Wei-Yang

    2014-12-01

    Alcohol overindulgence is a risk factor of type 2 diabetes mellitus. However, the mechanisms by which alcohol overindulgence damages glucose metabolism remain unclear. Pancreatic islet β-cells are endowed with type-A γ-aminobutyric acid receptor (GABAAR) mediated autocrine signaling mechanism, which regulates insulin secretion and fine-tunes glucose metabolism. In neurons GABAAR is one of the major targets for alcohol. This study investigated whether ethanol alters glucose metabolism by affecting GABAAR signaling in pancreatic β-cells. Blood glucose level of test mice was measured using a blood glucose meter. Insulin secretion by the pancreatic β-cell line INS-1 cells was examined using a specific insulin ELISA kit. Whole-cell patch-clamp recording was used to evaluate GABA-elicited current in INS-1 cells. Western blot and immunostaining were used to measure the expression of GABAAR subunits in mouse pancreatic tissues or in INS-1 cells. Intraperitoneal (i.p.) administration of ethanol (3.0g/kg body weight) to mice altered glucose metabolism, which was associated with decreased expression of GABAAR α1- and δ- subunits on the surface of pancreatic β-cells. Acute treatment of cultured INS-1cells with ethanol (60mM) decreased the GABA-induced current and reduced insulin secretion. In contrast, treating INS-1 cells with GABA (100μM) largely prevented the ethanol-induced reduction of insulin release. Importantly, pre-treating mice with GABA (i.p., 1.5mg/kg body weight) partially reversed ethanol-induced impairment of glucose homeostasis in mice. Our data suggest a novel role of pancreatic GABA signaling in protecting pancreatic islet β-cells from ethanol-induced dysfunction. PMID:25456265

  12. Tumor-induced osteomalacia. Evidence of a surgically correctable alteration in vitamin D metabolism.

    PubMed

    Parker, M S; Klein, I; Haussler, M R; Mintz, D H

    1981-02-01

    A 15-year-old boy was treated for nonfamilial hypophosphatemic rickets. Treatment with ergocalciferol, 100,000 units/day, and phosphorus, 2 to 4 g/day, failed to alleviate the rickets. Levels of 1 alpha, 25-dihydroxyvitamin D were low while levels of 25-hydroxyvitamin D were elevated. After removal of a benign fibroma, the level of 1 alpha, 25-dihydroxyvitamin D increased, the serum phosphorus level became normal, and the osteomalacia was cured. The alteration of vitamin D metabolism and associated hypophosphatemia in oncogenic osteomalacia is a potentially reversible cause of bone disease mediated by the tumor. PMID:7452873

  13. The influence of altered gravity on carbohydrate metabolism in excised wheat leaves

    NASA Technical Reports Server (NTRS)

    Obenland, D. M.; Brown, C. S.

    1994-01-01

    We developed a system to study the influence of altered gravity on carbohydrate metabolism in excised wheat leaves by means of clinorotation. The use of excised leaves in our clinostat studies offered a number of advantages over the use of whole plants, most important of which were minimization of exogenous mechanical stress and a greater amount of carbohydrate accumulation during the time of treatment. We found that horizontal clinorotation of excised wheat leaves resulted in significant reductions in the accumulation of fructose, sucrose, starch and fructan relative to control, vertically clinorotated leaves. Photosynthesis, dark respiration and the extractable activities of ADP glucose pyrophosphorylase (EC 2.7.7.27), sucrose phosphate synthase (EC 2.4.4.14), sucrose sucrose fructosyltransferase (EC 2.4.1.99), and fructan hydrolase (EC 3.2.1.80) were unchanged due to altered gravity treatment.

  14. Aquatic metabolism response to the hydrologic alteration in the Yellow River estuary, China

    NASA Astrophysics Data System (ADS)

    Shen, Xiaomei; Sun, Tao; Liu, Fangfang; Xu, Jing; Pang, Aiping

    2015-06-01

    Successful artificial hydrologic regulation and environmental flow assessments for the ecosystem protection require an accurate understanding of the linkages between flow events and biotic responses. To explore an ecosystem's functional responses to hydrologic alterations, we analysed spatial and temporal variations in aquatic metabolism and the main factors influenced by artificial hydrologic alterations based on the data collected from 2009 to 2012 in the Yellow River estuary, China. Gross primary production (GPP) ranged from 0.002 to 8.488 mg O2 L-1 d-1. Ecosystem respiration (ER) ranged from 0.382 to 8.968 mg O2 L-1 d-1. Net ecosystem production (NEP) ranged from -5.792 to 7.293 mg O2 L-1 d-1 and the mean of NEP was -0.506 mg O2 L-1 d-1, which means that the trophic status of entire estuary was near to balance. The results showed that seasonal variations in the aquatic metabolism are influenced by the hydrologic alteration in the estuary. High water temperature and solar radiation in summer are associated with low turbidity and consequently high rates of GPP and ER, making the estuary net autotrophic in summer, and that also occurred after water-sediment regulation in August. Turbidity and water temperature were identified as two particularly important factors that influenced the variation in the metabolic balance. As a result, metabolism rate did not decrease but increased after the regulation. ER increased significantly in summer and autumn and reached a maximum after the water-sediment regulation in September. GPP and NEP reached a maximum value after the water-sediment regulation in August, and then decreased in autumn. Estuarine ecosystem shifted from net heterotrophy in spring to net autotrophy in summer, and then to net heterotrophy in autumn. Our study indicated that estuarine metabolism may recover to a high level faster in summer than that in other seasons after the short-term water-sediment regulation due to higher water temperature and nutrients.

  15. Methionine Metabolism Alters Oxidative Stress Resistance via the Pentose Phosphate Pathway.

    PubMed

    Campbell, Kate; Vowinckel, Jakob; Keller, Markus A; Ralser, Markus

    2016-04-01

    Nutrient uptake and metabolism have a significant impact on the way cells respond to stress. The amino acid methionine is, in particular, a key player in the oxidative stress response, and acting as a reactive oxygen species scavenger, methionine is implicated in caloric restriction phenotypes and aging. We here provide evidence that some effects of methionine in stress situations are indirect and caused by altered activity of the nicotinamide adenine dinucleotide phosphate (NADPH) producing oxidative part of the pentose phosphate pathway (PPP). In Saccharomyces cerevisiae, both methionine prototrophic (MET15) and auxotrophic (met15Δ) cells supplemented with methionine showed an increase in PPP metabolite concentrations downstream of the NADPH producing enzyme, 6-phosphogluconate dehydrogenase. Proteomics revealed this enzyme to also increase in expression compared to methionine self-synthesizing cells. Oxidant tolerance was increased in cells preincubated with methionine; however, this effect was abolished when flux through the oxidative PPP was prevented by deletion of its rate limiting enzyme, ZWF1. Stress resistance phenotypes that follow methionine supplementation hence involve the oxidative PPP. Effects of methionine on oxidative metabolism, stress signaling, and aging have thus to be seen in the context of an altered activity of this NADP reducing pathway. Antioxid. Redox Signal. 24, 543-547. PMID:26596469

  16. Fluoxetine Treatment Rescues Energy Metabolism Pathway Alterations in a Posttraumatic Stress Disorder Mouse Model.

    PubMed

    Kao, Chi-Ya; He, Zhisong; Henes, Kathrin; Asara, John M; Webhofer, Christian; Filiou, Michaela D; Khaitovich, Philipp; Wotjak, Carsten T; Turck, Christoph W

    2016-05-01

    Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder. Several studies have attempted to characterize molecular alterations associated with PTSD, but most findings were limited to the investigation of specific cellular markers in the periphery or defined brain regions. In the current study, we aimed to unravel affected molecular pathways/mechanisms in the fear circuitry associated with PTSD. We interrogated a foot shock-induced PTSD mouse model by integrating proteomics and metabolomics profiling data. Alterations at the proteome level were analyzed using in vivo (15)N metabolic labeling combined with mass spectrometry in the prelimbic cortex (PrL), anterior cingulate cortex (ACC), basolateral amygdala, central nucleus of the amygdala and CA1 of the hippocampus between shocked and nonshocked (control) mice, with and without fluoxetine treatment. In silico pathway analyses revealed an upregulation of the citric acid cycle pathway in PrL, and downregulation in ACC and nucleus accumbens (NAc). Chronic fluoxetine treatment prevented decreased citric acid cycle activity in NAc and ACC and ameliorated conditioned fear response in shocked mice. Our results shed light on the role of energy metabolism in PTSD pathogenesis and suggest potential therapy through mitochondrial targeting. PMID:27606320

  17. Methionine Metabolism Alters Oxidative Stress Resistance via the Pentose Phosphate Pathway

    PubMed Central

    Campbell, Kate; Vowinckel, Jakob; Keller, Markus A.

    2016-01-01

    Abstract Nutrient uptake and metabolism have a significant impact on the way cells respond to stress. The amino acid methionine is, in particular, a key player in the oxidative stress response, and acting as a reactive oxygen species scavenger, methionine is implicated in caloric restriction phenotypes and aging. We here provide evidence that some effects of methionine in stress situations are indirect and caused by altered activity of the nicotinamide adenine dinucleotide phosphate (NADPH) producing oxidative part of the pentose phosphate pathway (PPP). In Saccharomyces cerevisiae, both methionine prototrophic (MET15) and auxotrophic (met15Δ) cells supplemented with methionine showed an increase in PPP metabolite concentrations downstream of the NADPH producing enzyme, 6-phosphogluconate dehydrogenase. Proteomics revealed this enzyme to also increase in expression compared to methionine self-synthesizing cells. Oxidant tolerance was increased in cells preincubated with methionine; however, this effect was abolished when flux through the oxidative PPP was prevented by deletion of its rate limiting enzyme, ZWF1. Stress resistance phenotypes that follow methionine supplementation hence involve the oxidative PPP. Effects of methionine on oxidative metabolism, stress signaling, and aging have thus to be seen in the context of an altered activity of this NADP reducing pathway. Antioxid. Redox Signal. 24, 543–547. PMID:26596469

  18. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands.

    PubMed

    Lamas, Bruno; Richard, Mathias L; Leducq, Valentin; Pham, Hang-Phuong; Michel, Marie-Laure; Da Costa, Gregory; Bridonneau, Chantal; Jegou, Sarah; Hoffmann, Thomas W; Natividad, Jane M; Brot, Loic; Taleb, Soraya; Couturier-Maillard, Aurélie; Nion-Larmurier, Isabelle; Merabtene, Fatiha; Seksik, Philippe; Bourrier, Anne; Cosnes, Jacques; Ryffel, Bernhard; Beaugerie, Laurent; Launay, Jean-Marie; Langella, Philippe; Xavier, Ramnik J; Sokol, Harry

    2016-06-01

    Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that functions in the immune response against microorganisms. CARD9 promotes recovery from colitis by promoting interleukin (IL)-22 production, and Card9(-/-) mice are more susceptible to colitis. The microbiota is altered in Card9(-/-) mice, and transfer of the microbiota from Card9(-/-) to wild-type, germ-free recipients increases their susceptibility to colitis. The microbiota from Card9(-/-) mice fails to metabolize tryptophan into metabolites that act as aryl hydrocarbon receptor (AHR) ligands. Intestinal inflammation is attenuated after inoculation of mice with three Lactobacillus strains capable of metabolizing tryptophan or by treatment with an AHR agonist. Reduced production of AHR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Our findings reveal that host genes affect the composition and function of the gut microbiota, altering the production of microbial metabolites and intestinal inflammation. PMID:27158904

  19. Retinoic acid metabolism proteins are altered in trichoblastomas induced by mouse papillomavirus 1.

    PubMed

    Everts, Helen B; Suo, Liye; Ghim, Shinge; Bennett Jenson, A; Sundberg, John P

    2015-12-01

    Skin cancer burden is significant as treatment costs have skyrocketed to $8.1 million annually and some forms metastasize, such as cutaneous squamous cell carcinoma (cSCC) and melanoma. cSCC is caused by altered growth factor signaling induced by chemical carcinogens, ultraviolet light (UV) exposure, and infections with papillomaviruses (PVs). One of the few options for preventing cSCC in high-risk patients is oral retinoids. While much is understood about retinoid treatments and metabolism in mouse models of chemically and UV exposure induced cSCC, little is known about the role of retinoids in PV-induced cSCC. To better understand how retinoid metabolism is altered in cSCC, we examined the expression of this pathway in the newly discovered mouse papillomavirus (MmuPV1), which produces trichoblastomas in dorsal skin but not cSCC. We found significant increases in a rate-limiting enzyme involved in retinoic acid synthesis and retinoic acid binding proteins, suggestive of increased RA synthesis, in MmuPV1-induced tumors in B6.Cg-Foxn1(nu)/J mice. Similar increases in these proteins were seen after acute UVB exposure in Crl:SKH1-Hr(hr) mice and in regressing pre-cancerous lesions in a chemically-induced mouse model, suggesting a common mechanism in limiting the progression of papillomas to full blown cSCC. PMID:26416148

  20. Altered cerebral blood flow and glucose metabolism in patients with liver disease and minimal encephalopathy

    SciTech Connect

    Lockwood, A.H.; Yap, E.W.; Rhoades, H.M.; Wong, W.H. )

    1991-03-01

    We measured CBF and the CMRglc in normal controls and in patients with severe liver disease and evidence for minimal hepatic encephalopathy using positron emission tomography. Regions were defined in frontal, temporal, parietal, and visual cortex; the thalamus; the caudate; the cerebellum; and the white matter along with a whole-slice value obtained at the level of the thalamus. There was no difference in whole-slice CBF and CMRglc values. Individual regional values were normalized to the whole-slice value and subjected to a two-way repeated measures analysis of variance. When normalized CBF and CMRglc values for regions were compared between groups, significant differences were demonstrated (F = 5.650, p = 0.00014 and F = 4.58, p = 0.0073, respectively). These pattern differences were due to higher CBF and CMRglc in the cerebellum, thalamus, and caudate in patients and lower values in the cortex. Standardized coefficients extracted from a discriminant function analysis permitted correct group assignment for 95.5% of the CBF studies and for 92.9% of the CMRglc studies. The similarity of the altered pattern of cerebral metabolism and flow in our patients to that seen in rats subjected to portacaval shunts or ammonia infusions suggests that this toxin may alter flow and metabolism and that this, in turn, causes the clinical expression of encephalopathy.

  1. Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses.

    PubMed

    Webb, Tonya J; Carey, Gregory B; East, James E; Sun, Wenji; Bollino, Dominique R; Kimball, Amy S; Brutkiewicz, Randy R

    2016-08-01

    Natural killer T (NKT) cells play a critical role in the host's innate immune response. CD1d-mediated presentation of glycolipid antigens to NKT cells has been established; however, the mechanisms by which NKT cells recognize infected or cancerous cells remain unclear. 5(')-AMP activated protein kinase (AMPK) is a master regulator of lipogenic pathways. We hypothesized that activation of AMPK during infection and malignancy could alter the repertoire of antigens presented by CD1d and serve as a danger signal to NKT cells. In this study, we examined the effect of alterations in metabolism on CD1d-mediated antigen presentation to NKT cells and found that an infection with lymphocytic choriomeningitis virus rapidly increased CD1d-mediated antigen presentation. Hypoxia inducible factors (HIF) enhance T-cell effector functions during infection, therefore antigen presenting cells pretreated with pharmacological agents that inhibit glycolysis, induce HIF and activate AMPK were assessed for their ability to induce NKT-cell responses. Pretreatment with 2-deoxyglucose, cobalt chloride, AICAR and metformin significantly enhanced CD1d-mediated NKT-cell activation. In addition, NKT cells preferentially respond to malignant B cells and B-cell lymphomas express HIF-1α. These data suggest that targeting cellular metabolism may serve as a novel means of inducing innate immune responses. PMID:27297969

  2. Liver disease alters high-density lipoprotein composition, metabolism and function.

    PubMed

    Trieb, Markus; Horvath, Angela; Birner-Gruenberger, Ruth; Spindelboeck, Walter; Stadlbauer, Vanessa; Taschler, Ulrike; Curcic, Sanja; Stauber, Rudolf E; Holzer, Michael; Pasterk, Lisa; Heinemann, Akos; Marsche, Gunther

    2016-07-01

    High-density lipoproteins (HDL) are important endogenous inhibitors of inflammatory responses. Functional impairment of HDL might contribute to the excess mortality experienced by patients with liver disease, but the effect of cirrhosis on HDL metabolism and function remain elusive. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function using apolipoprotein (apo) B-depleted sera from patients with compensated cirrhosis, patients with acutely decompensated cirrhosis and healthy controls. We observed that sera of cirrhotic patients showed reduced levels of HDL-cholesterol and profoundly suppressed activities of several enzymes involved in HDL maturation and metabolism. Native gel electrophoresis analyses revealed that cirrhotic serum HDL shifts towards the larger HDL2 subclass. Proteomic assessment of isolated HDL identified several proteins, including apoA-I, apoC-III, apoE, paraoxonase 1 and acute phase serum amyloid A to be significantly altered in cirrhotic patients. With regard to function, these alterations in levels, composition and structure of HDL were strongly associated with metrics of function of apoB-depleted sera, including cholesterol efflux capability, paraoxonase activity, the ability to inhibit monocyte production of cytokines and endothelial regenerative activities. Of particular interest, cholesterol efflux capacity appeared to be strongly associated with liver disease mortality. Our findings may be clinically relevant and improve our ability to monitor cirrhotic patients at high risk. PMID:27106140

  3. Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain.

    PubMed

    Ngai, Ying Fai; Sulistyoningrum, Dian C; O'Neill, Ryan; Innis, Sheila M; Weinberg, Joanne; Devlin, Angela M

    2015-09-01

    Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA dysregulation and hyperresponsiveness to stressors in adulthood. Molecular mechanisms mediating these alterations are not fully understood. Disturbances in one-carbon metabolism, a source of methyl donors for epigenetic processes, contributes to alcoholic liver disease. We assessed whether PAE affects one-carbon metabolism (including Mtr, Mat2a, Mthfr, and Cbs mRNA) and programming of HPA function genes (Nr3c1, Nr3c2, and Slc6a4) in offspring from ethanol-fed (E), pair-fed (PF), and ad libitum-fed control (C) dams. At gestation day 21, plasma total homocysteine and methionine concentrations were higher in E compared with C dams, and E fetuses had higher plasma methionine concentrations and lower whole brain Mtr and Mat2a mRNA compared with C fetuses. In adulthood (55 days), hippocampal Mtr and Cbs mRNA was lower in E compared with C males, whereas Mtr, Mat2a, Mthfr, and Cbs mRNA were higher in E compared with C females. We found lower Nr3c1 mRNA and lower nerve growth factor inducible protein A (NGFI-A) protein in the hippocampus of E compared with PF females, whereas hippocampal Slc6a4 mRNA was higher in E than C males. By contrast, hypothalamic Slc6a4 mRNA was lower in E males and females compared with C offspring. This was accompanied by higher hypothalamic Slc6a4 mean promoter methylation in E compared with PF females. These findings demonstrate that PAE is associated with alterations in one-carbon metabolism and has long-term and region-specific effects on gene expression in the brain. These findings advance our understanding of mechanisms of HPA dysregulation associated with PAE. PMID:26180184

  4. [Hepatic steatosis, visceral fat and metabolic alterations in apparently healthy overweight/obese individuals].

    PubMed

    Ryder, Elena; Mijac, Volga; Fernández, Erika; Palazzi, Nora; Morales, María Carolina; Connell, Lissette; Parra, Agner; Romero, Marlon; Fernández, Nelson

    2014-03-01

    Clinical observation indicates that many obese individuals do not display important metabolic alterations. Consequently, the objective of this study was to establish whether simple obesity, non concurrent with other important risk factors, was associated with metabolic alterations; or if the phenomenon known as "obesity paradox" was present. A clinical history, measurements of anthropometric and metabolic parameters and estimation of hepatic steatosis and visceral fat, were determined in 30, apparently healthy, individuals from Maracaibo, Venezuela, between 20 and 59 years of age and a body mass index (BMI) above 25 kg/m2, and compared to a lean control group of 11 individuals with BMI less than 25 kg/m2. The study demonstrated that only one third of overweight/obese individuals (OW/OB), with high body mass index (BMI) and waist circumference (WC), presented elevated values of insulin, HOMA-IR and triglycerides. Nevertheless, the presence of hepatic steatosis was elevated in the OW/OB group (91%) vs. 9% in the control group. The visceral fat in the lean control group was associated with both, WC and glycemia; however, it was not related to the BMI or insulin, HOMA-IR and HDLc. The visceral fat in the OW/OB group, although elevated in relation to the lean group, revealed a loss of these associations. In the OW/OB it was the BMI that was associated with insulin and HOMA-IR. The results emphasize the importance of investigating for the presence of hepatic steatosis, rather than visceral fat, in individuals with OW/OB, to identify subjects with high cardiometabolic risk. PMID:24758097

  5. Short-term cigarette smoke exposure leads to metabolic alterations in lung alveolar cells.

    PubMed

    Agarwal, Amit R; Yin, Fei; Cadenas, Enrique

    2014-08-01

    Cigarette smoke (CS)-induced alveolar destruction and energy metabolism changes are known contributors to the pathophysiology of chronic obstructive pulmonary disease (COPD). This study examines the effect of CS exposure on metabolism in alveolar type II cells. Male A/J mice (8 wk old) were exposed to CS generated from a smoking machine for 4 or 8 weeks, and a recovery group was exposed to CS for 8 weeks and allowed to recover for 2 weeks. Alveolar type II cells were isolated from air- or CS- exposed mice. Acute CS exposure led to a reversible airspace enlargement in A/J mice as measured by the increase in mean linear intercept, indicative of alveolar destruction. The effect of CS exposure on cellular respiration was studied using the XF Extracellular Flux Analyzer. A decrease in respiration while metabolizing glucose was observed in the CS-exposed group, indicating altered glycolysis that was compensated by an increase in palmitate utilization; palmitate utilization was accompanied by an increase in the expression of CD36 and carnitine-palmitoyl transferase 1 in type II alveolar cells for the transport of palmitate into the cells and into mitochondria, respectively. The increase in palmitate use for energy production likely affects the surfactant biosynthesis pathway, as evidenced by the decrease in phosphatidylcholine levels and the increase in phospholipase A2 activity after CS exposure. These findings help our understanding of the mechanism underlying the surfactant deficiency observed in smokers and provide a target to delay the onset of COPD. PMID:24625219

  6. Dose-Dependent Metabolic Alterations in Human Cells Exposed to Gamma Irradiation

    PubMed Central

    Kwon, Yong-Kook; Ha, In Jin; Bae, Hyun-Whee; Jang, Won Gyo; Yun, Hyun Jin; Kim, So Ra; Lee, Eun Kyeong; Kang, Chang-Mo; Hwang, Geum-Sook

    2014-01-01

    Radiation exposure is a threat to public health because it causes many diseases, such as cancers and birth defects, due to genetic modification of cells. Compared with the past, a greater number of people are more frequently exposed to higher levels of radioactivity today, not least due to the increased use of diagnostic and therapeutic radiation-emitting devices. In this study, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS)-based metabolic profiling was used to investigate radiation- induced metabolic changes in human fibroblasts. After exposure to 1 and 5 Gy of γ-radiation, the irradiated fibroblasts were harvested at 24, 48, and 72 h and subjected to global metabolite profiling analysis. Mass spectral peaks of cell extracts were analyzed by pattern recognition using principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA). The results showed that the cells irradiated with 1 Gy returned to control levels at 72 h post radiation, whereas cells irradiated with 5 Gy were quite unlike the controls; therefore, cells irradiated with 1 Gy had recovered, whereas those irradiated with 5 Gy had not. Lipid and amino acid levels increased after the higher-level radiation, indicating degradation of membranes and proteins. These results suggest that MS-based metabolite profiling of γ-radiation-exposed human cells provides insight into the global metabolic alterations in these cells. PMID:25419661

  7. Chronic unpredictive mild stress leads to altered hepatic metabolic profile and gene expression

    PubMed Central

    Jia, Hong-mei; Li, Qi; Zhou, Chao; Yu, Meng; Yang, Yong; Zhang, Hong-wu; Ding, Gang; Shang, Hai; Zou, Zhong-mei

    2016-01-01

    Depression is a complex disease characterized by a series of pathological changes. Research on depression is mainly focused on the changes in brain, but not on liver. Therefore, we initially explored the metabolic profiles of hepatic extracts from rats treated with chronic unpredictive mild stress (CUMS) by UPLC-Q-TOF/MS. Using multivariate statistical analysis, a total of 26 altered metabolites distinguishing CUMS-induced depression from normal control were identified. Using two-stage receiver operating characteristic (ROC) analysis, 18 metabolites were recognized as potential biomarkers related to CUMS-induced depression via 12 metabolic pathways. Subsequently, we detected the mRNA expressions levels of apoptosis-associated genes such as Bax and Bcl-2 and four key enzymes including Pla2g15, Pnpla6, Baat and Gad1 involved in phospholipid and primary bile acid biosynthesis in liver tissues of CUMS rats by real-time qRT-PCR assay. The expression levels of Bax, Bcl-2, Pla2g15, Pnpla6 and Gad1 mRNA were 1.43,1.68, 1.74, 1.67 and 1.42-fold higher, and those of Baat, Bax/Bcl-2 ratio mRNA were 0.83, 0.85-fold lower in CUMS rats compared with normal control. Results of liver-targeted metabonomics and mRNA expression demonstrated that CUMS-induced depression leads to variations in hepatic metabolic profile and gene expression, and ultimately results in liver injury. PMID:27006086

  8. Chronic social stress in puberty alters appetitive male sexual behavior and neural metabolic activity.

    PubMed

    Bastida, Christel C; Puga, Frank; Gonzalez-Lima, Francisco; Jennings, Kimberly J; Wommack, Joel C; Delville, Yvon

    2014-07-01

    Repeated social subjugation in early puberty lowers testosterone levels. We used hamsters to investigate the effects of social subjugation on male sexual behavior and metabolic activity within neural systems controlling social and motivational behaviors. Subjugated animals were exposed daily to aggressive adult males in early puberty for postnatal days 28 to 42, while control animals were placed in empty clean cages. On postnatal day 45, they were tested for male sexual behavior in the presence of receptive female. Alternatively, they were tested for mate choice after placement at the base of a Y-maze containing a sexually receptive female in one tip of the maze and an ovariectomized one on the other. Social subjugation did not affect the capacity to mate with receptive females. Although control animals were fast to approach females and preferred ovariectomized individuals, subjugated animals stayed away from them and showed no preference. Cytochrome oxidase activity was reduced within the preoptic area and ventral tegmental area in subjugated hamsters. In addition, the correlation of metabolic activity of these areas with the bed nucleus of the stria terminalis and anterior parietal cortex changed significantly from positive in controls to negative in subjugated animals. These data show that at mid-puberty, while male hamsters are capable of mating, their appetitive sexual behavior is not fully mature and this aspect of male sexual behavior is responsive to social subjugation. Furthermore, metabolic activity and coordination of activity in brain areas related to sexual behavior and motivation were altered by social subjugation. PMID:24852486

  9. Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism.

    PubMed

    Han, Seung Hyeok; Malaga-Dieguez, Laura; Chinga, Frank; Kang, Hyun Mi; Tao, Jianling; Reidy, Kimberly; Susztak, Katalin

    2016-02-01

    Renal tubule epithelial cells are high-energy demanding polarized epithelial cells. Liver kinase B1 (LKB1) is a key regulator of polarity, proliferation, and cell metabolism in epithelial cells, but the function of LKB1 in the kidney is unclear. Our unbiased gene expression studies of human control and CKD kidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1(flox/flox)) exhibited progressive kidney disease characterized by flattened dedifferentiated tubule epithelial cells, interstitial matrix accumulation, and dilated cystic-appearing tubules. Expression of epithelial polarity markers β-catenin and E-cadherin was not altered even at later stages. However, expression levels of key regulators of metabolism, AMP-activated protein kinase (Ampk), peroxisome proliferative activated receptor gamma coactivator 1-α (Ppargc1a), and Ppara, were significantly lower than those in controls and correlated with fibrosis development. Loss of Lkb1 in cultured epithelial cells resulted in energy depletion, apoptosis, less fatty acid oxidation and glycolysis, and a profibrotic phenotype. Treatment of Lkb1-deficient cells with an AMP-activated protein kinase (AMPK) agonist (A769662) or a peroxisome proliferative activated receptor alpha agonist (fenofibrate) restored the fatty oxidation defect and reduced apoptosis. In conclusion, we show that loss of LKB1 in renal tubular epithelial cells has an important role in kidney disease development by influencing intracellular metabolism. PMID:26054542

  10. NF-Y activates genes of metabolic pathways altered in cancer cells

    PubMed Central

    Benatti, Paolo; Chiaramonte, Maria Luisa; Lorenzo, Mariangela; Hartley, John A.; Hochhauser, Daniel; Gnesutta, Nerina; Mantovani, Roberto; Imbriano, Carol; Dolfini, Diletta

    2016-01-01

    The trimeric transcription factor NF-Y binds to the CCAAT box, an element enriched in promoters of genes overexpressed in tumors. Previous studies on the NF-Y regulome identified the general term metabolism as significantly enriched. We dissect here in detail the targeting of metabolic genes by integrating analysis of NF-Y genomic binding and profilings after inactivation of NF-Y subunits in different cell types. NF-Y controls de novo biosynthetic pathways of lipids, teaming up with the master SREBPs regulators. It activates glycolytic genes, but, surprisingly, is neutral or represses mitochondrial respiratory genes. NF-Y targets the SOCG (Serine, One Carbon, Glycine) and Glutamine pathways, as well as genes involved in the biosynthesis of polyamines and purines. Specific cancer-driving nodes are generally under NF-Y control. Altogether, these data delineate a coherent strategy to promote expression of metabolic genes fuelling anaerobic energy production and other anabolic pathways commonly altered in cancer cells. PMID:26646448

  11. Chronic Social Stress in Puberty Alters Appetitive Male Sexual Behavior and Neural Metabolic Activity

    PubMed Central

    Bastida, Christel C.; Puga, Frank; Gonzalez-Lima, Francisco; Jennings, Kimberly J.; Wommack, Joel C.; Delville, Yvon

    2014-01-01

    Repeated social subjugation in early puberty lowers testosterone levels. We used hamsters to investigate the effects of social subjugation on male sexual behavior and metabolic activity within neural systems controlling social and motivational behaviors. Subjugated animals were exposed daily to aggressive adult males in early puberty for postnatal days 28 to 42, while control animals were placed in empty clean cages. On postnatal day 45, they were tested for male sexual behavior in the presence of receptive female. Alternatively, they were tested for mate choice after placement at the base of a Y-maze containing a sexually receptive female in one tip of the maze and an ovariectomized one on the other. Social subjugation did not affect the capacity to mate with receptive females. Although control animals were fast to approach females and preferred ovariectomized individuals, subjugated animals stayed away from them and showed no preference. Cytochrome oxidase activity was reduced within the preoptic area and ventral tegmental area in subjugated hamsters. In addition, the correlation of metabolic activity of these areas with the bed nucleus of the stria terminalis and anterior parietal cortex changed significantly from positive in controls to negative in subjugated animals. These data show that at mid-puberty, while male hamsters are capable of mating, their appetitive sexual behavior is not fully mature and this aspect of male sexual behavior is responsive to social subjugation. Furthermore, metabolic activity and coordination of activity in brain areas related to sexual behavior and motivation was altered by social subjugation. PMID:24852486

  12. Probiotic Bifidobacterium longum alters gut luminal metabolism through modification of the gut microbial community

    PubMed Central

    Sugahara, Hirosuke; Odamaki, Toshitaka; Fukuda, Shinji; Kato, Tamotsu; Xiao, Jin-zhong; Abe, Fumiaki; Kikuchi, Jun; Ohno, Hiroshi

    2015-01-01

    Probiotics are well known as health-promoting agents that modulate intestinal microbiota. However, the molecular mechanisms underlying this effect remain unclear. Using gnotobiotic mice harboring 15 strains of predominant human gut-derived microbiota (HGM), we investigated the effects of Bifidobacterium longum BB536 (BB536-HGM) supplementation on the gut luminal metabolism. Nuclear magnetic resonance (NMR)-based metabolomics showed significantly increased fecal levels of pimelate, a precursor of biotin, and butyrate in the BB536-HGM group. In addition, the bioassay revealed significantly elevated fecal levels of biotin in the BB536-HGM group. Metatranscriptomic analysis of fecal microbiota followed by an in vitro bioassay indicated that the elevated biotin level was due to an alteration in metabolism related to biotin synthesis by Bacteroides caccae in this mouse model. Furthermore, the proportion of Eubacterium rectale, a butyrate producer, was significantly higher in the BB536-HGM group than in the group without B. longum BB536 supplementation. Our findings help to elucidate the molecular basis underlying the effect of B. longum BB536 on the gut luminal metabolism through its interactions with the microbial community. PMID:26315217

  13. Insulin resistance is associated with altered amino acid metabolism and adipose tissue dysfunction in normoglycemic women

    PubMed Central

    Wiklund, Petri; Zhang, Xiaobo; Pekkala, Satu; Autio, Reija; Kong, Lingjia; Yang, Yifan; Keinänen-Kiukaanniemi, Sirkka; Alen, Markku; Cheng, Sulin

    2016-01-01

    Insulin resistance is associated adiposity, but the mechanisms are not fully understood. In this study, we aimed to identify early metabolic alterations associated with insulin resistance in normoglycemic women with varying degree of adiposity. One-hundred and ten young and middle-aged women were divided into low and high IR groups based on their median HOMA-IR (0.9 ± 0.4 vs. 2.8 ± 1.2). Body composition was assessed using DXA, skeletal muscle and liver fat by proton magnetic resonance spectroscopy, serum metabolites by nuclear magnetic resonance spectroscopy and adipose tissue and skeletal muscle gene expression by microarrays. High HOMA-IR subjects had higher serum branched-chain amino acid concentrations (BCAA) (p < 0.05 for both). Gene expression analysis of subcutaneous adipose tissue revealed significant down-regulation of genes related to BCAA catabolism and mitochondrial energy metabolism and up-regulation of several inflammation-related pathways in high HOMA-IR subjects (p < 0.05 for all), but no differentially expressed genes in skeletal muscle were found. In conclusion, in normoglycemic women insulin resistance was associated with increased serum BCAA concentrations, down-regulation of mitochondrial energy metabolism and increased expression of inflammation-related genes in the adipose tissue. PMID:27080554

  14. Altered somatotroph feedback regulation improves metabolic efficiency and limits adipose deposition in male mice.

    PubMed

    Romero, Christopher J; Wolfe, Andrew; Law, Yi Ying; Costelloe, ChenChen Z; Miller, Ryan; Wondisford, Fredric; Radovick, Sally

    2016-04-01

    Several transgenic mouse models with disruption in the growth hormone (GH) axis support the role of GH in augmenting metabolic homeostasis. Specifically, interest has focused on GH's lipolytic properties and ability to affect adipose deposition. Furthermore, both GH and insulin growth factor 1 (IGF-1) may also play a direct or indirect role in adipose development. The somatotroph insulin-like growth factor-1 receptor knockout (SIGFRKO) mouse with only a modest increase in serum GH and IGF-1 demonstrates less adipose tissue than controls. In order to characterize the metabolic phenotype of SIGFRKO mice, histologic analysis of fat depots confirmed a smaller average diameter of adipocytes in the SIGFRKO mice compared to controls. These changes were accompanied by an increase in lipolytic gene expression in fat depots. Indirect calorimetry performed on 6-8week old male mice and again at 25weeks of age demonstrated that SIGFRKO mice, at both ages, had a higher VO2 and increased energy expenditure when compared with controls. The calculated respiratory exchange ratio (RER) was lower in the younger SIGFRKO mice compared to controls. No differences in food consumption or in either ambulatory or total activity were seen between SIGFRKO and control mice in either age group. These studies highlight the role of GH in adipose deposition and its influence on the expression of lipolytic genes resulting in an altered metabolic state, thus providing a mechanism for the decrease in weight gain seen in the SIGFRKO mouse model. PMID:26975547

  15. Glucose metabolism during fasting is altered in experimental porphobilinogen deaminase deficiency.

    PubMed

    Collantes, María; Serrano-Mendioroz, Irantzu; Benito, Marina; Molinet-Dronda, Francisco; Delgado, Mercedes; Vinaixa, María; Sampedro, Ana; Enríquez de Salamanca, Rafael; Prieto, Elena; Pozo, Miguel A; Peñuelas, Iván; Corrales, Fernando J; Barajas, Miguel; Fontanellas, Antonio

    2016-04-01

    Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks when hepatic heme synthesis is activated by endogenous or environmental factors including fasting. While the molecular mechanisms underlying the nutritional regulation of hepatic heme synthesis have been described, glucose homeostasis during fasting is poorly understood in porphyria. Our study aimed to analyse glucose homeostasis and hepatic carbohydrate metabolism during fasting in PBGD-deficient mice. To determine the contribution of hepatic PBGD deficiency to carbohydrate metabolism, AIP mice injected with a PBGD-liver gene delivery vector were included. After a 14 h fasting period, serum and liver metabolomics analyses showed that wild-type mice stimulated hepatic glycogen degradation to maintain glucose homeostasis while AIP livers activated gluconeogenesis and ketogenesis due to their inability to use stored glycogen. The serum of fasted AIP mice showed increased concentrations of insulin and reduced glucagon levels. Specific over-expression of the PBGD protein in the liver tended to normalize circulating insulin and glucagon levels, stimulated hepatic glycogen catabolism and blocked ketone body production. Reduced glucose uptake was observed in the primary somatosensorial brain cortex of fasted AIP mice, which could be reversed by PBGD-liver gene delivery. In conclusion, AIP mice showed a different response to fasting as measured by altered carbohydrate metabolism in the liver and modified glucose consumption in the brain cortex. Glucose homeostasis in fasted AIP mice was efficiently normalized after restoration of PBGD gene expression in the liver. PMID:26908609

  16. Defining the human adipose tissue proteome to reveal metabolic alterations in obesity.

    PubMed

    Mardinoglu, Adil; Kampf, Caroline; Asplund, Anna; Fagerberg, Linn; Hallström, Björn M; Edlund, Karolina; Blüher, Matthias; Pontén, Fredrik; Uhlen, Mathias; Nielsen, Jens

    2014-11-01

    White adipose tissue (WAT) has a major role in the progression of obesity. Here, we combined data from RNA-Seq and antibody-based immunohistochemistry to describe the normal physiology of human WAT obtained from three female subjects and explored WAT-specific genes by comparing WAT to 26 other major human tissues. Using the protein evidence in WAT, we validated the content of a genome-scale metabolic model for adipocytes. We employed this high-quality model for the analysis of subcutaneous adipose tissue (SAT) gene expression data obtained from subjects included in the Swedish Obese Subjects Sib Pair study to reveal molecular differences between lean and obese individuals. We integrated SAT gene expression and plasma metabolomics data, investigated the contribution of the metabolic differences in the mitochondria of SAT to the occurrence of obesity, and eventually identified cytosolic branched-chain amino acid (BCAA) transaminase 1 as a potential target that can be used for drug development. We observed decreased glutaminolysis and alterations in the BCAAs metabolism in SAT of obese subjects compared to lean subjects. We also provided mechanistic explanations for the changes in the plasma level of BCAAs, glutamate, pyruvate, and α-ketoglutarate in obese subjects. Finally, we validated a subset of our model-based predictions in 20 SAT samples obtained from 10 lean and 10 obese male and female subjects. PMID:25219818

  17. Metabolic profiling reveals altered pattern of central metabolism in navel orange plants as a result of boron deficiency.

    PubMed

    Liu, Guidong; Dong, Xiaochang; Liu, Leichao; Wu, Lishu; Peng, Shu'ang; Jiang, Cuncang

    2015-04-01

    We focused on the changes of metabolite profiles in navel orange plants under long-term boron (B) deficiency using a gas chromatography-mass spectrometry (GC-MS) approach. Curling of the leaves and leaf chlorosis were observed only in the upper leaves (present before start of the treatment) of B-deficient plants, while the lower leaves (grown during treatment) did not show any visible symptoms. The metabolites with up-accumulation in B-deficient leaves were mainly proline, l-ornithine, lysine, glucoheptonic acid, fucose, fumarate, oxalate, quinate, myo-inositol and allo-inositol, while the metabolites with down-accumulation in B-deficient leaves were mainly serine, asparagine, saccharic acid, citrate, succinate, shikimate and phytol. The levels of glucose and fructose were increased only in the upper leaves by B deficiency, while starch content was increased in all the leaves and in roots. The increased levels of malate, ribitol, gluconic acid and glyceric acid occurred only in the lower leaves of B-deficient plants. The increased levels of phenols only in the upper leaves indicated that the effects of B on phenol metabolism in citrus plants may be a consequence of disruptions in leaf structure. Metabolites with opposite reactions in upper and lower leaves were mainly glutamine, glycine and pyrrole-2-carboxylic acid. To our knowledge, the phenomena of allo-inositol even higher than myo-inositol occurred characterized for the first time in this species. These results suggested that the altered pattern of central metabolism may be either specific or adaptive responses of navel orange plants to B deficiency. PMID:25212059

  18. 5α-Reductase inhibitors alter steroid metabolism and may contribute to insulin resistance, diabetes, metabolic syndrome and vascular disease: a medical hypothesis.

    PubMed

    Traish, Abdulmaged M; Guay, Andre T; Zitzmann, Michael

    2014-12-01

    5α-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease. PMID:25460297

  19. Lipid Classes, Fatty Acid Composition, and Glycerolipid Molecular Species of the Red Alga Gracilaria vermiculophylla, a Prostaglandin-Producing Seaweed.

    PubMed

    Honda, Masaki; Ishimaru, Takashi; Itabashi, Yutaka

    2016-01-01

    The red alga Gracilaria vermiculophylla is a well-known producer of prostaglandins, such as PGE2 and PGF2α. In this study, the characteristics of glycerolipids as substrates of prostaglandin production were clarified, and the lipid classes, fatty acid composition, and glycerolipid molecular species were investigated in detail. The major lipid classes were monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG), and sulfoquinovosyldiacylglycerol (SQDG), as well as phosphatidylcholine (PC), which accounted for 43.0% of the total lipid profile. Arachidonic acid (20:4n-6), a prostaglandin precursor, and palmitic acid (16:0) were the predominant fatty acids in the total lipid profile. The 20:4n-6 content was significantly high in MGDG and PC (more than 60%), and the 16:0 content was significantly high in DGDG and SQDG (more than 50%). Chiral-phase high-performance liquid chromatography determined that fatty acids were esterified at the sn-1 and sn-2 positions of those lipids. The main glycerolipid molecular species were 20:4n-6/20:4n-6 (sn-1/sn-2) for MGDG (56.5%) and PC (40.0%), and 20:4n-6/16:0 for DGDG (75.4%) and SQDG (58.4%). Thus, it was considered that the glycerolipid molecular species containing one or two 20:4n-6 were the major substrates for prostaglandin production in G. vermiculophylla. PMID:27581490

  20. Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts

    PubMed Central

    Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

    2015-01-01

    The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird’s-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant’s developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an

  1. Meal time shift disturbs circadian rhythmicity along with metabolic and behavioral alterations in mice.

    PubMed

    Yoon, Ji-Ae; Han, Dong-Hee; Noh, Jong-Yun; Kim, Mi-Hee; Son, Gi Hoon; Kim, Kyungjin; Kim, Chang-Ju; Pak, Youngmi Kim; Cho, Sehyung

    2012-01-01

    In modern society, growing numbers of people are engaged in various forms of shift works or trans-meridian travels. Such circadian misalignment is known to disturb endogenous diurnal rhythms, which may lead to harmful physiological consequences including metabolic syndrome, obesity, cancer, cardiovascular disorders, and gastric disorders as well as other physical and mental disorders. However, the precise mechanism(s) underlying these changes are yet unclear. The present work, therefore examined the effects of 6 h advance or delay of usual meal time on diurnal rhythmicities in home cage activity (HCA), body temperature (BT), blood metabolic markers, glucose homeostasis, and expression of genes that are involved in cholesterol homeostasis by feeding young adult male mice in a time-restrictive manner. Delay of meal time caused locomotive hyperactivity in a significant portion (42%) of subjects, while 6 h advance caused a torpor-like symptom during the late scotophase. Accordingly, daily rhythms of blood glucose and triglyceride were differentially affected by time-restrictive feeding regimen with concurrent metabolic alterations. Along with these physiological changes, time-restrictive feeding also influenced the circadian expression patterns of low density lipoprotein receptor (LDLR) as well as most LDLR regulatory factors. Strikingly, chronic advance of meal time induced insulin resistance, while chronic delay significantly elevated blood glucose levels. Taken together, our findings indicate that persistent shifts in usual meal time impact the diurnal rhythms of carbohydrate and lipid metabolisms in addition to HCA and BT, thereby posing critical implications for the health and diseases of shift workers. PMID:22952870

  2. Nighttime feeding likely alters morning metabolism but not exercise performance in female athletes.

    PubMed

    Ormsbee, Michael J; Gorman, Katherine A; Miller, Elizabeth A; Baur, Daniel A; Eckel, Lisa A; Contreras, Robert J; Panton, Lynn B; Spicer, Maria T

    2016-07-01

    The timing of morning endurance competition may limit proper pre-race fueling and resulting performance. A nighttime, pre-sleep nutritional strategy could be an alternative method to target the metabolic and hydrating needs of the early morning athlete without compromising sleep or gastrointestinal comfort during exercise. Therefore, the purpose of this investigation was to examine the acute effects of pre-sleep chocolate milk (CM) ingestion on next-morning running performance, metabolism, and hydration status. Twelve competitive female runners and triathletes (age, 30 ± 7 years; peak oxygen consumption, 53 ± 4 mL·kg(-1)·min(-1)) randomly ingested either pre-sleep CM or non-nutritive placebo (PL) ∼30 min before sleep and 7-9 h before a morning exercise trial. Resting metabolic rate (RMR) was assessed prior to exercise. The exercise trial included a warm-up, three 5-min incremental workloads at 55%, 65%, and 75% peak oxygen consumption, and a 10-km treadmill time trial (TT). Physiological responses were assessed prior, during (incremental and TT), and postexercise. Paired t tests and magnitude-based inferences were used to determine treatment differences. TT performances were not different ("most likely trivial" improvement with CM) between conditions (PL: 52.8 ± 8.4 min vs CM: 52.8 ± 8.0 min). RMR was "likely" increased (4.8%) and total carbohydrate oxidation (g·min(-1)) during exercise was "possibly" or likely increased (18.8%, 10.1%, 9.1% for stage 1-3, respectively) with CM versus PL. There were no consistent changes to hydration indices. In conclusion, pre-sleep CM may alter next-morning resting and exercise metabolism to favor carbohydrate oxidation, but effects did not translate to 10-km running performance improvements. PMID:27329516

  3. Methoxychlor reduces estradiol levels by altering steroidogenesis and metabolism in mouse antral follicles in vitro

    SciTech Connect

    Basavarajappa, Mallikarjuna S. Craig, Zelieann R. Hernandez-Ochoa, Isabel Paulose, Tessie Leslie, Traci C. Flaws, Jodi A.

    2011-06-15

    The organochlorine pesticide methoxychlor (MXC) is a known endocrine disruptor that affects adult rodent females by causing reduced fertility, persistent estrus, and ovarian atrophy. Since MXC is also known to target antral follicles, the major producer of sex steroids in the ovary, the present study was designed to test the hypothesis that MXC decreases estradiol (E{sub 2}) levels by altering steroidogenic and metabolic enzymes in the antral follicles. To test this hypothesis, antral follicles were isolated from CD-1 mouse ovaries and cultured with either dimethylsulfoxide (DMSO) or MXC. Follicle growth was measured every 24 h for 96 h. In addition, sex steroid hormone levels were measured using enzyme-linked immunosorbent assays (ELISA) and mRNA expression levels of steroidogenic enzymes as well as the E{sub 2} metabolic enzyme Cyp1b1 were measured using qPCR. The results indicate that MXC decreased E{sub 2}, testosterone, androstenedione, and progesterone (P{sub 4}) levels compared to DMSO. In addition, MXC decreased expression of aromatase (Cyp19a1), 17{beta}-hydroxysteroid dehydrogenase 1 (Hsd17b1), 17{alpha}-hydroxylase/17,20-lyase (Cyp17a1), 3{beta} hydroxysteroid dehydrogenase 1 (Hsd3b1), cholesterol side-chain cleavage (Cyp11a1), steroid acute regulatory protein (Star), and increased expression of Cyp1b1 enzyme levels. Thus, these data suggest that MXC decreases steroidogenic enzyme levels, increases metabolic enzyme expression and this in turn leads to decreased sex steroid hormone levels. - Highlights: > MXC inhibits steroidogenesis > MXC inhibits steroidogenic enzymes > MXC induces metabolic enzymes

  4. Morning and Evening Blue-Enriched Light Exposure Alters Metabolic Function in Normal Weight Adults.

    PubMed

    Cheung, Ivy N; Zee, Phyllis C; Shalman, Dov; Malkani, Roneil G; Kang, Joseph; Reid, Kathryn J

    2016-01-01

    Increasing evidence points to associations between light-dark exposure patterns, feeding behavior, and metabolism. This study aimed to determine the acute effects of 3 hours of morning versus evening blue-enriched light exposure compared to dim light on hunger, metabolic function, and physiological arousal. Nineteen healthy adults completed this 4-day inpatient protocol under dim light conditions (<20lux). Participants were randomized to 3 hours of blue-enriched light exposure on Day 3 starting either 0.5 hours after wake (n = 9; morning group) or 10.5 hours after wake (n = 10; evening group). All participants remained in dim light on Day 2 to serve as their baseline. Subjective hunger and sleepiness scales were collected hourly. Blood was sampled at 30-minute intervals for 4 hours in association with the light exposure period for glucose, insulin, cortisol, leptin, and ghrelin. Homeostatic model assessment of insulin resistance (HOMA-IR) and area under the curve (AUC) for insulin, glucose, HOMA-IR and cortisol were calculated. Comparisons relative to baseline were done using t-tests and repeated measures ANOVAs. In both the morning and evening groups, insulin total area, HOMA-IR, and HOMA-IR AUC were increased and subjective sleepiness was reduced with blue-enriched light compared to dim light. The evening group, but not the morning group, had significantly higher glucose peak value during blue-enriched light exposure compared to dim light. There were no other significant differences between the morning or the evening groups in response to blue-enriched light exposure. Blue-enriched light exposure acutely alters glucose metabolism and sleepiness, however the mechanisms behind this relationship and its impacts on hunger and appetite regulation remain unclear. These results provide further support for a role of environmental light exposure in the regulation of metabolism. PMID:27191727

  5. Morning and Evening Blue-Enriched Light Exposure Alters Metabolic Function in Normal Weight Adults

    PubMed Central

    Cheung, Ivy N.; Zee, Phyllis C.; Shalman, Dov; Malkani, Roneil G.; Kang, Joseph; Reid, Kathryn J.

    2016-01-01

    Increasing evidence points to associations between light-dark exposure patterns, feeding behavior, and metabolism. This study aimed to determine the acute effects of 3 hours of morning versus evening blue-enriched light exposure compared to dim light on hunger, metabolic function, and physiological arousal. Nineteen healthy adults completed this 4-day inpatient protocol under dim light conditions (<20lux). Participants were randomized to 3 hours of blue-enriched light exposure on Day 3 starting either 0.5 hours after wake (n = 9; morning group) or 10.5 hours after wake (n = 10; evening group). All participants remained in dim light on Day 2 to serve as their baseline. Subjective hunger and sleepiness scales were collected hourly. Blood was sampled at 30-minute intervals for 4 hours in association with the light exposure period for glucose, insulin, cortisol, leptin, and ghrelin. Homeostatic model assessment of insulin resistance (HOMA-IR) and area under the curve (AUC) for insulin, glucose, HOMA-IR and cortisol were calculated. Comparisons relative to baseline were done using t-tests and repeated measures ANOVAs. In both the morning and evening groups, insulin total area, HOMA-IR, and HOMA-IR AUC were increased and subjective sleepiness was reduced with blue-enriched light compared to dim light. The evening group, but not the morning group, had significantly higher glucose peak value during blue-enriched light exposure compared to dim light. There were no other significant differences between the morning or the evening groups in response to blue-enriched light exposure. Blue-enriched light exposure acutely alters glucose metabolism and sleepiness, however the mechanisms behind this relationship and its impacts on hunger and appetite regulation remain unclear. These results provide further support for a role of environmental light exposure in the regulation of metabolism. PMID:27191727

  6. Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts.

    PubMed

    Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

    2015-01-01

    The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird's-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant's developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an

  7. Virus-induced atherosclerosis. Herpesvirus infection alters aortic cholesterol metabolism and accumulation.

    PubMed Central

    Hajjar, D. P.; Fabricant, C. G.; Minick, C. R.; Fabricant, J.

    1986-01-01

    that lipid accretion in aortas of MDV-infected chickens results, in part, from alterations in cholesterol/CE metabolism during early stages of the disease. These findings support the hypothesis that human atherosclerosis may result from specific herpesvirus infection which can alter lipid metabolism and lead to lipid accretion. PMID:2934987

  8. Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health.

    PubMed

    Li, Yusheng; Xiao, Wenfeng; Luo, Wei; Zeng, Chao; Deng, Zhenhan; Ren, Wenkai; Wu, Guoyao; Lei, Guanghua

    2016-04-01

    Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA. PMID:26767374

  9. Altered surfactant protein A gene expression and protein metabolism associated with repeat exposure to inhaled endotoxin.

    PubMed

    George, Caroline L S; White, Misty L; O'Neill, Marsha E; Thorne, Peter S; Schwartz, David A; Snyder, Jeanne M

    2003-12-01

    Chronically inhaled endotoxin, which is ubiquitous in many occupational and domestic environments, can adversely affect the respiratory system resulting in an inflammatory response and decreased lung function. Surfactant-associated protein A (SP-A) is part of the lung innate immune system and may attenuate the inflammatory response in various types of lung injury. Using a murine model to mimic occupational exposures to endotoxin, we hypothesized that SP-A gene expression and protein would be elevated in response to repeat exposure to inhaled grain dust and to purified lipopolysaccharide (LPS). Our results demonstrate that repeat exposure to inhaled endotoxin, either in the form of grain dust or purified LPS, results in increased whole lung SP-A gene expression and type II alveolar epithelial cell hyperplasia, whereas SP-A protein levels in lung lavage fluid are decreased. Furthermore, these alterations in SP-A gene activity and protein metabolism are dependent on an intact endotoxin signaling system. PMID:12922979

  10. Microbial metabolism alters pore water chemistry and increases consolidation of oil sands tailings.

    PubMed

    Arkell, Nicholas; Kuznetsov, Petr; Kuznetsova, Alsu; Foght, Julia M; Siddique, Tariq

    2015-01-01

    Tailings produced during bitumen extraction from surface-mined oil sands ores (tar sands) comprise an aqueous suspension of clay particles that remain dispersed for decades in tailings ponds. Slow consolidation of the clays hinders water recovery for reuse and retards volume reduction, thereby increasing the environmental footprint of tailings ponds. We investigated mechanisms of tailings consolidation and revealed that indigenous anaerobic microorganisms altered porewater chemistry by producing CO and CH during metabolism of acetate added as a labile carbon amendment. Entrapped biogenic CO decreased tailings pH, thereby increasing calcium (Ca) and magnesium (Mg) cations and bicarbonate (HCO) concentrations in the porewater through dissolution of carbonate minerals. Soluble ions increased the porewater ionic strength, which, with higher exchangeable Ca and Mg, decreased the diffuse double layer of clays and increased consolidation of tailings compared with unamended tailings in which little microbial activity was observed. These results are relevant to effective tailings pond management strategies. PMID:25602329

  11. Fetal PCB syndrome: clinical features, intrauterine growth retardation and possible alteration in calcium metabolism

    SciTech Connect

    Yamashita, F.; Hayashi, M.

    1985-02-01

    Pregnant mothers with Yusho in Fukuoka, Nagasaki and Kochi Prefectures delivered babies with a peculiar clinical manifestation which will be called fetal PCB syndrome (FPS). The birth rate incidences were 3.6% (Fukuoka Prefecture), 4% (Nagasaki Prefecture), 2.9% (Kochi Prefecture) and 3.9% (total). The manifestations consisted of dark brown pigmentation of the skin and the mucous membrane, gingival hyperplasia, exophthalmic edematous eye, dentition at birth, abnormal calcification of the skull as demonstrated by X-ray, rocker bottom heel and high incidence of light for date (low birth weight) babies. The authors suggest that there may be a possible alteration in calcium metabolism in these babies, related to the fragile egg shells observed in PCB-contaminated birds and to the female hormone-enhancing effect of PCB. The high incidence of low birth weight among these newborns and two other similar studies indicated that PCBs suppress fetal growth.

  12. Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on Cosmos 1887

    NASA Technical Reports Server (NTRS)

    Merrill, A. H. Jr; Hoel, M.; Wang, E.; Mullins, R. E.; Hargrove, J. L.; Jones, D. P.; Popova, I. A.; Merrill AH, J. r. (Principal Investigator)

    1990-01-01

    To determine the possible biochemical effects of prolonged weightlessness on liver function, samples of liver from rats that had flown aboard Cosmos 1887 were analyzed for protein, glycogen, and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. Among the parameters measured, the major differences were elevations in the glycogen content and hydroxymethylglutaryl-CoA (HMG-CoA) reductase activities for the rats flown on Cosmos 1887 and decreases in the amount of microsomal cytochrome P-450 and the activities of aniline hydroxylase and ethylmorphine N-demethylase, cytochrome P-450-dependent enzymes. These results support the earlier finding of differences in these parameters and suggest that altered hepatic function could be important during spaceflight and/or the postflight recovery period.

  13. Glycerolipid biosynthesis in Saccharomyces cerevisiae: sn-glycerol-3-phosphate and dihydroxyacetone phosphate acyltransferase activities.

    PubMed Central

    Schlossman, D M; Bell, R M

    1978-01-01

    Yeast acyl-coenzyme A:dihydroxyacetone-phosphate O-acyltransferase (DHAP acyltransferase; EC 2.3.1.42) was investigated to (i) determine whether its activity and that of acyl-coenzyme A:sn-glycerol-3-phosphate O-acyltransferase (glycerol-P acyltransferase; EC 2.3.1.15) represent dual catalytic functions of a single membranous enzyme, (ii) estimate the relative contributions of the glycerol-P and DHAP pathways for yeast glycerolipid synthesis, and (iii) evaluate the suitability of yeast for future genetic investigations of the eucaryotic glycerol-P and DHAP acyltransferase activities. The membranous DHAP acyltransferase activity showed an apparent Km of 0.79 mM for DHAP, with a Vmax of 5.3 nmol/min per mg, whereas the glycerol-P acyltransferase activity showed an apparent Km of 0.05 mM for glycerol-P, with a Vmax of 3.4 nmol/min per mg. Glycerol-P was a competitive inhibitor (Ki, 0.07 mM) of the DHAP acyltransferase activity, and DHAP was a competitive inhibitor (Ki, 0.91 mM) of the glycerol-P acyltransferase activity. The two acyltransferase activities exhibited marked similarities in their pH dependence, acyl-coenzyme A chain length preference and substrate concentration dependencies, thermolability, and patterns of inactivation by N-ethylmaleimide, trypsin, and detergents. Thus, the data strongly suggest that yeast glycerol-P and DHAP acyltransferase activities represent dual catalytic functions of a single membrane-bound enzyme. Furthermore, since no acyl-DHAP oxidoreductase activity could be detected in yeast membranes, the DHAP pathway for glycerolipid synthesis may not operate in yeast. PMID:25265

  14. Injury timing alters metabolic, inflammatory and functional outcomes following repeated mild traumatic brain injury.

    PubMed

    Weil, Zachary M; Gaier, Kristopher R; Karelina, Kate

    2014-10-01

    Repeated head injuries are a major public health concern both for athletes, and members of the police and armed forces. There is ample experimental and clinical evidence that there is a period of enhanced vulnerability to subsequent injury following head trauma. Injuries that occur close together in time produce greater cognitive, histological, and behavioral impairments than do injuries separated by a longer period. Traumatic brain injuries alter cerebral glucose metabolism and the resolution of altered glucose metabolism may signal the end of the period of greater vulnerability. Here, we injured mice either once or twice separated by three or 20days. Repeated injuries that were separated by three days were associated with greater axonal degeneration, enhanced inflammatory responses, and poorer performance in a spatial learning and memory task. A single injury induced a transient but marked increase in local cerebral glucose utilization in the injured hippocampus and sensorimotor cortex, whereas a second injury, three days after the first, failed to induce an increase in glucose utilization at the same time point. In contrast, when the second injury occurred substantially later (20days after the first injury), an increase in glucose utilization occurred that paralleled the increase observed following a single injury. The increased glucose utilization observed after a single injury appears to be an adaptive component of recovery, while mice with 2 injuries separated by three days were not able to mount this response, thus this second injury may have produced a significant energetic crisis such that energetic demands outstripped the ability of the damaged cells to utilize energy. These data strongly reinforce the idea that too rapid return to activity after a traumatic brain injury can induce permanent damage and disability, and that monitoring cerebral energy utilization may be a tool to determine when it is safe to return to the activity that caused the initial

  15. Metformin suppressed the proliferation of LoVo cells and induced a time-dependent metabolic and transcriptional alteration.

    PubMed

    He, Jiaojiao; Wang, Ke; Zheng, Ningning; Qiu, Yunping; Xie, Guoxiang; Su, Mingming; Jia, Wei; Li, Houkai

    2015-01-01

    Metformin is a widely used anti-diabetic drug with potential anti-tumor activity. However, little is known about its global metabolic and transcriptional impacts on tumor cells. In current study, we performed a metabolic profiling on human-derived colon cancer LoVo cells treated by 10 mM metformin for 8, 24 and 48 h. An obvious time-dependent metabolic alteration was observed from 8 to 48 h, prior to the reduction of cell viability. A total of 47, 45 and 66 differential metabolites were identified between control and metformin-treated cells at three time points. Most of the metabolites were up-regulated at 8 h, but down-regulated at 24 and 48 h by metformin. These metabolites were mainly involved in carbohydrates, lipids, amino acids, vitamins and nucleotides metabolism pathways. Meanwhile, the transcirptomic profile revealed 134 and 3061 differentially expressed genes at 8 and 24 h by metformin. In addition to the cancer signaling pathways, expression of genes involved in cell energy metabolism pathways was significantly altered, which were further validated with genes in glucose metabolism pathway. Altogether, our current data indicate that metformin suppressed the proliferation of LoVo cells, which may be due to the modulation on cell energy metabolism at both metabolic and transcriptional levels in a time-dependent way. PMID:26616174

  16. Metformin suppressed the proliferation of LoVo cells and induced a time-dependent metabolic and transcriptional alteration

    PubMed Central

    He, Jiaojiao; Wang, Ke; Zheng, Ningning; Qiu, Yunping; Xie, Guoxiang; Su, Mingming; Jia, Wei; Li, Houkai

    2015-01-01

    Metformin is a widely used anti-diabetic drug with potential anti-tumor activity. However, little is known about its global metabolic and transcriptional impacts on tumor cells. In current study, we performed a metabolic profiling on human-derived colon cancer LoVo cells treated by 10 mM metformin for 8, 24 and 48 h. An obvious time-dependent metabolic alteration was observed from 8 to 48 h, prior to the reduction of cell viability. A total of 47, 45 and 66 differential metabolites were identified between control and metformin-treated cells at three time points. Most of the metabolites were up-regulated at 8 h, but down-regulated at 24 and 48 h by metformin. These metabolites were mainly involved in carbohydrates, lipids, amino acids, vitamins and nucleotides metabolism pathways. Meanwhile, the transcirptomic profile revealed 134 and 3061 differentially expressed genes at 8 and 24 h by metformin. In addition to the cancer signaling pathways, expression of genes involved in cell energy metabolism pathways was significantly altered, which were further validated with genes in glucose metabolism pathway. Altogether, our current data indicate that metformin suppressed the proliferation of LoVo cells, which may be due to the modulation on cell energy metabolism at both metabolic and transcriptional levels in a time-dependent way. PMID:26616174

  17. XPC silencing in normal human keratinocytes triggers metabolic alterations through NOX-1 activation-mediated reactive oxygen species

    PubMed Central

    Rezvani, Hamid Reza; Rossignol, Rodrigue; Ali, Nsrein; Benard, Giovanni; Tang, Xiuwei; Yang, Hee Seung; Jouary, Thomas; de Verneuil, Hubert; Taïeb, Alain; Kim, Arianna L.; Mazurier, Frédéric

    2011-01-01

    Summary Cancer cells utilize complex mechanisms to remodel their bioenergetic properties. We exploited the intrinsic genomic stability of xeroderma pigmentosum C (XPC) to understand the interrelationships between genomic instability, reactive oxygen species (ROS) generation, and metabolic alterations during neoplastic transformation. We showed that knockdown of XPC (XPCKD) in normal human keratinocytes results in metabolism remodeling through NADPH oxidase-1 (NOX-1) activation, which in turn leads to increased ROS levels. While enforcing antioxidant defenses by overexpressing catalase, CuZnSOD, or MnSOD could not block the metabolism remodeling, impaired NOX-1 activation abrogates both alteration in ROS levels and modifications of energy metabolism. As NOX-1 activation is observed in human squamous cell carcinomas (SCCs), the blockade of NOX-1 could be a target for the prevention and the treatment of skin cancers. PMID:21167810

  18. Lysosomotropic agents selectively target chronic lymphocytic leukemia cells due to altered sphingolipid metabolism.

    PubMed

    Dielschneider, R F; Eisenstat, H; Mi, S; Curtis, J M; Xiao, W; Johnston, J B; Gibson, S B

    2016-06-01

    Lysosome membrane permeabilization (LMP) mediates cell death in a variety of cancer cells. However, little is known about lysosomes and LMP in chronic lymphocytic leukemia (CLL). Owing to drug resistance and toxicity in CLL patients, better treatment strategies are required. Our results show that CLL cells were sensitive to the lysosomotropic agent siramesine. Furthermore, this drug was more effective in CLL cells, regardless of prognostic factors, compared with normal B cells. Siramesine caused LMP, lipid peroxidation and transcription factor EB nuclear translocation followed by mitochondrial membrane potential loss and reactive oxygen species release. Siramesine-induced cell death was blocked by lipid antioxidants, but not by soluble antioxidants or protease inhibitors. To determine whether CLL cells had altered lysosomes, we investigated sphingolipid metabolism as the lysosome is a hub for lipid metabolism. We found that CLL cells had more lysosomes, increased sphingosine-1-phosphate phosphatase 1 (SPP1) expression, and increased levels of sphingosine compared with normal B cells. Raising sphingosine levels increased LMP and cell death in CLL cells, but not in normal B cells. Together, these results show that excess sphingosine in CLL cells could contribute to their sensitivity toward LMP. Thus, targeting the lysosome could be a novel therapeutic strategy in CLL. PMID:26859075

  19. Mitochondrial (Dys)function in Adipocyte (De)differentiation and Systemic Metabolic Alterations

    PubMed Central

    De Pauw, Aurélia; Tejerina, Silvia; Raes, Martine; Keijer, Jaap; Arnould, Thierry

    2009-01-01

    In mammals, adipose tissue, composed of BAT and WAT, collaborates in energy partitioning and performs metabolic regulatory functions. It is the most flexible tissue in the body, because it is remodeled in size and shape by modifications in adipocyte cell size and/or number, depending on developmental status and energy fluxes. Although numerous reviews have focused on the differentiation program of both brown and white adipocytes as well as on the pathophysiological role of white adipose tissues, the importance of mitochondrial activity in the differentiation or the dedifferentiation programs of adipose cells and in systemic metabolic alterations has not been extensively reviewed previously. Here, we address the crucial role of mitochondrial functions during adipogenesis and in mature adipocytes and discuss the cellular responses of white adipocytes to mitochondrial activity impairment. In addition, we discuss the increase in scientific knowledge regarding mitochondrial functions in the last 10 years and the recent suspicion of mitochondrial dysfunction in several 21st century epidemics (ie, obesity and diabetes), as well as in lipodystrophy found in HIV-treated patients, which can contribute to the development of new therapeutic strategies targeting adipocyte mitochondria. PMID:19700756

  20. Cocaine abstinence following chronic treatment alters cerebral metabolism in dopaminergic reward regions. Bromocriptine enhances recovery

    SciTech Connect

    Clow, D.W.; Hammer, R.P. Jr. )

    1991-01-01

    2-(14C)deoxyglucose autoradiography was used to determine local cerebral glucose utilization (lCGU) in rats following chronic cocaine treatment and subsequent abstinence. lCGU was examined in 43 discrete brain regions in animals which had received daily injections of cocaine for 14 days (10 mg/kg) followed by 3 days of saline or bromocriptine (10 mg/kg) treatment. Cocaine abstinence following chronic treatment significantly reduced lCGU in several regions including mesocorticolimbic structures such as ventral tegmental area, medial prefrontal cortex, and nucleus accumbens (NAc). Within the NAc, however, only the rostral pole showed significant reduction. In contrast, when bromocriptine treatment accompanied abstinence, lCGU was no longer reduced in mesocorticolimbic and most other regions, implying that metabolic recovery was enhanced by bromocriptine treatment during early abstinence following chronic cocaine treatment. These data suggest that cerebral metabolism is decreased during cocaine abstinence following chronic treatment in critical brain regions, and that this alteration can be prevented by treatment with direct-acting dopamine agonists such as bromocriptine.

  1. Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever.

    PubMed

    Blohmke, Christoph J; Darton, Thomas C; Jones, Claire; Suarez, Nicolas M; Waddington, Claire S; Angus, Brian; Zhou, Liqing; Hill, Jennifer; Clare, Simon; Kane, Leanne; Mukhopadhyay, Subhankar; Schreiber, Fernanda; Duque-Correa, Maria A; Wright, James C; Roumeliotis, Theodoros I; Yu, Lu; Choudhary, Jyoti S; Mejias, Asuncion; Ramilo, Octavio; Shanyinde, Milensu; Sztein, Marcelo B; Kingsley, Robert A; Lockhart, Stephen; Levine, Myron M; Lynn, David J; Dougan, Gordon; Pollard, Andrew J

    2016-05-30

    Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host-pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever. PMID:27217537

  2. Heat-stress-induced metabolic changes and altered male reproductive function.

    PubMed

    Hou, Yuanlong; Wang, Xiaoyan; Lei, Zhihai; Ping, Jihui; Liu, Jiajian; Ma, Zhiyu; Zhang, Zheng; Jia, Cuicui; Jin, Mengmeng; Li, Xiang; Li, Xiaoliang; Chen, Shaoqiu; Lv, Yingfang; Gao, Yingdong; Jia, Wei; Su, Juan

    2015-03-01

    Heat stress can cause systemic physiological and biochemical alterations in living organisms. In reproductive systems, heat stress induces germ cell loss and poor quality semen. However, until now, little has been known about such a complex regulation process, particularly in the perspective of metabolism. In this study, serum, hypothalamus, and epididymis samples derived from male SD (Sprague-Dawley) rats being exposed to high environmental temperature (40 °C) 2 h per day for 7 consecutive days were analyzed using metabonomics strategies based on GC/TOFMS. Differentially expressed metabolites reveal that the energy metabolism, amino acid neurotransmitters, and monoamine neurotransmitters pathways are associated with heat stress, in accordance with changes of the three upstream neuroendocrine system pathways in the SNS (sympathetic adrenergic system), hypothalamic pituitary adrenal axis (HPA), and hypothalamic pituitary testis axis (HPT) axis. Many of these metabolites, especially in the epididymis, were found to be up-regulated, presumably due to a self-preserving action to resist the environmental hot irritation to maintain normal functioning of the male reproductive system. PMID:25607524

  3. Oral MSG administration alters hepatic expression of genes for lipid and nitrogen metabolism in suckling piglets.

    PubMed

    Chen, Gang; Zhang, Jun; Zhang, Yuzhe; Liao, Peng; Li, Tiejun; Chen, Lixiang; Yin, Yulong; Wang, Jinquan; Wu, Guoyao

    2014-01-01

    This experiment was conducted to investigate the effects of oral administration of monosodium glutamate (MSG) on expression of genes for hepatic lipid and nitrogen metabolism in piglets. A total of 24 newborn pigs were assigned randomly into one of four treatments (n = 6/group). The doses of oral MSG administration, given at 8:00 and 18:00 to sow-reared piglets between 0 and 21 days of age, were 0 (control), 0.06 (low dose), 0.5 (intermediate dose), and 1 (high dose) g/kg body weight/day. At the end of the 3-week treatment, serum concentrations of total protein and high-density lipoprotein cholesterol in the intermediate dose group were elevated than those in the control group (P < 0.05). Hepatic mRNA levels for fatty acid synthase, acetyl-coA carboxylase, insulin-like growth factor-1, glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase were higher in the middle-dose group (P < 0.05), compared with the control group. MSG administration did not affect hepatic mRNA levels for hormone-sensitive lipase or carnitine palmitoyl transferase-1. We conclude that oral MSG administration alters hepatic expression of certain genes for lipid and nitrogen metabolism in suckling piglets. PMID:24221354

  4. Bacillus subtilis attachment to Aspergillus niger hyphae results in mutually altered metabolism.

    PubMed

    Benoit, Isabelle; van den Esker, Marielle H; Patyshakuliyeva, Aleksandrina; Mattern, Derek J; Blei, Felix; Zhou, Miaomiao; Dijksterhuis, Jan; Brakhage, Axel A; Kuipers, Oscar P; de Vries, Ronald P; Kovács, Ákos T

    2015-06-01

    Interaction between microbes affects the growth, metabolism and differentiation of members of the microbial community. While direct and indirect competition, like antagonism and nutrient consumption have a negative effect on the interacting members of the population, microbes have also evolved in nature not only to fight, but in some cases to adapt to or support each other, while increasing the fitness of the community. The presence of bacteria and fungi in soil results in various interactions including mutualism. Bacilli attach to the plant root and form complex communities in the rhizosphere. Bacillus subtilis, when grown in the presence of Aspergillus niger, interacts similarly with the fungus, by attaching and growing on the hyphae. Based on data obtained in a dual transcriptome experiment, we suggest that both fungi and bacteria alter their metabolism during this interaction. Interestingly, the transcription of genes related to the antifungal and putative antibacterial defence mechanism of B. subtilis and A. niger, respectively, are decreased upon attachment of bacteria to the mycelia. Analysis of the culture supernatant suggests that surfactin production by B. subtilis was reduced when the bacterium was co-cultivated with the fungus. Our experiments provide new insights into the interaction between a bacterium and a fungus. PMID:25040940

  5. Gene expression analysis in mitochondria from chagasic mice: alterations in specific metabolic pathways

    PubMed Central

    2004-01-01

    Cardiac hypertrophy and remodelling in chagasic disease might be associated with mitochondrial dysfunction. In the present study, we characterized the cardiac metabolic responses to Trypanosoma cruzi infection and progressive disease severity using a custom-designed mitoarray (mitochondrial function-related gene array). Mitoarrays consisting of known, well-characterized mitochondrial function-related cDNAs were hybridized with 32P-labelled cDNA probes generated from the myocardium of mice during immediate early, acute and chronic phases of infection and disease development. The mitoarray successfully identified novel aspects of the T. cruzi-induced alterations in the expression of the genes related to mitochondrial function and biogenesis that were further confirmed by real-time reverse transcriptase–PCRs. Of note is the up-regulation of transcripts essential for fatty acid metabolism associated with repression of the mRNAs for pyruvate dehydrogenase complex in infected hearts. We observed no statistically significant changes in mRNAs for the enzymes of tricarboxylic acid cycle. These results suggest that fatty acid metabolism compensates the pyruvate dehydrogenase complex deficiencies for the supply of acetyl-CoA for a tricarboxylic acid cycle, and chagasic hearts may not be limited in reduced energy (NADH and FADH2). The observation of a decrease in mRNA level for several subunits of the respiratory chain complexes by mitoarray as well as global genome analysis suggests a limitation in mitochondrial oxidative phosphorylation-mediated ATP-generation capacity as the probable basis for cardiac homoeostasis in chagasic disease. PMID:15101819

  6. Neurophysiological activity underlying altered brain metabolism in epileptic encephalopathies with CSWS.

    PubMed

    De Tiège, Xavier; Trotta, Nicola; Op de Beeck, Marc; Bourguignon, Mathieu; Marty, Brice; Wens, Vincent; Nonclercq, Antoine; Goldman, Serge; Van Bogaert, Patrick

    2013-08-01

    We investigated the neurophysiological correlate of altered regional cerebral glucose metabolism observed in children with epileptic encephalopathy with continuous spike-waves during sleep (CSWS) by using a multimodal approach combining time-sensitive magnetic source imaging (MSI) and positron emission tomography with [(18)F]-fluorodeoxyglucose (FDG-PET). Six patients (4 boys and 2 girls, age range: 4-8 years, 3 patients with Landau-Kleffner syndrome (LKS), 3 patients with atypical rolandic epilepsy (ARE)) were investigated by FDG-PET and MSI at the acute phase of CSWS. In all patients, the onset(s) of spike-waves discharges were associated with significant focal hypermetabolism. The propagation of epileptic discharges to other brain areas was associated with focal hypermetabolism (five patients), hypometabolism (one patient) or the absence of any significant metabolic change (one patient). Interestingly, most of the hypometabolic areas were not involved in the epileptic network per se. This study shows that focal hypermetabolism observed at the acute phase of CSWS are related to the onset or propagation sites of spike-wave discharges. Spike-wave discharges propagation can be associated to other types of metabolic changes, suggesting the occurrence of various neurophysiological mechanisms at the cellular level. Most of the hypometabolic areas are not involved in the epileptic network as such and are probably related to a mechanism of remote inhibition. These findings highlight the critical value of combining FDG-PET with time-sensitive functional neuroimaging approaches such as MSI to assess CSWS epileptic network when surgery is considered as a therapeutic approach. PMID:23561286

  7. A forage-only diet alters the metabolic response of horses in training.

    PubMed

    Jansson, A; Lindberg, J E

    2012-12-01

    Most athletic horses are fed a high-starch diet despite the risk of health problems. Replacing starch concentrate with high-energy forage would alleviate these health problems, but could result in a shift in major substrates for muscle energy supply from glucose to short-chain fatty acids (SCFA) due to more hindgut fermentation of fibre. Dietary fat inclusion has previously been shown to promote aerobic energy supply during exercise, but the contribution of SCFA to exercise metabolism has received little attention. This study compared metabolic response with exercise and lactate threshold (VLa4) in horses fed a forage-only diet (F) and a more traditional high-starch, low-energy forage diet (forage-concentrate diet - FC). The hypothesis was that diet F would increase plasma acetate concentration and increase VLa4 compared with diet FC. Six Standardbred geldings in race training were used in a 29-day change-over experiment. Plasma acetate, non-esterified fatty acids (NEFA), lactate, glucose and insulin concentrations and venous pH were measured in samples collected before, during and after a treadmill exercise test (ET, day 25) and muscle glycogen concentrations before and after ET. Plasma acetate concentration was higher before and after exercise in horses on diet F compared with diet FC, and there was a tendency (P = 0.09) for increased VLa4 on diet F. Venous pH and plasma glucose concentrations during exercise were higher in horses on diet F than diet FC, as was plasma NEFA on the day after ET. Plasma insulin and muscle glycogen concentrations were lower for diet F, but glycogen utilisation was similar for the two diets. The results show that a high-energy, forage-only diet alters the metabolic response to exercise and, with the exception of lowered glycogen stores, appears to have positive rather than negative effects on performance traits. PMID:22717208

  8. A role for heme in Alzheimer's disease: heme binds amyloid beta and has altered metabolism.

    PubMed

    Atamna, Hani; Frey, William H

    2004-07-27

    Heme is a common factor linking several metabolic perturbations in Alzheimer's disease (AD), including iron metabolism, mitochondrial complex IV, heme oxygenase, and bilirubin. Therefore, we determined whether heme metabolism was altered in temporal lobes obtained at autopsy from AD patients and age-matched nondemented subjects. AD brain demonstrated 2.5-fold more heme-b (P < 0.01) and 26% less heme-a (P = 0.16) compared with controls, resulting in a highly significant 2.9-fold decrease in heme-a/heme-b ratio (P < 0.001). Moreover, the strong Pearson correlation between heme-a and heme-b measured in control individuals (r(2) = 0.66, P < 0.002, n = 11) was abolished in AD subjects (r(2) = 0.076, P = 0.39, n = 12). The level of ferrochelatase (which makes heme-b in the mitochondrial matrix) in AD subjects was 4.2 times (P < 0.04) that in nondemented controls, suggesting up-regulated heme synthesis. To look for a possible connection between these observations and established mechanisms in AD pathology, we examined possible interactions between amyloid beta (A beta) and heme. A beta((1-40)) and A beta((1-42)) induced a redshift of 15-20 nm in the spectrum of heme-b and heme-a, suggesting that heme binds A beta, likely to one or more of the histidine residues. Lastly, in a tissue culture model, we found that clioquinol, a metal chelator in clinical trials for AD therapy, decreased intracellular heme. In light of these observations, we have proposed a model of AD pathobiology in which intracellular A beta complexes with free heme, thereby decreasing its bioavailability (e.g., heme-a) and resulting in functional heme deficiency. The model integrates disparate observations, including A beta, mitochondrial dysfunction, cholesterol, and the proposed efficacy of clioquinol. PMID:15263070

  9. Inflammatory and Metabolic Alterations of Kager's Fat Pad in Chronic Achilles Tendinopathy

    PubMed Central

    Fredberg, Ulrich; Kjær, Søren G.; Quistorff, Bjørn; Langberg, Henning; Hansen, Jacob B.

    2015-01-01

    Background Achilles tendinopathy is a painful inflammatory condition characterized by swelling, stiffness and reduced function of the Achilles tendon. Kager’s fat pad is an adipose tissue located in the area anterior to the Achilles tendon. Observations reveal a close physical interplay between Kager’s fat pad and its surrounding structures during movement of the ankle, suggesting that Kager’s fat pad may stabilize and protect the mechanical function of the ankle joint. Aim The aim of this study was to characterize whether Achilles tendinopathy was accompanied by changes in expression of inflammatory markers and metabolic enzymes in Kager’s fat pad. Methods A biopsy was taken from Kager’s fat pad from 31 patients with chronic Achilles tendinopathy and from 13 healthy individuals. Gene expression was measured by reverse transcription-quantitative PCR. Focus was on genes related to inflammation and lipid metabolism. Results Expression of the majority of analyzed inflammatory marker genes was increased in patients with Achilles tendinopathy compared to that in healthy controls. Expression patterns of the patient group were consistent with reduced lipolysis and increased fatty acid β-oxidation. In the fat pad, the pain-signaling neuropeptide substance P was found to be present in one third of the subjects in the Achilles tendinopathy group but in none of the healthy controls. Conclusion Gene expression changes in Achilles tendinopathy patient samples were consistent with Kager’s fat pad being more inflamed than in the healthy control group. Additionally, the results indicate an altered lipid metabolism in Kager’s fat pad of Achilles tendinopathy patients. PMID:25996876

  10. Inducible Arginase 1 Deficiency in Mice Leads to Hyperargininemia and Altered Amino Acid Metabolism

    PubMed Central

    St. Amand, Tim; Kyriakopoulou, Lianna; Schulze, Andreas; Funk, Colin D.

    2013-01-01

    Arginase deficiency is a rare autosomal recessive disorder resulting from a loss of the liver arginase isoform, arginase 1 (ARG1), which is the final step in the urea cycle for detoxifying ammonia. ARG1 deficiency leads to hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes of hyperammonemia. Using the Cre/loxP-directed conditional gene knockout system, we generated an inducible Arg1-deficient mouse model by crossing “floxed” Arg1 mice with CreERT2 mice. The resulting mice (Arg-Cre) die about two weeks after tamoxifen administration regardless of the starting age of inducing the knockout. These treated mice were nearly devoid of Arg1 mRNA, protein and liver arginase activity, and exhibited symptoms of hyperammonemia. Plasma amino acid analysis revealed pronounced hyperargininemia and significant alterations in amino acid and guanidino compound metabolism, including increased citrulline and guanidinoacetic acid. Despite no alteration in ornithine levels, concentrations of other amino acids such as proline and the branched-chain amino acids were reduced. In summary, we have generated and characterized an inducible Arg1-deficient mouse model exhibiting several pathologic manifestations of hyperargininemia. This model should prove useful for exploring potential treatment options of ARG1 deficiency. PMID:24224027

  11. Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism.

    PubMed

    Sin, Yuan Yan; Ballantyne, Laurel L; Mukherjee, Kamalika; St Amand, Tim; Kyriakopoulou, Lianna; Schulze, Andreas; Funk, Colin D

    2013-01-01

    Arginase deficiency is a rare autosomal recessive disorder resulting from a loss of the liver arginase isoform, arginase 1 (ARG1), which is the final step in the urea cycle for detoxifying ammonia. ARG1 deficiency leads to hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes of hyperammonemia. Using the Cre/loxP-directed conditional gene knockout system, we generated an inducible Arg1-deficient mouse model by crossing "floxed" Arg1 mice with CreER(T2) mice. The resulting mice (Arg-Cre) die about two weeks after tamoxifen administration regardless of the starting age of inducing the knockout. These treated mice were nearly devoid of Arg1 mRNA, protein and liver arginase activity, and exhibited symptoms of hyperammonemia. Plasma amino acid analysis revealed pronounced hyperargininemia and significant alterations in amino acid and guanidino compound metabolism, including increased citrulline and guanidinoacetic acid. Despite no alteration in ornithine levels, concentrations of other amino acids such as proline and the branched-chain amino acids were reduced. In summary, we have generated and characterized an inducible Arg1-deficient mouse model exhibiting several pathologic manifestations of hyperargininemia. This model should prove useful for exploring potential treatment options of ARG1 deficiency. PMID:24224027

  12. Alteration of cellular lipids and lipid metabolism markers in RTL-W1 cells exposed to model endocrine disrupters.

    PubMed

    Dimastrogiovanni, Giorgio; Córdoba, Marlon; Navarro, Isabel; Jáuregui, Olga; Porte, Cinta

    2015-08-01

    This work investigates the suitability of the rainbow trout liver cell line (RTL-W1) as an in-vitro model to study the ability of model endocrine disrupters, namely TBT, TPT, 4-NP, BPA and DEHP, to act as metabolic disrupters by altering cellular lipids and markers of lipid metabolism. Among the tested compounds, BPA and DEHP significantly increased the intracellular accumulation of triacylglycerols (TAGs), while all the compounds -apart from TPT-, altered membrane lipids - phosphatidylcholines (PCs) and plasmalogen PCs - indicating a strong interaction of the toxicants with cell membranes and cell signaling. RTL-W1 expressed a number of genes involved in lipid metabolism that were modulated by exposure to BPA, TBT and TPT (up-regulation of FATP1 and FAS) and 4-NP and DEHP (down-regulation of FAS and LPL). Multiple and complex modes of action of these chemicals were observed in RTL-W1 cells, both in terms of expression of genes related to lipid metabolism and alteration of cellular lipids. Although further characterization is needed, this might be a useful model for the detection of chemicals leading to steatosis or other diseases associated with lipid metabolism in fish. PMID:26143618

  13. Global characterization of the photosynthetic glycerolipids from a marine diatom Stephanodiscus sp. by ultra performance liquid chromatography coupled with electrospray ionization-quadrupole-time of flight mass spectrometry.

    PubMed

    Xu, Jilin; Chen, Deying; Yan, Xiaojun; Chen, Juanjuan; Zhou, Chengxu

    2010-03-17

    The photosynthetic glycerolipids composition of algae is crucial for structural and physiological aspects. In this work, a comprehensive characterization of the photosynthetic glycerolipids of the diatom Stephanodiscus sp. was carried out by ultra performance liquid chromatography-electrospray ionization-quadrupole-time of flight mass spectrometry (UPLC-ESI-Q-TOF MS). By use of the MS(E) data collection mode, the Q-TOF instrument offered a very viable alternative to triple quadrupoles for precursor ion scanning of photosynthetic glycerolipids and had the advantage of high efficiency, selectivity, sensitivity and mass accuracy. Characteristic fragment ions were utilized to identify the structures and acyl compositions of photosynthetic glycerolipids. Comparing the abundance of fragment ions, it was possible to determine the position of the sn-glycerol-bound fatty acyl chains. As a result, four classes of photosynthetic glycerolipid in the extract of Stephanodiscus sp. were unambiguously identified, including 16 monogalactosyldiacylglycerols (MGDGs), 9 digalactosyldiacylglycerols (DGDGs), 23 sulfoquinovosyldiacylglycerols (SQDGs) and 8 phosphatidylglycerols (PGs). As far as our knowledge, this is the first report on global identification of photosynthetic glycerolipids, including lipid classes, fatty acyl composition within lipids and the location of fatty acids in lipids (sn-1 vs. sn-2), in the extract of marine microalgae by UPLC-ESI-Q-TOF MS directly. PMID:20172098

  14. Cholinesterase inhibition and alterations of hepatic metabolism by oral acute and repeated chlorpyrifos administration to mice.

    PubMed

    Cometa, Maria Francesca; Buratti, Franca Maria; Fortuna, Stefano; Lorenzini, Paola; Volpe, Maria Teresa; Parisi, Laura; Testai, Emanuela; Meneguz, Annarita

    2007-05-01

    Chlorpyrifos (CPF) is a broad spectrum organophosphorus insecticide bioactivated in vivo to chlorpyrifos-oxon (CPFO), a very potent anticholinesterase. A great majority of available animal studies on CPF and CPFO toxicity are performed in rats. The use of mice in developmental neurobehavioural studies and the availability of transgenic mice warrant a better characterization of CPF-induced toxicity in this species. CD1 mice were exposed to a broad range of acute (12.5-100.0mg/kg) and subacute (1.56-25mg/kg/day from 5 to 30 days) CPF oral doses. Functional and biochemical parameters such as brain and serum cholinesterase (ChE) and liver xenobiotic metabolizing system, including the biotransformation of CPF itself, have been studied and the no observed effect levels (NOELs) identified. Mice seem to be more susceptible than rats at least to acute CPF treatment (oral LD(50) 4.5-fold lower). The species-related differences were not so evident after repeated exposures. In mice a good correlation was observed between brain ChE inhibition and classical cholinergic signs of toxicity. After CPF-repeated treatment, mice seemed to develop some tolerance to CPF-induced effects, which could not be attributed to an alteration of P450-mediated CPF hepatic metabolism. CPF-induced effects on hepatic microsomal carboxylesterase (CE) activity and reduced glutathione (GSH) levels observed at an early stage of treatment and then recovered after 30 days, suggest that the detoxifying mechanisms are actively involved in the protection of CPF-induced effects and possibly in the induction of tolerance in long term exposure. The mouse could be considered a suitable experimental model for future studies on the toxic action of organophosphorus pesticides focused on mechanisms, long term and age-related effects. PMID:17382447

  15. First demonstration that brain CYP2D-mediated opiate metabolic activation alters analgesia in vivo.

    PubMed

    Zhou, Kaidi; Khokhar, Jibran Y; Zhao, Bin; Tyndale, Rachel F

    2013-06-15

    The response to centrally acting drugs is highly variable between individuals and does not always correlate with plasma drug levels. Drug-metabolizing CYP enzymes in the brain may contribute to this variability by affecting local drug and metabolite concentrations. CYP2D metabolizes codeine to the active morphine metabolite. We investigated the effect of inhibiting brain, and not liver, CYP2D activity on codeine-induced analgesia. Rats received intracerebroventricular injections of CYP2D inhibitors (20 μg propranolol or 40 μg propafenone) or vehicle controls. Compared to vehicle-pretreated rats, inhibitor-pretreated rats had: (a) lower analgesia in the tail-flick test (p<0.05) and lower areas under the analgesia-time curve (p<0.02) within the first hour after 30 mg/kg subcutaneous codeine, (b) lower morphine concentrations and morphine to codeine ratios in the brain (p<0.02 and p<0.05, respectively), but not in plasma (p>0.6 and p>0.7, respectively), tested at 30 min after 30 mg/kg subcutaneous codeine, and (c) lower morphine formation from codeine ex vivo by brain membranes (p<0.04), but not by liver microsomes (p>0.9). Analgesia trended toward a correlation with brain morphine concentrations (p=0.07) and correlated with brain morphine to codeine ratios (p<0.005), but not with plasma morphine concentrations (p>0.8) or plasma morphine to codeine ratios (p>0.8). Our findings suggest that brain CYP2D affects brain morphine levels after peripheral codeine administration, and may thereby alter codeine's therapeutic efficacy, side-effect profile and abuse liability. Brain CYPs are highly variable due to genetics, environmental factors and age, and may therefore contribute to interindividual variation in the response to centrally acting drugs. PMID:23623752

  16. Altered response to neuroendocrine challenge linked to indices of the metabolic syndrome in healthy adults.

    PubMed

    Tyrka, A R; Walters, O C; Price, L H; Anderson, G M; Carpenter, L L

    2012-06-01

    Metabolic syndrome (MetS) is characterized by central obesity, hypertension, insulin resistance, and hypercholesterolemia. Hypothalamic-pituitary-adrenal (HPA) axis activity is frequently abnormal in MetS, and excessive cortisol exposure may be implicated in metabolic derangements. We investigated the hypothesis that cortisol and adrenocorticotropic hormone (ACTH) responses to a standardized neuroendocrine challenge test would be associated with indices of MetS in a community sample of healthy adults. Healthy adults, 125 men and 170 women, without significant medical problems or chronic medications were recruited from the community. Participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, and anthropometric measurements, blood pressure, glycosylated hemoglobin (HbA1c), and cholesterol were measured. Participants reported on their history of early life stress and recent stress, as well as mood and anxiety symptoms. Cortisol and ACTH responses to the Dex/CRH test were negatively associated with measures of central adiposity (p<0.001) and blood pressure (p<0.01), and positively associated with HDL cholesterol (p<0.01). These findings remained significant after controlling for body mass index (BMI). Measures of stress and anxiety and depressive symptoms were negatively correlated with cortisol and ACTH responses in the Dex/CRH test but were not related to MetS indices. That altered HPA axis function is linked to MetS components even in a healthy community sample suggests that these processes may be involved in the pathogenesis of MetS. Identification of premorbid risk processes might allow for detection and intervention prior to the development of disease. PMID:22549400

  17. Androgen Deficiency Exacerbates High-Fat Diet-Induced Metabolic Alterations in Male Mice.

    PubMed

    Dubois, Vanessa; Laurent, Michaël R; Jardi, Ferran; Antonio, Leen; Lemaire, Katleen; Goyvaerts, Lotte; Deldicque, Louise; Carmeliet, Geert; Decallonne, Brigitte; Vanderschueren, Dirk; Claessens, Frank

    2016-02-01

    Androgen deficiency is associated with obesity, metabolic syndrome, and type 2 diabetes mellitus in men, but the mechanisms behind these associations remain unclear. In this study, we investigated the combined effects of androgen deficiency and high-fat diet (HFD) on body composition and glucose homeostasis in C57BL/6J male mice. Two models of androgen deficiency were used: orchidectomy (ORX) and androgen receptor knockout mice. Both models displayed higher adiposity and serum leptin levels upon HFD, whereas no differences were seen on a regular diet. Fat accumulation in HFD ORX animals was accompanied by increased sedentary behavior and occurred in spite of reduced food intake. HFD ORX mice showed white adipocyte hypertrophy, correlated with decreased mitochondrial content but not function as well as increased lipogenesis and decreased lipolysis suggested by the up-regulation of fatty acid synthase and the down-regulation of hormone-sensitive lipase. Both ORX and androgen receptor knockout exacerbated HFD-induced glucose intolerance by impairing insulin action in liver and skeletal muscle, as evidenced by the increased triglyceride and decreased glycogen content in these tissues. In addition, serum IL-1β levels were elevated, and pancreatic insulin secretion was impaired after ORX. Testosterone but not dihydrotestosterone supplementation restored the castration effects on body composition and glucose homeostasis. We conclude that sex steroid deficiency in combination with HFD exacerbates adiposity, insulin resistance, and β-cell failure in 2 preclinical male mouse models. Our findings stress the importance of a healthy diet in a clinical context of androgen deficiency and may have implications for the prevention of metabolic alterations in hypogonadal men. PMID:26562264

  18. Interaction of Metabolic Stress with Chronic Mild Stress in Altering Brain Cytokines and Sucrose Preference

    PubMed Central

    Remus, Jennifer L.; Stewart, Luke T.; Camp, Robert M.; Novak, Colleen M.; Johnson, John D.

    2015-01-01

    There is growing evidence that metabolic stressors increase an organism’s risk of depression. Chronic mild stress is a popular animal model of depression and several serendipitous findings have suggested that food deprivation prior to sucrose testing in this model is necessary to observe anhedonic behaviors. Here, we directly tested this hypothesis by exposing animals to chronic mild stress and used an overnight two bottle sucrose test (food ad libitum) on day 5 and 10, then food and water deprive animals overnight and tested their sucrose consumption and preference in a 1h sucrose test the following morning. Approximately 65% of stressed animals consumed sucrose and showed a sucrose preference similar to non-stressed controls in an overnight sucrose test, while 35% showed a decrease in sucrose intake and preference. Following overnight food and water deprivation the previously ‘resilient’ animals showed a significant decrease in sucrose preference and greatly reduced sucrose intake. In addition, we evaluated whether the onset of anhedonia following food and water deprivation corresponds to alterations in corticosterone, epinephrine, circulating glucose, or interleukin-1 beta expression in limbic brain areas. While all stressed animals showed adrenal hypertrophy and elevated circulating epinephrine, only stressed animals that were food deprived were hypoglycemic compared to food deprived controls. Additionally, food and water deprivation significantly increased hippocampus IL-1β while food and water deprivation only increased hypothalamus IL-1β in stress susceptible animals. These data demonstrate that metabolic stress of food and water deprivation interacts with chronic stressor exposure to induce physiological and anhedonic responses. PMID:25914924

  19. Altered adipose tissue metabolism in offspring of dietary obese rat dams.

    PubMed

    Benkalfat, Nassira Batoul; Merzouk, Hafida; Bouanane, Samira; Merzouk, Sid-Ahmed; Bellenger, Jérôme; Gresti, Joseph; Tessier, Christian; Narce, Michel

    2011-07-01

    To investigate further the mechanisms of developmental programming, we analysed the effects of maternal overnutrition and of postnatal high-fat feeding on adipose tissue metabolism in the offspring. Postnatal changes in serum adiponectin, leptin and TAG [triacylglycerol (triglyceride)] levels, adipose tissue TAGs, fatty acids and enzyme activities were determined in offspring of cafeteria-diet-fed dams during gestation and lactation, weaned on to standard chow or on to cafeteria diet. Obese rats showed higher adiposity (+35% to 85%) as well as a significant increase in serum glucose, insulin, leptin, adiponectin and TAG levels (P<0.01) and adipose tissue LPL (lipoprotein lipase) and GPDH (glycerol-3-phosphate dehydrogenase) activities (P<0.01), compared with control pups at weaning (day 21) and at adulthood (day 90). Adipose HSL (hormone-sensitive lipase) activity was increased only at day 90 (P<0.05), and FAS (fatty acid synthase) activity remained unchanged. The proportions of SFAs (saturated fatty acids) and MUFAs (mono-unsaturated fatty acids) and the Δ(9)-desaturation index were significantly increased (P<0.05), whereas PUFAs (polyunsaturated fatty acids) were decreased (P<0.01) in serum and adipose TAGs of obese pups compared with controls. The cafeteria diet at weaning induced more severe abnormalities in obese rats. In conclusion, maternal overnutrition induced permanent changes in adipose tissue metabolism of the offspring. These pre-existing alterations in offspring were worsened under a high-fat diet from weaning to adulthood. Consequently, adipose adipokines and enzymes could provide a potential therapeutic target, and new investigations in this field could constitute strategies to improve the impact of early-life overnutrition. PMID:21288203

  20. Ocean warming alters cellular metabolism and induces mortality in fish early life stages: A proteomic approach.

    PubMed

    Madeira, D; Araújo, J E; Vitorino, R; Capelo, J L; Vinagre, C; Diniz, M S

    2016-07-01

    Climate change has pervasive effects on marine ecosystems, altering biodiversity patterns, abundance and distribution of species, biological interactions, phenology, and organisms' physiology, performance and fitness. Fish early life stages have narrow thermal windows and are thus more vulnerable to further changes in water temperature. The aim of this study was to address the sensitivity and underlying molecular changes of larvae of a key fisheries species, the sea bream Sparus aurata, towards ocean warming. Larvae were exposed to three temperatures: 18°C (control), 24°C (warm) and 30°C (heat wave) for seven days. At the end of the assay, i) survival curves were plotted for each temperature treatment and ii) entire larvae were collected for proteomic analysis via 2D gel electrophoresis, image analysis and mass spectrometry. Survival decreased with increasing temperature, with no larvae surviving at 30°C. Therefore, proteomic analysis was only carried out for 18°C and 24°C. Larvae up-regulated protein folding and degradation, cytoskeletal re-organization, transcriptional regulation and the growth hormone while mostly down-regulating cargo transporting and porphyrin metabolism upon exposure to heat stress. No changes were detected in proteins related to energetic metabolism suggesting that larval fish may not have the energetic plasticity needed to sustain cellular protection in the long-term. These results indicate that despite proteome modulation, S. aurata larvae do not seem able to fully acclimate to higher temperatures as shown by the low survival rates. Consequently, elevated temperatures seem to have bottleneck effects during fish early life stages, and future ocean warming can potentially compromise recruitment's success of key fisheries species. PMID:27062348

  1. Plant polyphenols alter a pathway of energy metabolism by inhibiting fecal Bacteroidetes and Firmicutes in vitro.

    PubMed

    Xue, Bin; Xie, Jinli; Huang, Jiachen; Chen, Long; Gao, Lijuan; Ou, Shiyi; Wang, Yong; Peng, Xichun

    2016-03-01

    The function of plant polyphenols in controlling body weight has been in focus for a long time. The aim of this study was to investigate the effect of plant polyphenols on fecal microbiota utilizing oligosaccharides. Three plant polyphenols, quercetin, catechin and puerarin, were added into liquid media for fermenting for 24 h. The pH values, OD600 of the cultures and the content of carbohydrates at 0, 6, 10, 14, 18 and 24 h were determined. The abundance of Bacteroidetes and Firmicutes in each culture was quantified with qPCR after 10 h of fermentation, and the bacterial composition was analyzed using the software Quantitative Insights Into Microbial Ecology. The results revealed that all three plant polyphenols could significantly inhibit the growth of Bacteroidetes (P < 0.01) and Firmicutes (P < 0.01) while at the same time down-regulate the ratio of Bacteroidetes to Firmicutes (P < 0.01). But the fecal bacteria could maintain the ability to hydrolyze fructo-oligosaccharide (FOS) in vitro. Among the tested polyphenols, catechin presented the most intense inhibitory activity towards the growth of Bacteroidetes and Firmicutes, and quercetin was the second. Only the samples with catechin had a significantly lower energy metabolism (P < 0.05). In conclusion, plant polyphenols can change the pathway of degrading FOS or even energy metabolism in vivo by altering gut microbiota composition. It may be one of the mechanisms in which plant polyphenols can lead to body weight loss. It's the first report to study in vitro gastrointestinal microbiota fermenting dietary fibers under the intervention of plant polyphenols. PMID:26882962

  2. Altered mineral metabolism as a mechanism underlying fetal alcohol syndrome in the rat

    SciTech Connect

    Zidenberg-Cherr, S.; Hurley, L.S.; Keen, C.L.

    1986-03-05

    The authors have observed that consumption of EtOH by dams fed diets low in Zn can result in small fetuses and a high incidence of fetal abnormalities. To test the hypothesis that EtOH alters maternal and fetal mineral metabolism, virgin female rats were fed liquid diets containing Zn at 2 ..mu..g/ml (low;LZn) 30 ..mu..g/ml (adequate;AZn), or 300 ..mu..g/ml (supplemented;SZn); EtOH contributed 0% kcals or 36% of kcals (EtOH). After 4 weeks females were bred and fed the same diets. Rats were killed on d21 of gestation; maternal and fetal tissues were collected. EtOH and fed AZn dams had plasma Zn levels which were 10% lower than their controls. Plasma Zn was similar between LZn and LZnEtOH dams; levels were 80% lower than in AZn dams. Plasma Cu was higher in EtOH fed dams than their controls; dams fed the SZn diets had low plasma Cu levels compared to all other groups. Fetal Zn increased with dietary Zn; levels were affected by EtOH only in the SZn group as levels were lower than their controls. Fetal Cu levels were not consistently affected by EtOH; levels were lower in the SZn groups than all other groups. Fetal Fe levels were higher in EtOH groups than their controls. These results show that EtOH affects fetal mineral metabolism supporting the hypothesis that this may be a mechanism underlying FAS. While induced Zn deficiency may be one component of this disorder it is evident that excess Zn supplementation may also be deleterious to the conceptus.

  3. Resistance to chemotherapy is associated with altered glucose metabolism in acute myeloid leukemia

    PubMed Central

    SONG, KUI; LI, MIN; XU, XIAOJUN; XUAN, LI; HUANG, GUINIAN; LIU, QIFA

    2016-01-01

    Altered glucose metabolism has been described as a cause of chemoresistance in multiple tumor types. The present study aimed to identify the expression profile of glucose metabolism in drug-resistant acute myeloid leukemia (AML) cells and provide potential strategies for the treatment of drug-resistant AML. Bone marrow and serum samples were obtained from patients with AML that were newly diagnosed or had relapsed. The messenger RNA expression of hypoxia inducible factor (HIF)-1α, glucose transporter (GLUT)1, and hexokinase-II was measured by quantitative polymerase chain reaction. The levels of LDH and β subunit of human F1-F0 adenosine triphosphate synthase (β-F1-ATPase) were detected by enzyme-linked immunosorbent and western blot assays. The HL-60 and HL-60/ADR cell lines were used to evaluate glycolytic activity and effect of glycolysis inhibition on cellular proliferation and apoptosis. Drug-resistant HL-60/ADR cells exhibited a significantly increased level of glycolysis compared with the drug-sensitive HL-60 cell line. The expression of HIF-1α, hexokinase-II, GLUT1 and LDH were increased in AML patients with no remission (NR), compared to healthy control individuals and patients with complete remission (CR) and partial remission. The expression of β-F1-ATPase in patients with NR was decreased compared with the expression in the CR group. Treatment of HL-60/ADR cells with 2-deoxy-D-glucose or 3-bromopyruvate increased in vitro sensitivity to Adriamycin (ADR), while treatment of HL-60 cells did not affect drug cytotoxicity. Subsequent to treatment for 24 h, apoptosis in these two cell lines showed no significant difference. However, glycolytic inhibitors in combination with ADR increased cellular necrosis. These findings indicate that increased glycolysis and low efficiency of oxidative phosphorylation may contribute to drug resistance. Targeting glycolysis is a viable strategy for modulating chemoresistance in AML. PMID:27347147

  4. Long-acting insulins alter milk composition and metabolism of lactating dairy cows.

    PubMed

    Winkelman, L A; Overton, T R

    2013-01-01

    administered long-acting insulins. Western blot analysis of mammary tissue collected by biopsy indicated that the ratios of phosphorylated protein kinase b (Akt) to total Akt and phosphorylated ribosomal protein S6 (rpS6) to total rpS6 were not affected by long-acting insulins. Modestly elevating insulin activity in lactating dairy cows using long-acting insulins altered milk composition and metabolism. Future research should explore mechanisms by which either insulin concentrations or insulin signaling pathways in the mammary gland can be altered to enhance milk fat and protein production. PMID:24119807

  5. Metabolic and histopathological alterations in the marine bivalve Mytilus galloprovincialis induced by chronic exposure to acrylamide.

    PubMed

    Larguinho, Miguel; Cordeiro, Ana; Diniz, Mário S; Costa, Pedro M; Baptista, Pedro V

    2014-11-01

    Although the neurotoxic and genotoxic potential of acrylamide has been established in freshwater fish, the full breadth of the toxicological consequences induced by this xenobiotic has not yet been disclosed, particularly in aquatic invertebrates. To assess the effects of acrylamide on a bivalve model, the Mediterranean mussel (Mytilus galloprovincialis), two different setups were accomplished: 1) acute exposure to several concentrations of waterborne acrylamide to determine lethality thresholds of the substance and 2) chronic exposure to more reduced acrylamide concentrations to survey phases I and II metabolic endpoints and to perform a whole-body screening for histopathological alterations. Acute toxicity was low (LC50≈400mg/L). However, mussels were responsive to prolonged exposure to chronic concentrations of waterborne acrylamide (1-10mg/L), yielding a significant increase in lipid peroxidation plus EROD and GST activities. Still, total anti-oxidant capacity was not exceeded. In addition, no neurotoxic effects could be determined through acetylcholine esterase (AChE) activity. The findings suggest aryl-hydrocarbon receptor (Ahr)-dependent responses in mussels exposed to acrylamide, although reduced comparatively to vertebrates. No significant histological damage was found in digestive gland or gills but female gonads endured severe necrosis and oocyte atresia. Altogether, the results indicate that acrylamide may induce gonadotoxicity in mussels, although the subject should benefit from further research. Altogether, the findings suggest that the risk of acrylamide to aquatic animals, especially molluscs, may be underestimated. PMID:25262075

  6. Alteration of heme metabolism in a cellular model of Diamond-Blackfan anemia.

    PubMed

    Mercurio, Sonia; Aspesi, Anna; Silengo, Lorenzo; Altruda, Fiorella; Dianzani, Irma; Chiabrando, Deborah

    2016-04-01

    Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia often associated with skeletal malformations. Mutations in ribosomal protein coding genes, mainly in RPS19, account for the majority of DBA cases. The molecular mechanisms underlying DBA pathogenesis are still not completely understood. Alternative spliced isoforms of FLVCR1 (feline leukemia virus subgroup C receptor 1) transcript coding for non-functional proteins have been reported in some DBA patients. Consistently, a phenotype very close to DBA has been described in animal models of FLVCR1 deficiency. FLVCR1 gene codes for two proteins: the plasma membrane heme exporter FLVCR1a and the mitochondrial heme exporter FLVCR1b. The coordinated expression of both FLVCR1 isoforms regulates an intracellular heme pool, necessary for proper expansion and differentiation of erythroid precursors. Here, we investigate the role of FLVCR1 isoforms in a cellular model of DBA. RPS19-downregulated TF1 cells show reduced FLVCR1a and FLVCR1b mRNA levels associated with heme overload. The downregulation of FLVCR1 isoforms affects cell cycle progression and apoptosis in differentiating K562 cells, a phenotype similar to DBA. Taken together, these data suggest that alteration of heme metabolism could play a role in the pathogenesis of DBA. PMID:26058344

  7. Alterations in glucose and protein metabolism in animals subjected to simulated microgravity

    NASA Astrophysics Data System (ADS)

    Mondon, C. E.; Rodnick, K. J.; Dolkas, C. B.; Azhar, S.; Reaven, G. M.

    1992-09-01

    Reduction of physical activity due to disease or environmental restraints, such as total bed rest or exposure to spaceflight, leads to atrophy of skeletal muscle and is frequently accompanied by alterations in food intake and the concentration of metabolic regulatory hormones such as insulin. Hindlimb suspension of laboratory rats, as a model for microgravity, also shows marked atrophy of gravity dependent muscles along with a reduced gain in body weight. Suspended rats exhibit enhanced sensitivity to insulin-induced glucose uptake when compared with normal control rats and resistance to insulin action when compared with control rats matched similarly for reduced body weight gain. These changes are accompanied by decreased insulin binding and tyrosine kinase activity in soleus but not plantaris muscle, unchanged glucose uptake by perfused hindlimb and decreased sensitivity but not responsiveness to insulin-induced suppression of net proteolysis in hindlimb skeletal muscle. These findings suggest that loss of insulin sensitivity during muscle atrophy is associated with decreased insulin binding and tyrosine kinase activity in atrophied soleus muscle along with decreased sensitivity to the effects of insulin on suppressing net protein breakdown but not on enhancing glucose uptake by perfused hindlimb.

  8. Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations.

    PubMed

    Rolfs, Frank; Huber, Marcel; Kuehne, Andreas; Kramer, Stefan; Haertel, Eric; Muzumdar, Sukalp; Wagner, Johanna; Tanner, Yasmine; Böhm, Friederike; Smola, Sigrun; Zamboni, Nicola; Levesque, Mitchell P; Dummer, Reinhard; Beer, Hans-Dietmar; Hohl, Daniel; Werner, Sabine; Schäfer, Matthias

    2015-11-15

    Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis. PMID:26530903

  9. (-)-Hydroxycitric Acid Nourishes Protein Synthesis via Altering Metabolic Directions of Amino Acids in Male Rats.

    PubMed

    Han, Ningning; Li, Longlong; Peng, Mengling; Ma, Haitian

    2016-08-01

    (-)-Hydroxycitric acid (HCA), a major active ingredient of Garcinia Cambogia extracts, had shown to suppress body weight gain and fat accumulation in animals and humans. While, the underlying mechanism of (-)-HCA has not fully understood. Thus, this study was aimed to investigate the effects of long-term supplement with (-)-HCA on body weight gain and variances of amino acid content in rats. Results showed that (-)-HCA treatment reduced body weight gain and increased feed conversion ratio in rats. The content of hepatic glycogen, muscle glycogen, and serum T4 , T3 , insulin, and Leptin were increased in (-)-HCA treatment groups. Protein content in liver and muscle were significantly increased in (-)-HCA treatment groups. Amino acid profile analysis indicated that most of amino acid contents in serum and liver, especially aromatic amino acid and branched amino acid, were higher in (-)-HCA treatment groups. However, most of the amino acid contents in muscle, especially aromatic amino acid and branched amino acid, were reduced in (-)-HCA treatment groups. These results indicated that (-)-HCA treatment could reduce body weight gain through promoting energy expenditure via regulation of thyroid hormone levels. In addition, (-)-HCA treatment could promote protein synthesis by altering the metabolic directions of amino acids. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27145492

  10. Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy

    PubMed Central

    Rodríguez-Cruz, Maricela; Sanchez, Raúl; Escobar, Rosa E.; Cruz-Guzmán, Oriana del Rocío; López-Alarcón, Mardia; Bernabe García, Mariela; Coral-Vázquez, Ramón; Matute, Guadalupe; Velázquez Wong, Ana Claudia

    2015-01-01

    Aim. Our aim was (1) to determine the frequency of insulin resistance (IR) in patients with Duchenne/Becker muscular dystrophy (DMD/BMD), (2) to identify deleted exons of DMD gene associated with obesity and IR, and (3) to explore some likely molecular mechanisms leading to IR. Materials and Methods. In 66 patients with DMD/BMD without corticosteroids treatment, IR, obesity, and body fat mass were evaluated. Molecules involved in glucose metabolism were analyzed in muscle biopsies. Results show that 18.3%, 22.7%, and 68% were underweight, overweight, or obese, and with high adiposity, respectively; 48.5% and 36.4% presented hyperinsulinemia and IR, respectively. Underweight patients (27.3%) exhibited hyperinsulinemia and IR. Carriers of deletions in exons 45 (OR = 9.32; 95% CI = 1.16–74.69) and 50 (OR = 8.73; 95% CI = 1.17–65.10) from DMD gene presented higher risk for IR than noncarriers. We observed a greater staining of cytoplasmic aggregates for GLUT4 in muscle biopsies than healthy muscle tissue. Conclusion. Obesity, hyperinsulinemia, and IR were observed in DMD/BMD patients and are independent of corticosteroids treatment. Carriers of deletion in exons 45 or 50 from DMD gene are at risk for developing IR. It is suggested that alteration in GLUT4 in muscle fibers from DMD patients could be involved in IR. PMID:26089900