Circulating Levels of Uric Acid and Risk for Metabolic Syndrome.

PubMed

Rubio-Guerra, Alberto F; Morales-López, Herlinda; Garro-Almendaro, Ana K; Vargas-Ayala, German; Durán-Salgado, Montserrat B; Huerta-Ramírez, Saul; Lozano-Nuevo, Jose J

2017-01-01

Hyperuricemia leads to insulin resistance, whereas insulin resistance decreases renal excretion of uric acid, both mechanisms link elevated serum uric acid with metabolic syndrome. The aim of this study is to evaluate the probability for the development of metabolic syndrome in low-income young adults with hyperuricaemia. We evaluated 103 patients less than 40 years of age, from a low-income population, and without history of cardiovascular disease, in all of them the presence of metabolic syndrome was assessed in accordance with the International Diabetes Federation criteria. In all patients, fasting serum uric acid levels were measured; hyperuricaemia was defined as serum uric acid values 6.5 mg/dl in men and 5.1 mg/dl in women. Statistical analysis was performed with odds ratio. 83 of our patients (80.5%) suffered metabolic syndrome, the odds ratio for the presence of metabolic syndrome in patients with hyperuricaemia was 5.1 (p=0.002, I.C 1.8- 14.5). When patients were evaluated by gender a significantly association between hyperuricaemia and metabolic syndrome was found in women (odds ratio 3.6, p=0.048, C.I. 1.0-12.9), and men (odds ratio 10.2, p= 0.015, IC 1.5-13.2). When uric acid was correlated with the components of metabolic syndrome, we only found a positive correlation with waist circumference (r=0.483). Our results showed a significant association between hyperuricemia and metabolic syndrome in low-income young adults in Mexico. DR is associated with estimated risk of CVD in type 2 diabetic patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Relation between uric acid and metabolic syndrome in subjects with cardiometabolic risk

PubMed Central

da Silva, Hellen Abreu; Carraro, Júlia Cristina Cardoso; Bressan, Josefina; Hermsdorff, Helen Hermana Miranda

2015-01-01

Objective To identify possible relations between serum uric acid levels and metabolic syndrome and its components in a population with cardiometabolic risk. Methods This cross-sectional study included 80 subjects (46 women), with mean age of 48±16 years, seen at the Cardiovascular Health Program. Results The prevalence of hyperuricemia and metabolic syndrome was 6.3% and 47.1%, respectively. Uric acid level was significantly higher in individuals with metabolic syndrome (5.1±1.6mg/dL), as compared to those with no syndrome or with pre-syndrome (3.9±1.2 and 4.1±1.3mg/dL, respectively; p<0.05). The uric acid levels were significantly higher in men presenting abdominal obesity, and among women with abdominal obesity, lower HDL-c levels and higher blood pressure (p<0.05). Conclusion Uric acid concentrations were positively related to the occurrence of metabolic syndrome and its components, and there were differences between genders. Our results indicate serum uric acid as a potential biomarker for patients with cardiometabolic risk. PMID:26018145

Metabolomics Reveals that Dietary Ferulic Acid and Quercetin Modulate Metabolic Homeostasis in Rats.

PubMed

Zhang, Limin; Dong, Manyuan; Guangyong Xu; Yuan Tian; Tang, Huiru; Wang, Yulan

2018-02-21

Phenolic compounds ingestion has been shown to have potential preventive and therapeutic effects against various metabolic diseases such as obesity and cancer. To provide a better understanding of these potential benefit effects, we investigated the metabolic alterations in urine and feces of rat ingested ferulic acid (FA) and quercetin (Qu) using NMR-based metabolomics approach. Our results suggested that dietary FA and/or Qu significantly decreased short chain fatty acids and elevated oligosaccharides in the feces, implying that dietary FA and Qu may modulate gut microbial community with inhibition of bacterial fermentation of dietary fibers. We also found that dietary FA and/or Qu regulated several host metabolic pathways including TCA cycle and energy metabolism, bile acid, amino acid, and nucleic acid metabolism. These biological effects suggest that FA and Qu display outstanding bioavailability and bioactivity and could be used for treatment of some metabolic syndromes, such as inflammatory bowel diseases and obesity.

Fatty acid metabolism in breast cancer subtypes

PubMed Central

Monaco, Marie E.

2017-01-01

Dysregulation of fatty acid metabolism is recognized as a component of malignant transformation in many different cancers, including breast; yet the potential for targeting this pathway for prevention and/or treatment of cancer remains unrealized. Evidence indicates that proteins involved in both synthesis and oxidation of fatty acids play a pivotal role in the proliferation, migration and invasion of breast cancer cells. The following essay summarizes data implicating specific fatty acid metabolic enzymes in the genesis and progression of breast cancer, and further categorizes the relevance of specific metabolic pathways to individual intrinsic molecular subtypes of breast cancer. Based on mRNA expression data, the less aggressive luminal subtypes appear to rely on a balance between de novo fatty acid synthesis and oxidation as sources for both biomass and energy requirements, while basal-like, receptor negative subtypes overexpress genes involved in the utilization of exogenous fatty acids. With these differences in mind, treatments may need to be tailored to individual subtypes. PMID:28412757

STUDIES ON ORGANIC ACID METABOLISM,

DTIC Science & Technology

Lipoic acid metabolism: The acetyl and succinyl thio esters of civinyl dimercapto were prepared by chemical and enzymatic means. The oxidation...reduction reactions of the disulfide-dimercapto groups in pyrimidine nucleotide-linked reactions were explored in the initial lipoic acid assay organiam...disulfide couple. The studies appeared to indicate a bound form of lipoic acid to be the coenzyme, and suggested that an amide or possibly another

Regulation of uric acid metabolism and excretion.

PubMed

Maiuolo, Jessica; Oppedisano, Francesca; Gratteri, Santo; Muscoli, Carolina; Mollace, Vincenzo

2016-06-15

Purines perform many important functions in the cell, being the formation of the monomeric precursors of nucleic acids DNA and RNA the most relevant one. Purines which also contribute to modulate energy metabolism and signal transduction, are structural components of some coenzymes and have been shown to play important roles in the physiology of platelets, muscles and neurotransmission. All cells require a balanced quantity of purines for growth, proliferation and survival. Under physiological conditions the enzymes involved in the purine metabolism maintain in the cell a balanced ratio between their synthesis and degradation. In humans the final compound of purines catabolism is uric acid. All other mammals possess the enzyme uricase that converts uric acid to allantoin that is easily eliminated through urine. Overproduction of uric acid, generated from the metabolism of purines, has been proven to play emerging roles in human disease. In fact the increase of serum uric acid is inversely associated with disease severity and especially with cardiovascular disease states. This review describes the enzymatic pathways involved in the degradation of purines, getting into their structure and biochemistry until the uric acid formation. Copyright © 2015. Published by Elsevier Ireland Ltd.

Regulation of renal amino acid transporters during metabolic acidosis.

PubMed

Moret, Caroline; Dave, Mital H; Schulz, Nicole; Jiang, Jean X; Verrey, Francois; Wagner, Carsten A

2007-02-01

The kidney plays a major role in acid-base homeostasis by adapting the excretion of acid equivalents to dietary intake and metabolism. Urinary acid excretion is mediated by the secretion of protons and titratable acids, particularly ammonia. NH(3) is synthesized in proximal tubule cells from glutamine taken up via specific amino acid transporters. We tested whether kidney amino acid transporters are regulated in mice in which metabolic acidosis was induced with NH(4)Cl. Blood gas and urine analysis confirmed metabolic acidosis. Real-time RT-PCR was performed to quantify the mRNAs of 16 amino acid transporters. The mRNA of phosphoenolpyruvate carboxykinase (PEPCK) was quantified as positive control for the regulation and that of GAPDH, as internal standard. In acidosis, the mRNA of kidney system N amino acid transporter SNAT3 (SLC38A3/SN1) showed a strong induction similar to that of PEPCK, whereas all other tested mRNAs encoding glutamine or glutamate transporters were unchanged or reduced in abundance. At the protein level, Western blotting and immunohistochemistry demonstrated an increased abundance of SNAT3 and reduced expression of the basolateral cationic amino acid/neutral amino acid exchanger subunit y(+)-LAT1 (SLC7A7). SNAT3 was localized to the basolateral membrane of the late proximal tubule S3 segment in control animals, whereas its expression was extended to the earlier S2 segment of the proximal tubule during acidosis. Our results suggest that the selective regulation of SNAT3 and y(+)LAT1 expression may serve a major role in the renal adaptation to acid secretion and thus for systemic acid-base balance.

Systems metabolic engineering design: Fatty acid production as an emerging case study

PubMed Central

Tee, Ting Wei; Chowdhury, Anupam; Maranas, Costas D; Shanks, Jacqueline V

2014-01-01

Increasing demand for petroleum has stimulated industry to develop sustainable production of chemicals and biofuels using microbial cell factories. Fatty acids of chain lengths from C6 to C16 are propitious intermediates for the catalytic synthesis of industrial chemicals and diesel-like biofuels. The abundance of genetic information available for Escherichia coli and specifically, fatty acid metabolism in E. coli, supports this bacterium as a promising host for engineering a biocatalyst for the microbial production of fatty acids. Recent successes rooted in different features of systems metabolic engineering in the strain design of high-yielding medium chain fatty acid producing E. coli strains provide an emerging case study of design methods for effective strain design. Classical metabolic engineering and synthetic biology approaches enabled different and distinct design paths towards a high-yielding strain. Here we highlight a rational strain design process in systems biology, an integrated computational and experimental approach for carboxylic acid production, as an alternative method. Additional challenges inherent in achieving an optimal strain for commercialization of medium chain-length fatty acids will likely require a collection of strategies from systems metabolic engineering. Not only will the continued advancement in systems metabolic engineering result in these highly productive strains more quickly, this knowledge will extend more rapidly the carboxylic acid platform to the microbial production of carboxylic acids with alternate chain-lengths and functionalities. PMID:24481660

Towards systems metabolic engineering of microorganisms for amino acid production.

PubMed

Park, Jin Hwan; Lee, Sang Yup

2008-10-01

Microorganisms capable of efficient production of amino acids have traditionally been developed by random mutation and selection method, which might cause unwanted physiological changes in cellular metabolism. Rational genome-wide metabolic engineering based on systems and synthetic biology tools, which is termed 'systems metabolic engineering', is rising as an alternative to overcome these problems. Recently, several amino acid producers have been successfully developed by systems metabolic engineering, where the metabolic engineering procedures were performed within a systems biology framework, and entire metabolic networks, including complex regulatory circuits, were engineered in an integrated manner. Here we review the current status of systems metabolic engineering successfully applied for developing amino acid producing strains and discuss future prospects.

Phylogenomic reconstruction of archaeal fatty acid metabolism

PubMed Central

Dibrova, Daria V.; Galperin, Michael Y.; Mulkidjanian, Armen Y.

2014-01-01

While certain archaea appear to synthesize and/or metabolize fatty acids, the respective pathways still remain obscure. By analyzing the genomic distribution of the key lipid-related enzymes, we were able to identify the likely components of the archaeal pathway of fatty acid metabolism, namely, a combination of the enzymes of bacterial-type β-oxidation of fatty acids (acyl-CoA-dehydrogenase, enoyl-CoA hydratase, and 3-hydroxyacyl-CoA dehydrogenase) with paralogs of the archaeal acetyl-CoA C-acetyltransferase, an enzyme of the mevalonate biosynthesis pathway. These three β-oxidation enzymes working in the reverse direction could potentially catalyze biosynthesis of fatty acids, with paralogs of acetyl-CoA C-acetyltransferase performing addition of C2 fragments. The presence in archaea of the genes for energy-transducing membrane enzyme complexes, such as cytochrome bc complex, cytochrome c oxidase, and diverse rhodopsins, was found to correlate with the presence of the proposed system of fatty acid biosynthesis. We speculate that because these membrane complexes functionally depend on fatty acid chains, their genes could have been acquired via lateral gene transfer from bacteria only by those archaea that already possessed a system of fatty acid biosynthesis. The proposed pathway of archaeal fatty acid metabolism operates in extreme conditions and therefore might be of interest in the context of biofuel production and other industrial applications. PMID:24818264

Inhibition of Fatty Acid Metabolism Reduces Human Myeloma Cells Proliferation

PubMed Central

Tirado-Vélez, José Manuel; Joumady, Insaf; Sáez-Benito, Ana; Cózar-Castellano, Irene; Perdomo, Germán

2012-01-01

Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40–70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma. PMID:23029529

Dietary fatty acid metabolism in prediabetes.

PubMed

Noll, Christophe; Carpentier, André C

2017-02-01

Experimental evidences are strong for a role of long-chain saturated fatty acids in the development of insulin resistance and type 2 diabetes. Ectopic accretion of triglycerides in lean organs is a characteristic of prediabetes and type 2 diabetes and has been linked to end-organ complications. The contribution of disordered dietary fatty acid (DFA) metabolism to lean organ overexposure and lipotoxicity is still unclear, however. DFA metabolism is very complex and very difficult to study in vivo in humans. We have recently developed a novel imaging method using PET with oral administration of 14-R,S-F-fluoro-6-thia-heptadecanoic acid (FTHA) to quantify organ-specific DFA partitioning. Our studies thus far confirmed impaired storage of DFA per volume of fat mass in abdominal adipose tissues of individuals with prediabetes. They also highlighted the increased channeling of DFA toward the heart, associated with subclinical reduction in cardiac systolic and diastolic function in individuals with prediabetes. In the present review, we summarize previous work on DFA metabolism in healthy and prediabetic states and discuss these in the light of our novel findings using PET imaging of DFA metabolism. We herein provide an integrated view of abnormal organ-specific DFA partitioning in prediabetes in humans.

Recurrent high anion gap metabolic acidosis secondary to 5-oxoproline (pyroglutamic acid).

PubMed

Tailor, Prayus; Raman, Tuhina; Garganta, Cheryl L; Njalsson, Runa; Carlsson, Katarina; Ristoff, Ellinor; Carey, Hugh B

2005-07-01

High anion gap metabolic acidosis in adults is a severe metabolic disorder for which the primary organic acid usually is apparent by clinical history and standard laboratory testing. We report a case of recurrent high anion gap metabolic acidosis in a 48-year-old man who initially presented with anorexia and malaise. Physical examination was unrevealing. Arterial pH was 6.98, P co 2 was 5 mm Hg, and chemistry tests showed a bicarbonate level of 3 mEq/L (3 mmol/L), anion gap of 32 mEq/L (32 mmol/L), and a negative toxicology screen result, except for an acetaminophen (paracetamol) level of 7.5 mug/mL. Metabolic acidosis resolved with administration of intravenous fluids. Subsequently, he experienced 5 more episodes of high anion gap metabolic acidosis during an 8-month span. Methanol, ethylene glycol, acetone, ethanol, d -lactate, and hippuric acid screens were negative. Lactate levels were modestly elevated, and acetaminophen levels were elevated for 5 of 6 admissions. These episodes defied explanation until 3 urinary organic acid screens, obtained on separate admissions, showed striking elevations of 5-oxoproline levels. Inborn errors of metabolism in the gamma-glutamyl cycle causing recurrent 5-oxoprolinuria and high anion gap metabolic acidosis are rare, but well described in children. Recently, there have been several reports of apparent acquired 5-oxoprolinuria and high anion gap metabolic acidosis in adults in association with acetaminophen use. Acetaminophen may, in susceptible individuals, disrupt regulation of the gamma-glutamyl cycle and result in excessive 5-oxoproline production. Suspicion for 5-oxoproline-associated high anion gap metabolic acidosis should be entertained when the cause of high anion gap metabolic acidosis remains poorly defined, the anion gap cannot be explained reasonably by measured organic acids, and there is concomitant acetaminophen use.

Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice.

PubMed

Liu, Qian; Shao, Wentao; Zhang, Chunlan; Xu, Cheng; Wang, Qihan; Liu, Hui; Sun, Haidong; Jiang, Zhaoyan; Gu, Aihua

2017-07-01

Organochlorine pesticides (OCPs) can persistently accumulate in body and threaten human health. Bile acids and intestinal microbial metabolism have emerged as important signaling molecules in the host. However, knowledge on which intestinal microbiota and bile acids are modified by OCPs remains unclear. In this study, adult male C57BL/6 mice were exposed to p, p'-dichlorodiphenyldichloroethylene (p, p'-DDE) and β-hexachlorocyclohexane (β-HCH) for 8 weeks. The relative abundance and composition of various bacterial species were analyzed by 16S rRNA gene sequencing. Bile acid composition was analyzed by metabolomic analysis using UPLC-MS. The expression of genes involved in hepatic and enteric bile acids metabolism was measured by real-time PCR. Expression of genes in bile acids synthesis and transportation were measured in HepG2 cells incubated with p, p'-DDE and β-HCH. Our findings showed OCPs changed relative abundance and composition of intestinal microbiota, especially in enhanced Lactobacillus with bile salt hydrolase (BSH) activity. OCPs affected bile acid composition, enhanced hydrophobicity, decreased expression of genes on bile acid reabsorption in the terminal ileum and compensatory increased expression of genes on synthesis of bile acids in the liver. We demonstrated that chronic exposure of OCPs could impair intestinal microbiota; as a result, hepatic and enteric bile acid profiles and metabolism were influenced. The findings in this study draw our attention to the hazards of chronic OCPs exposure in modulating bile acid metabolism that might cause metabolic disorders and their potential to cause related diseases in human. Copyright © 2017 Elsevier Ltd. All rights reserved.

Systems metabolic engineering design: fatty acid production as an emerging case study.

PubMed

Tee, Ting Wei; Chowdhury, Anupam; Maranas, Costas D; Shanks, Jacqueline V

2014-05-01

Increasing demand for petroleum has stimulated industry to develop sustainable production of chemicals and biofuels using microbial cell factories. Fatty acids of chain lengths from C6 to C16 are propitious intermediates for the catalytic synthesis of industrial chemicals and diesel-like biofuels. The abundance of genetic information available for Escherichia coli and specifically, fatty acid metabolism in E. coli, supports this bacterium as a promising host for engineering a biocatalyst for the microbial production of fatty acids. Recent successes rooted in different features of systems metabolic engineering in the strain design of high-yielding medium chain fatty acid producing E. coli strains provide an emerging case study of design methods for effective strain design. Classical metabolic engineering and synthetic biology approaches enabled different and distinct design paths towards a high-yielding strain. Here we highlight a rational strain design process in systems biology, an integrated computational and experimental approach for carboxylic acid production, as an alternative method. Additional challenges inherent in achieving an optimal strain for commercialization of medium chain-length fatty acids will likely require a collection of strategies from systems metabolic engineering. Not only will the continued advancement in systems metabolic engineering result in these highly productive strains more quickly, this knowledge will extend more rapidly the carboxylic acid platform to the microbial production of carboxylic acids with alternate chain-lengths and functionalities. © 2014 Wiley Periodicals, Inc.

Primary Metabolism and Medium-Chain Fatty Acid Alterations Precede Long-Chain Fatty Acid Changes Impacting Neutral Lipid Metabolism in Response to an Anticancer Lysophosphatidylcholine Analogue in Yeast.

PubMed

Tambellini, Nicolas P; Zaremberg, Vanina; Krishnaiah, Saikumari; Turner, Raymond J; Weljie, Aalim M

2017-10-06

The nonmetabolizable lysophosphatidylcholine (LysoPC) analogue edelfosine is the prototype of a class of compounds being investigated for their potential as selective chemotherapeutic agents. Edelfosine targets membranes, disturbing cellular homeostasis. Is not clear at this point how membrane alterations are communicated between intracellular compartments leading to growth inhibition and eventual cell death. In the present study, a combined metabolomics/lipidomics approach for the unbiased identification of metabolic pathways altered in yeast treated with sublethal concentrations of the LysoPC analogue was employed. Mass spectrometry of polar metabolites, fatty acids, and lipidomic profiling was used to study the effects of edelfosine on yeast metabolism. Amino acid and sugar metabolism, the Krebs cycle, and fatty acid profiles were most disrupted, with polar metabolites and short-medium chain fatty acid changes preceding long and very long-chain fatty acid variations. Initial increases in metabolites such as trehalose, proline, and γ-amino butyric acid with a concomitant decrease in metabolites of the Krebs cycle, citrate and fumarate, are interpreted as a cellular attempt to offset oxidative stress in response to mitochondrial dysfunction induced by the treatment. Notably, alanine, inositol, and myristoleic acid showed a steady increase during the period analyzed (2, 4, and 6 h after treatment). Of importance was the finding that edelfosine induced significant alterations in neutral glycerolipid metabolism resulting in a significant increase in the signaling lipid diacylglycerol.

Combined metabolomic and correlation networks analyses reveal fumarase insufficiency altered amino acid metabolism.

PubMed

Hou, Entai; Li, Xian; Liu, Zerong; Zhang, Fuchang; Tian, Zhongmin

2018-04-01

Fumarase catalyzes the interconversion of fumarate and l-malate in the tricarboxylic acid cycle. Fumarase insufficiencies were associated with increased levels of fumarate, decreased levels of malate and exacerbated salt-induced hypertension. To gain insights into the metabolism profiles induced by fumarase insufficiency and identify key regulatory metabolites, we applied a GC-MS based metabolomics platform coupled with a network approach to analyze fumarase insufficient human umbilical vein endothelial cells (HUVEC) and negative controls. A total of 24 altered metabolites involved in seven metabolic pathways were identified as significantly altered, and enriched for the biological module of amino acids metabolism. In addition, Pearson correlation network analysis revealed that fumaric acid, l-malic acid, l-aspartic acid, glycine and l-glutamic acid were hub metabolites according to Pagerank based on their three centrality indices. Alanine aminotransferase and glutamate dehydrogenase activities increased significantly in fumarase deficiency HUVEC. These results confirmed that fumarase insufficiency altered amino acid metabolism. The combination of metabolomics and network methods would provide another perspective on expounding the molecular mechanism at metabolomics level. Copyright © 2017 John Wiley & Sons, Ltd.

Higher plant metabolism and energetics in hypogravity: Amino acid metabolism in higher plants

NASA Technical Reports Server (NTRS)

Mazelis, M.

1976-01-01

Laboratory's investigation into the amino acid metabolism of dwarf marigolds exposed to an environment of simulated hypogravity is summarized. Using both in vivo, and/or in vitro studies, the following effects of hypogravitational stress have been shown: (1) increased proline incorporation into cell wall protein, (2) inhibition of amino acid decarboxylation, (3) decrease in glutamic acid decarboxylase activity; and (4) decrease in the relative amount of a number of soluble amino acids present in deproteinized extracts of marigold leaves. It is concluded from these data there are several rapid, major alterations in amino acid metabolism associated with hypogravitational stress in marigolds. The mechanism(s) and generality of these effects with regard to other species is still unknown.

Uric Acid, Metabolic Syndrome and Atherosclerosis: The Chicken or the Egg, Which Comes First?

PubMed

De Pergola, Giovanni; Cortese, Francesca; Termine, Gaetano; Meliota, Giovanni; Carbonara, Rossella; Masiello, Michele; Cortese, Anna M; Silvestris, Francesco; Caccavo, Domenico; Ciccone, Marco Matteo

2018-01-01

A great debate in literature exists nowadays on the role of uric acid as a marker of cardiovascular and metabolic organ damage or a risk factor for cardiovascular and metabolic disease. The study aimed to determine the relationship among serum uric acid and metabolic syndrome and atherosclerosis, by means of carotid intima media-thickness, in a cohort of 811 otherwise healthy overweight/obese subjects, without overt atherosclerosis not using any kind of drug. Uric acid levels were positively related to male gender, waist circumference, BMI, systolic and diastolic pressure levels, fasting insulin, fasting glucose, HOMA-IR, triglycerides, total cholesterol, LDL cholesterol, the presence of metabolic syndrome and the number of the components of metabolic syndrome and negatively related to HDL cholesterol levels. No correlation was found between uric acid and carotid intima media thickness. At the multiple regression analysis, only waist circumference and triglycerides (positively) and HDL-cholesterol (negatively) maintained an independent association with uric acid as dependent variable, while age, female gender and uric acid showed a significant independent association with metabolic syndrome as dependent variable. Moreover, the analysis of the odd ratios showed that the risk of developing metabolic syndrome was consistent with uric acid levels ranging from 3 mg/dl to 8 mg/dl. The presence of metabolic syndrome does not seem to provide hyperuricemia. By contrast, higher serum uric acid level may predict the risk of metabolic syndrome. Moreover, our results suggest that uric acid cannot be considered a risk factor for early atherosclerosis, at least when assessed using carotid ultrasound. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Modulating the gut flora alters amino acid metabolism in neonatal pigs

USDA-ARS?s Scientific Manuscript database

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 ...

Body energy metabolism and oxidative stress in mice supplemented with conjugated linoleic acid (CLA) associated to oleic acid.

PubMed

Baraldi, Flavia; Dalalio, Felipe; Teodoro, Bruno; Prado, Ieda; Curti, Carlos; Alberici, Luciane

2014-10-01

Some fatty acids may play an important role in regulating metabolism through PPARs activation. Conjugated linoleic acid (CLA) has been shown to reduce body fat accumulation and increase body metabolism; this effect has been associated with up-regulation of mitochondrial uncoupling proteins (UCPs) and PPARalfa activation. Oleic acid has shown beneficial effects on health, decreasing oxidative stress and improving clinical conditions related to obesity. Therefore, in this work, we addressed the effects of a oleic plus CLA-supplemented murine diet on body metabolism, mitochondrial energetics and oxidative stress in the liver, as well as on other associated morphological and functional parameters in C57BL/6 mice. The diet was supplemented with 2% CLA mixture (cis-9, trans-10 and trans-10, cis-12 isomers; 45% of each isomer) and/or 0.7% olive oil on alternating days (60 days) by gavage. The results showed that diet supplementation with CLA increases body metabolism and reduces lipid accumulation in adipose tissues. Groups that received oleic acid (oleic and CLA oleic) showed decreased levels of total cholesterol and cholesterol non-HDL, and increased levels of HDL-cholesterol. Livers of mice fed a diet supplemented with CLA showed high levels UCP2 mRNA, and the isolated hepatic mitochondria showed indications of UCP activity and increased ROS generation. Oleic acid partially reversed the lower lipid accumulation increasing PPARgamma content, reversed the higher ROS generation by liver mitochondria and improved liver oxidative status. These results indicate a beneficial and secure dose of CLA and oleic acid for diet supplementation in mice, which increases body metabolism inducing UCP2 overexpression/activity in liver while preserving the redox state of the liver. Therefore, diet supplementation with CLA associated to oleic acid may be regarded as a potential strategy for controlling obesity and oxidative stress. Supported by FAPESP. Copyright © 2014. Published by

'Trophic' and 'source' amino acids in trophic estimation: a likely metabolic explanation.

PubMed

O'Connell, T C

2017-06-01

Amino acid nitrogen isotopic analysis is a relatively new method for estimating trophic position. It uses the isotopic difference between an individual's 'trophic' and 'source' amino acids to determine its trophic position. So far, there is no accepted explanation for the mechanism by which the isotopic signals in 'trophic' and 'source' amino acids arise. Yet without a metabolic understanding, the utility of nitrogen isotopic analyses as a method for probing trophic relations, at either bulk tissue or amino acid level, is limited. I draw on isotopic tracer studies of protein metabolism, together with a consideration of amino acid metabolic pathways, to suggest that the 'trophic'/'source' groupings have a fundamental metabolic origin, to do with the cycling of amino-nitrogen between amino acids. 'Trophic' amino acids are those whose amino-nitrogens are interchangeable, part of a metabolic amino-nitrogen pool, and 'source' amino acids are those whose amino-nitrogens are not interchangeable with the metabolic pool. Nitrogen isotopic values of 'trophic' amino acids will reflect an averaged isotopic signal of all such dietary amino acids, offset by the integrated effect of isotopic fractionation from nitrogen cycling, and modulated by metabolic and physiological effects. Isotopic values of 'source' amino acids will be more closely linked to those of equivalent dietary amino acids, but also modulated by metabolism and physiology. The complexity of nitrogen cycling suggests that a single identifiable value for 'trophic discrimination factors' is unlikely to exist. Greater consideration of physiology and metabolism should help in better understanding observed patterns in nitrogen isotopic values.

Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism.

PubMed

Porporato, Paolo E; Payen, Valéry L; Baselet, Bjorn; Sonveaux, Pierre

2016-04-01

Metabolic alterations are a hallmark of cancer controlling tumor progression and metastasis. Among the various metabolic phenotypes encountered in tumors, this review focuses on the contributions of mitochondria, lipid and amino acid metabolism to the metastatic process. Tumor cells require functional mitochondria to grow, proliferate and metastasize, but shifts in mitochondrial activities confer pro-metastatic traits encompassing increased production of mitochondrial reactive oxygen species (mtROS), enhanced resistance to apoptosis and the increased or de novo production of metabolic intermediates of the TCA cycle behaving as oncometabolites, including succinate, fumarate, and D-2-hydroxyglutarate that control energy production, biosynthesis and the redox state. Lipid metabolism and the metabolism of amino acids, such as glutamine, glutamate and proline are also currently emerging as focal control points of cancer metastasis.

Arachidonic Acid and Eicosapentaenoic Acid Metabolism in Juvenile Atlantic Salmon as Affected by Water Temperature.

PubMed

Norambuena, Fernando; Morais, Sofia; Emery, James A; Turchini, Giovanni M

2015-01-01

Salmons raised in aquaculture farms around the world are increasingly subjected to sub-optimal environmental conditions, such as high water temperatures during summer seasons. Aerobic scope increases and lipid metabolism changes are known plasticity responses of fish for a better acclimation to high water temperature. The present study aimed at investigating the effect of high water temperature on the regulation of fatty acid metabolism in juvenile Atlantic salmon fed different dietary ARA/EPA ratios (arachidonic acid, 20:4n-6/ eicosapentaenoic acid, 20:5n-3), with particular focus on apparent in vivo enzyme activities and gene expression of lipid metabolism pathways. Three experimental diets were formulated to be identical, except for the ratio EPA/ARA, and fed to triplicate groups of Atlantic salmon (Salmo salar) kept either at 10°C or 20°C. Results showed that fatty acid metabolic utilisation, and likely also their dietary requirements for optimal performance, can be affected by changes in their relative levels and by environmental temperature in Atlantic salmon. Thus, the increase in temperature, independently from dietary treatment, had a significant effect on the β-oxidation of a fatty acid including EPA, as observed by the apparent in vivo enzyme activity and mRNA expression of pparα -transcription factor in lipid metabolism, including β-oxidation genes- and cpt1 -key enzyme responsible for the movement of LC-PUFA from the cytosol into the mitochondria for β-oxidation-, were both increased at the higher water temperature. An interesting interaction was observed in the transcription and in vivo enzyme activity of Δ5fad-time-limiting enzyme in the biosynthesis pathway of EPA and ARA. Such, at lower temperature, the highest mRNA expression and enzyme activity was recorded in fish with limited supply of dietary EPA, whereas at higher temperature these were recorded in fish with limited ARA supply. In consideration that fish at higher water temperature

Bile acid receptors link nutrient sensing to metabolic regulation

PubMed Central

Li, Jibiao; Li, Tiangang

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease in Western populations. Non-alcoholic steatohepatitis (NASH) is a more debilitating form of NAFLD characterized by hepatocellular injury and inflammation, which significantly increase the risk of end-stage liver and cardiovascular diseases. Unfortunately, there are no available drug therapies for NASH. Bile acids are physiological detergent molecules that are synthesized from cholesterol exclusively in the hepatocytes. Bile acids circulate between the liver and intestine, where they are required for cholesterol solubilization in the bile and dietary fat emulsification in the gut. Bile acids also act as signaling molecules that regulate metabolic homeostasis and inflammatory processes. Many of these effects are mediated by the bile acid-activated nuclear receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. Nutrient signaling regulates hepatic bile acid synthesis and circulating plasma bile acid concentrations, which in turn control metabolic homeostasis. The FXR agonist obeticholic acid has had beneficial effects on NASH in recent clinical trials. Preclinical studies have suggested that the TGR5 agonist and the FXR/TGR5 dual agonist are also potential therapies for metabolic liver diseases. Extensive studies in the past few decades have significantly improved our understanding of the metabolic regulatory function of bile acids, which has provided the molecular basis for developing promising bile acid-based therapeutic agents for NASH treatment. PMID:29098111

Pleiotropic Roles of Bile Acids in Metabolism

PubMed Central

de Aguiar Vallim, Thomas Q.; Tarling, Elizabeth J.; Edwards, Peter A.

2013-01-01

Summary Enzymatic oxidation of cholesterol generates numerous distinct bile acids that function both as detergents that facilitate digestion and absorption of dietary lipids, and as hormones that activate four distinct receptors. Activation of these receptors alters gene expression in multiple tissues leading to changes not only in bile acid metabolism, but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility and bacterial growth, inflammation, liver regeneration and hepato-carcinogenesis. This review covers the roles of specific bile acids, synthetic agonists and their cognate receptors in controlling these diverse functions, as well as their current use in treating human diseases. PMID:23602448

Dietary intake and plasma metabolomic analysis of polyunsaturated fatty acids in bipolar subjects reveal dysregulation of linoleic acid metabolism.

PubMed

Evans, Simon J; Ringrose, Rachel N; Harrington, Gloria J; Mancuso, Peter; Burant, Charles F; McInnis, Melvin G

2014-10-01

Polyunsaturated fatty acids (PUFA) profiles associate with risk for mood disorders. This poses the hypothesis of metabolic differences between patients and unaffected healthy controls that relate to the primary illness or are secondary to medication use or dietary intake. However, dietary manipulation or supplementation studies show equivocal results improving mental health outcomes. This study investigates dietary patterns and metabolic profiles relevant to PUFA metabolism, in bipolar I individuals compared to non-psychiatric controls. We collected seven-day diet records and performed metabolomic analysis of fasted plasma collected immediately after diet recording. Regression analyses adjusted for age, gender and energy intake found that bipolar individuals had significantly lower intake of selenium and PUFAs, including eicosapentaenoic acid (EPA) (n-3), docosahexaenoic acid (DHA) (n-3), arachidonic acid (AA) (n-6) and docosapentaenoic acid (DPA) (n-3/n-6 mix); and significantly increased intake of the saturated fats, eicosanoic and docosanoic acid. Regression analysis of metabolomic data derived from plasma samples, correcting for age, gender, BMI, psychiatric medication use and dietary PUFA intake, revealed that bipolar individuals had reduced 13S-HpODE, a major peroxidation product of the n-6, linoleic acid (LA), reduced eicosadienoic acid (EDA), an elongation product of LA; reduced prostaglandins G2, F2 alpha and E1, synthesized from n-6 PUFA; and reduced EPA. These observations remained significant or near significant after Bonferroni correction and are consistent with metabolic variances between bipolar and control individuals with regard to PUFA metabolism. These findings suggest that specific dietary interventions aimed towards correcting these metabolic disparities may impact health outcomes for individuals with bipolar disorder. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effect of dietary n-3 fatty acids supplementation on fatty acid metabolism in atorvastatin-administered SHR.Cg-Leprcp/NDmcr rats, a metabolic syndrome model.

PubMed

Al Mamun, Abdullah; Hashimoto, Michio; Katakura, Masanori; Tanabe, Yoko; Tsuchikura, Satoru; Hossain, Shahdat; Shido, Osamu

2017-01-01

The effects of cholesterol-lowering statins, which substantially benefit future cardiovascular events, on fatty acid metabolism have remained largely obscured. In this study, we investigated the effects of atorvastatin on fatty acid metabolism together with the effects of TAK-085 containing highly purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl ester on atorvastatin-induced n-3 polyunsaturated fatty acid lowering in SHR.Cg-Lepr cp /NDmcr (SHRcp) rats, as a metabolic syndrome model. Supplementation with 10mg/kg body weight/day of atorvastatin for 17 weeks significantly decreased plasma total cholesterol and very low density lipoprotein cholesterol. Atorvastatin alone caused a subtle change in fatty acid composition particularly of EPA and DHA in the plasma, liver or erythrocyte membranes. However, the TAK-085 consistently increased both the levels of EPA and DHA in the plasma, liver and erythrocyte membranes. After confirming the reduction of plasma total cholesterol, 300mg/kg body weight/day of TAK-085 was continuously administered for another 6 weeks. Supplementation with TAK-085 did not decrease plasma total cholesterol but significantly increased the EPA and DHA levels in both the plasma and liver compared with rats administered atorvastatin only. Supplementation with atorvastatin alone significantly decreased sterol regulatory element-binding protein-1c, Δ5- and Δ6-desaturases, elongase-5, and stearoyl-coenzyme A (CoA) desaturase-2 levels and increased 3-hydroxy-3-methylglutaryl-CoA reductase mRNA expression in the liver compared with control rats. TAK-085 supplementation significantly increased stearoyl-CoA desaturase-2 mRNA expression. These results suggest that long-term supplementation with atorvastatin decreases the EPA and DHA levels by inhibiting the desaturation and elongation of n-3 fatty acid metabolism, while TAK-085 supplementation effectively replenishes this effect in SHRcp rat liver. Copyright © 2016 Elsevier Masson

Metabolic engineering of Clostridium acetobutylicum for enhanced production of butyric acid.

PubMed

Jang, Yu-Sin; Woo, Hee Moon; Im, Jung Ae; Kim, In Ho; Lee, Sang Yup

2013-11-01

Clostridium acetobutylicum has been considered as an attractive platform host for biorefinery due to its metabolic diversity. Considering its capability to overproduce butanol through butyrate, it was thought that butyric acid can also be efficiently produced by this bacterium through metabolic engineering. The pta-ctfB-deficient C. acetobutylicum CEKW, in which genes encoding phosphotransacetylase and CoA-transferase were knocked out, was assessed for its potential as a butyric acid producer in fermentations with four controlled pH values at 5.0, 5.5, 6.0, and 6.4. Butyric acid could be best produced by fermentation of the CEKW at pH 6.0, resulting in the highest titer of 26.6 g/l, which is 6.4 times higher than that obtained with the wild type. However, due to the remaining solventogenic ability of the CEKW, 3.6 g/l solvents were also produced. Thus, the CEKW was further engineered by knocking out the adhE1-encoding aldehyde/alcohol dehydrogenase to prevent solvent production. Batch fermentation of the resulting C. acetobutylicum HCEKW at pH 6.0 showed increased butyric acid production to 30.8 g/l with a ratio of butyric-to-acetic acid (BA/AA) of 6.6 g/g and a productivity of 0.72 g/l/h from 86.9 g/l glucose, while negligible solvent (0.8 g/l ethanol only) was produced. The butyric acid titer, BA/AA ratio, and productivity obtained in this study were the highest values reported for C. acetobutylicum, and the BA/AA ratio and productivity were also comparable to those of native butyric acid producer Clostridium tyrobutyricum. These results suggested that the simultaneous deletion of the pta-ctfB-adhE1 in C. acetobutylicum resulted in metabolic switch from biphasic to acidogenic fermentation, which enhanced butyric acid production.

Metabolic pathways regulated by abscisic acid, salicylic acid and γ-aminobutyric acid in association with improved drought tolerance in creeping bentgrass (Agrostis stolonifera).

PubMed

Li, Zhou; Yu, Jingjin; Peng, Yan; Huang, Bingru

2017-01-01

Abscisic acid (ABA), salicylic acid (SA) and γ-aminobutyric acid (GABA) are known to play roles in regulating plant stress responses. This study was conducted to determine metabolites and associated pathways regulated by ABA, SA and GABA that could contribute to drought tolerance in creeping bentgrass (Agrostis stolonifera). Plants were foliar sprayed with ABA (5 μM), GABA (0.5 mM) and SA (10 μM) or water (untreated control) prior to 25 days drought stress in controlled growth chambers. Application of ABA, GABA or SA had similar positive effects on alleviating drought damages, as manifested by the maintenance of lower electrolyte leakage and greater relative water content in leaves of treated plants relative to the untreated control. Metabolic profiling showed that ABA, GABA and SA induced differential metabolic changes under drought stress. ABA mainly promoted the accumulation of organic acids associated with tricarboxylic acid cycle (aconitic acid, succinic acid, lactic acid and malic acid). SA strongly stimulated the accumulation of amino acids (proline, serine, threonine and alanine) and carbohydrates (glucose, mannose, fructose and cellobiose). GABA enhanced the accumulation of amino acids (GABA, glycine, valine, proline, 5-oxoproline, serine, threonine, aspartic acid and glutamic acid) and organic acids (malic acid, lactic acid, gluconic acid, malonic acid and ribonic acid). The enhanced drought tolerance could be mainly due to the enhanced respiration metabolism by ABA, amino acids and carbohydrates involved in osmotic adjustment (OA) and energy metabolism by SA, and amino acid metabolism related to OA and stress-defense secondary metabolism by GABA. © 2016 Scandinavian Plant Physiology Society.

Buffered hydrochloric acid: a modern method of treating metabolic alkalosis.

PubMed

Finkle, D; Dean, R E

1981-03-01

Twenty-one patients with metabolic alkalosis were treated successfully with intravenous hydrochloric acid (HCl) buffered in an amino acid solution (TPN). No complications of HCl were seen. TPN was used to meet energy needs and provide a buffering effect through the interaction of HCl and amino acids. Buffered HCl therapy should be considered as the initial treatment in patients with metabolic alkalosis associated with congestive heart failure, renal failure, hepatic failure, cerebral edema, or refractory metabolic alkalosis.

Metabolic evolution of Escherichia coli strains that produce organic acids

DOEpatents

Grabar, Tammy; Gong, Wei; Yocum, R Rogers

2014-10-28

This invention relates to the metabolic evolution of a microbial organism previously optimized for producing an organic acid in commercially significant quantities under fermentative conditions using a hexose sugar as sole source of carbon in a minimal mineral medium. As a result of this metabolic evolution, the microbial organism acquires the ability to use pentose sugars derived from cellulosic materials for its growth while retaining the original growth kinetics, the rate of organic acid production and the ability to use hexose sugars as a source of carbon. This invention also discloses the genetic change in the microorganism that confers the ability to use both the hexose and pentose sugars simultaneously in the production of commercially significant quantities of organic acids.

Insulin resistance and the metabolism of branched-chain amino acids.

PubMed

Lu, Jingyi; Xie, Guoxiang; Jia, Weiping; Jia, Wei

2013-03-01

Insulin resistance (IR) is a key pathological feature of metabolic syndrome and subsequently causes serious health problems with an increased risk of several common metabolic disorders. IR related metabolic disturbance is not restricted to carbohydrates but impacts global metabolic network. Branched-chain amino acids (BCAAs), namely valine, leucine and isoleucine, are among the nine essential amino acids, accounting for 35% of the essential amino acids in muscle proteins and 40% of the preformed amino acids required by mammals. The BCAAs are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in insulin resistant conditions and/or insulin deficiency. Although increased circulating BCAA concentration in insulin resistant conditions has been noted for many years and BCAAs have been reported to be involved in the regulation of glucose homeostasis and body weight, it is only recently that BCAAs are found to be closely associated with IR. This review will focus on the recent findings on BCAAs from both epidemic and mechanistic studies.

Acid-base metabolism: implications for kidney stones formation.

PubMed

Hess, Bernhard

2006-04-01

The physiology and pathophysiology of renal H+ ion excretion and urinary buffer systems are reviewed. The main focus is on the two major conditions related to acid-base metabolism that cause kidney stone formation, i.e., distal renal tubular acidosis (dRTA) and abnormally low urine pH with subsequent uric acid stone formation. Both the entities can be seen on the background of disturbances of the major urinary buffer system, NH3+ <--> NH4+. On the one hand, reduced distal tubular secretion of H+ ions results in an abnormally high urinary pH and either incomplete or complete dRTA. On the other hand, reduced production/availability of NH4+ is the cause of an abnormally low urinary pH, which predisposes to uric acid stone formation. Most recent research indicates that the latter abnormality may be a renal manifestation of the increasingly prevalent metabolic syndrome. Despite opposite deviations from normal urinary pH values, both the dRTA and uric acid stone formation due to low urinary pH require the same treatment, i.e., alkali. In the dRTA, alkali is needed for improving the body's buffer capacity, whereas the goal of alkali treatment in uric acid stone formers is to increase the urinary pH to 6.2-6.8 in order to minimize uric acid crystallization.

Amino Acid Flux from Metabolic Network Benefits Protein Translation: the Role of Resource Availability.

PubMed

Hu, Xiao-Pan; Yang, Yi; Ma, Bin-Guang

2015-06-09

Protein translation is a central step in gene expression and affected by many factors such as codon usage bias, mRNA folding energy and tRNA abundance. Despite intensive previous studies, how metabolic amino acid supply correlates with protein translation efficiency remains unknown. In this work, we estimated the amino acid flux from metabolic network for each protein in Escherichia coli and Saccharomyces cerevisiae by using Flux Balance Analysis. Integrated with the mRNA expression level, protein abundance and ribosome profiling data, we provided a detailed description of the role of amino acid supply in protein translation. Our results showed that amino acid supply positively correlates with translation efficiency and ribosome density. Moreover, with the rank-based regression model, we found that metabolic amino acid supply facilitates ribosome utilization. Based on the fact that the ribosome density change of well-amino-acid-supplied genes is smaller than poorly-amino-acid-supply genes under amino acid starvation, we reached the conclusion that amino acid supply may buffer ribosome density change against amino acid starvation and benefit maintaining a relatively stable translation environment. Our work provided new insights into the connection between metabolic amino acid supply and protein translation process by revealing a new regulation strategy that is dependent on resource availability.

Roles of renal ammonia metabolism other than in acid-base homeostasis.

PubMed

Weiner, I David

2017-06-01

The importance of renal ammonia metabolism in acid-base homeostasis is well known. However, the effects of renal ammonia metabolism other than in acid-base homeostasis are not as widely recognized. First, ammonia differs from almost all other solutes in the urine in that it does not result from arterial delivery. Instead, ammonia is produced by the kidney, and only a portion of the ammonia produced is excreted in the urine, with the remainder returned to the systemic circulation through the renal veins. In normal individuals, systemic ammonia addition is metabolized efficiently by the liver, but in patients with either acute or chronic liver disease, conditions that increase the addition of ammonia of renal origin to the systemic circulation can result in precipitation and/or worsening of hyperammonemia. Second, ammonia appears to serve as an intrarenal paracrine signaling molecule. Hypokalemia increases proximal tubule ammonia production and secretion as well as reabsorption in the thick ascending limb of the loop of Henle, thereby increasing delivery to the renal interstitium and the collecting duct. In the collecting duct, ammonia decreases potassium secretion and stimulates potassium reabsorption, thereby decreasing urinary potassium excretion and enabling feedback correction of the initiating hypokalemia. Finally, the stimulation of renal ammonia metabolism by hypokalemia may contribute to the development of metabolic alkalosis, which in turn can stimulate NaCl reabsorption and contribute to the intravascular volume expansion, increased blood pressure and diuretic resistance that can develop with hypokalemia. The evidence supporting these novel non-acid-base roles of renal ammonia metabolism is discussed in this review.

Arachidonic Acid and Eicosapentaenoic Acid Metabolism in Juvenile Atlantic Salmon as Affected by Water Temperature

PubMed Central

Norambuena, Fernando; Morais, Sofia; Emery, James A.; Turchini, Giovanni M.

2015-01-01

Salmons raised in aquaculture farms around the world are increasingly subjected to sub-optimal environmental conditions, such as high water temperatures during summer seasons. Aerobic scope increases and lipid metabolism changes are known plasticity responses of fish for a better acclimation to high water temperature. The present study aimed at investigating the effect of high water temperature on the regulation of fatty acid metabolism in juvenile Atlantic salmon fed different dietary ARA/EPA ratios (arachidonic acid, 20:4n-6/ eicosapentaenoic acid, 20:5n-3), with particular focus on apparent in vivo enzyme activities and gene expression of lipid metabolism pathways. Three experimental diets were formulated to be identical, except for the ratio EPA/ARA, and fed to triplicate groups of Atlantic salmon (Salmo salar) kept either at 10°C or 20°C. Results showed that fatty acid metabolic utilisation, and likely also their dietary requirements for optimal performance, can be affected by changes in their relative levels and by environmental temperature in Atlantic salmon. Thus, the increase in temperature, independently from dietary treatment, had a significant effect on the β-oxidation of a fatty acid including EPA, as observed by the apparent in vivo enzyme activity and mRNA expression of pparα -transcription factor in lipid metabolism, including β-oxidation genes- and cpt1 -key enzyme responsible for the movement of LC-PUFA from the cytosol into the mitochondria for β-oxidation-, were both increased at the higher water temperature. An interesting interaction was observed in the transcription and in vivo enzyme activity of Δ5fad–time-limiting enzyme in the biosynthesis pathway of EPA and ARA. Such, at lower temperature, the highest mRNA expression and enzyme activity was recorded in fish with limited supply of dietary EPA, whereas at higher temperature these were recorded in fish with limited ARA supply. In consideration that fish at higher water temperature

Metabolic engineering of Pichia pastoris to produce ricinoleic acid, a hydroxy fatty acid of industrial importance.

PubMed

Meesapyodsuk, Dauenpen; Chen, Yan; Ng, Siew Hon; Chen, Jianan; Qiu, Xiao

2015-11-01

Ricinoleic acid (12-hydroxyoctadec-cis-9-enoic acid) has many specialized uses in bioproduct industries, while castor bean is currently the only commercial source for the fatty acid. This report describes metabolic engineering of a microbial system (Pichia pastoris) to produce ricinoleic acid using a "push" (synthesis) and "pull" (assembly) strategy. CpFAH, a fatty acid hydroxylase from Claviceps purpurea, was used for synthesis of ricinoleic acid, and CpDGAT1, a diacylglycerol acyl transferase for the triacylglycerol synthesis from the same species, was used for assembly of the fatty acid. Coexpression of CpFAH and CpDGAT1 produced higher lipid contents and ricinoleic acid levels than expression of CpFAH alone. Coexpression in a mutant haploid strain defective in the Δ12 desaturase activity resulted in a higher level of ricinoleic acid than that in the diploid strain. Intriguingly, the ricinoleic acid produced was mainly distributed in the neutral lipid fractions, particularly the free fatty acid form, but with little in the polar lipids. This work demonstrates the effectiveness of the metabolic engineering strategy and excellent capacity of the microbial system for production of ricinoleic acid as an alternative to plant sources for industrial uses. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

Metabolic regulation of manganese superoxide dismutase expression via essential amino acid deprivation.

PubMed

Aiken, Kimberly J; Bickford, Justin S; Kilberg, Michael S; Nick, Harry S

2008-04-18

Organisms respond to available nutrient levels by rapidly adjusting metabolic flux, in part through changes in gene expression. A consequence of adaptations in metabolic rate is the production of mitochondria-derived reactive oxygen species. Therefore, we hypothesized that nutrient sensing could regulate the synthesis of the primary defense of the cell against superoxide radicals, manganese superoxide dismutase. Our data establish a novel nutrient-sensing pathway for manganese superoxide dismutase expression mediated through essential amino acid depletion concurrent with an increase in cellular viability. Most relevantly, our results are divergent from current mechanisms governing amino acid-dependent gene regulation. This pathway requires the presence of glutamine, signaling via the tricarboxylic acid cycle/electron transport chain, an intact mitochondrial membrane potential, and the activity of both the MEK/ERK and mammalian target of rapamycin kinases. Our results provide evidence for convergence of metabolic cues with nutrient control of antioxidant gene regulation, revealing a potential signaling strategy that impacts free radical-mediated mutations with implications in cancer and aging.

Volatile profiling reveals intracellular metabolic changes in Aspergillus parasiticus: veA regulates branched chain amino acid and ethanol metabolism

PubMed Central

2010-01-01

Background Filamentous fungi in the genus Aspergillus produce a variety of natural products, including aflatoxin, the most potent naturally occurring carcinogen known. Aflatoxin biosynthesis, one of the most highly characterized secondary metabolic pathways, offers a model system to study secondary metabolism in eukaryotes. To control or customize biosynthesis of natural products we must understand how secondary metabolism integrates into the overall cellular metabolic network. By applying a metabolomics approach we analyzed volatile compounds synthesized by Aspergillus parasiticus in an attempt to define the association of secondary metabolism with other metabolic and cellular processes. Results Volatile compounds were examined using solid phase microextraction - gas chromatography/mass spectrometry. In the wild type strain Aspergillus parasiticus SU-1, the largest group of volatiles included compounds derived from catabolism of branched chain amino acids (leucine, isoleucine, and valine); we also identified alcohols, esters, aldehydes, and lipid-derived volatiles. The number and quantity of the volatiles produced depended on media composition, time of incubation, and light-dark status. A block in aflatoxin biosynthesis or disruption of the global regulator veA affected the volatile profile. In addition to its multiple functions in secondary metabolism and development, VeA negatively regulated catabolism of branched chain amino acids and synthesis of ethanol at the transcriptional level thus playing a role in controlling carbon flow within the cell. Finally, we demonstrated that volatiles generated by a veA disruption mutant are part of the complex regulatory machinery that mediates the effects of VeA on asexual conidiation and sclerotia formation. Conclusions 1) Volatile profiling provides a rapid, effective, and powerful approach to identify changes in intracellular metabolic networks in filamentous fungi. 2) VeA coordinates the biosynthesis of secondary

Protein and metabolic engineering for the production of organic acids.

PubMed

Liu, Jingjing; Li, Jianghua; Shin, Hyun-Dong; Liu, Long; Du, Guocheng; Chen, Jian

2017-09-01

Organic acids are natural metabolites of living organisms. They have been widely applied in the food, pharmaceutical, and bio-based materials industries. In recent years, biotechnological routes to organic acids production from renewable raw materials have been regarded as very promising approaches. In this review, we provide an overview of current developments in the production of organic acids using protein and metabolic engineering strategies. The organic acids include propionic acid, pyruvate, itaconic acid, succinic acid, fumaric acid, malic acid and citric acid. We also expect that rapid developments in the fields of systems biology and synthetic biology will accelerate protein and metabolic engineering for microbial organic acid production in the future. Copyright © 2017. Published by Elsevier Ltd.

alpha-Ketoglutarate application in hemodialysis patients improves amino acid metabolism.

PubMed

Riedel, E; Nündel, M; Hampl, H

1996-01-01

In hemodialysis patients, free amino acids and alpha-ketoacids in plasma were determined by fluorescence HPLC to assess the effect of alpha-ketoglutarate administration in combination with the phosphate binder calcium carbonate on the amino acid metabolism. During 1 year of therapy in parallel to inorganic phosphate, urea in plasma decreased significantly, histidine, arginine and proline as well as branched chain alpha-ketoacids, in particular alpha-ketoisocaproate, a regulator of protein metabolism, increased. Thus, administration of alpha-ketoglutarate with calcium carbonate effectively improves amino acid metabolism in hemodialysis patients as it decreases hyperphosphatemia.

Aspects of astrocyte energy metabolism, amino acid neurotransmitter homoeostasis and metabolic compartmentation

PubMed Central

Kreft, Marko; Bak, Lasse K; Waagepetersen, Helle S; Schousboe, Arne

2012-01-01

Astrocytes are key players in brain function; they are intimately involved in neuronal signalling processes and their metabolism is tightly coupled to that of neurons. In the present review, we will be concerned with a discussion of aspects of astrocyte metabolism, including energy-generating pathways and amino acid homoeostasis. A discussion of the impact that uptake of neurotransmitter glutamate may have on these pathways is included along with a section on metabolic compartmentation. PMID:22435484

Hepatic Metabolism of Perfluorinated Carboxylic Acids: A Nuclear Magnetic Resonance Investigation

DTIC Science & Technology

1990-12-14

perfluoro -n- octanoic acid ( PFOA ) and perfluoro -n-decanoic acid ( PFDA ) In the rat. Spectra obtained at various times following the administration of PFOA ...used to monitor the metabolic fate of perfluoro -n-octanoic acid ( PFOA ) and perfluoro -n-decanoic acid ( PFDA ) in the rat. Spectra obtained at various...specifically Investigate the metabolic effects caused by perfluoro -n-octanoic acid ( PFOA ) and perfluoro -n-decanoic acid ( PFDA ) in rats.

Amino acid metabolism during exercise in trained rats: the potential role of carnitine in the metabolic fate of branched-chain amino acids.

PubMed

Ji, L L; Miller, R H; Nagle, F J; Lardy, H A; Stratman, F W

1987-08-01

The influence of endurance training and an acute bout of exercise on plasma concentrations of free amino acids and the intermediates of branched-chain amino acid (BCAA) metabolism were investigated in the rat. Training did not affect the plasma amino acid levels in the resting state. Plasma concentrations of alanine (Ala), aspartic acid (Asp), asparagine (Asn), arginine (Arg), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), and valine (Val) were significantly lower, whereas glutamate (Glu), glycine (Gly), ornithine (Orn), tryptophan (Trp), tyrosine (Tyr), creatinine, urea, and ammonia levels were unchanged, after one hour of treadmill running in the trained rats. Plasma concentration of glutamine (Glu), the branched-chain keto acids (BCKA) and short-chain acyl carnitines were elevated with exercise. Ratios of plasma BCAA/BCKA were dramatically lowered by exercise in the trained rats. A decrease in plasma-free carnitine levels was also observed. These data suggest that amino acid metabolism is enhanced by exercise even in the trained state. BCAA may only be partially metabolized within muscle and some of their carbon skeletons are released into the circulation in forms of BCKA and short-chain acyl carnitines.

Production of amino acids - Genetic and metabolic engineering approaches.

PubMed

Lee, Jin-Ho; Wendisch, Volker F

2017-12-01

The biotechnological production of amino acids occurs at the million-ton scale and annually about 6milliontons of l-glutamate and l-lysine are produced by Escherichia coli and Corynebacterium glutamicum strains. l-glutamate and l-lysine production from starch hydrolysates and molasses is very efficient and access to alternative carbon sources and new products has been enabled by metabolic engineering. This review focusses on genetic and metabolic engineering of amino acid producing strains. In particular, rational approaches involving modulation of transcriptional regulators, regulons, and attenuators will be discussed. To address current limitations of metabolic engineering, this article gives insights on recent systems metabolic engineering approaches based on functional tools and method such as genome reduction, amino acid sensors based on transcriptional regulators and riboswitches, CRISPR interference, small regulatory RNAs, DNA scaffolding, and optogenetic control, and discusses future prospects. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mass spectrometry characterisation of fatty acids from metabolically engineered soybean seeds.

PubMed

Murad, André M; Vianna, Giovanni R; Machado, Alex M; da Cunha, Nicolau B; Coelho, Cíntia M; Lacerda, Valquiria A M; Coelho, Marly C; Rech, Elibio L

2014-05-01

Improving the quality and performance of soybean oil as biodiesel depends on the chemical composition of its fatty acids and requires an increase in monounsaturated acids and a reduction in polyunsaturated acids. Despite its current use as a source of biofuel, soybean oil contains an average of 25 % oleic acid and 13 % palmitic acid, which negatively impacts its oxidative stability and freezing point, causing a high rate of nitrogen oxide emission. Gas chromatography and ion mobility mass spectrometry were conducted on soybean fatty acids from metabolically engineered seed extracts to determine the nature of the structural oleic and palmitic acids. The soybean genes FAD2-1 and FatB were placed under the control of the 35SCaMV constitutive promoter, introduced to soybean embryonic axes by particle bombardment and down-regulated using RNA interference technology. Results indicate that the metabolically engineered plants exhibited a significant increase in oleic acid (up to 94.58 %) and a reduction in palmitic acid (to <3 %) in their seed oil content. No structural differences were observed between the fatty acids of the transgenic and non-transgenic oil extracts.

Effect of aspartic acid and glutamate on metabolism and acid stress resistance of Acetobacter pasteurianus.

PubMed

Yin, Haisong; Zhang, Renkuan; Xia, Menglei; Bai, Xiaolei; Mou, Jun; Zheng, Yu; Wang, Min

2017-06-15

Acetic acid bacteria (AAB) are widely applied in food, bioengineering and medicine fields. However, the acid stress at low pH conditions limits acetic acid fermentation efficiency and high concentration of vinegar production with AAB. Therefore, how to enhance resistance ability of the AAB remains as the major challenge. Amino acids play an important role in cell growth and cell survival under severe environment. However, until now the effects of amino acids on acetic fermentation and acid stress resistance of AAB have not been fully studied. In the present work the effects of amino acids on metabolism and acid stress resistance of Acetobacter pasteurianus were investigated. Cell growth, culturable cell counts, acetic acid production, acetic acid production rate and specific production rate of acetic acid of A. pasteurianus revealed an increase of 1.04, 5.43, 1.45, 3.30 and 0.79-folds by adding aspartic acid (Asp), and cell growth, culturable cell counts, acetic acid production and acetic acid production rate revealed an increase of 0.51, 0.72, 0.60 and 0.94-folds by adding glutamate (Glu), respectively. For a fully understanding of the biological mechanism, proteomic technology was carried out. The results showed that the strengthening mechanism mainly came from the following four aspects: (1) Enhancing the generation of pentose phosphates and NADPH for the synthesis of nucleic acid, fatty acids and glutathione (GSH) throughout pentose phosphate pathway. And GSH could protect bacteria from low pH, halide, oxidative stress and osmotic stress by maintaining the viability of cells through intracellular redox equilibrium; (2) Reinforcing deamination of amino acids to increase intracellular ammonia concentration to maintain stability of intracellular pH; (3) Enhancing nucleic acid synthesis and reparation of impaired DNA caused by acid stress damage; (4) Promoting unsaturated fatty acids synthesis and lipid transport, which resulted in the improvement of cytomembrane

Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis

PubMed Central

Henry, Curtis J.; Nemkov, Travis; Casás-Selves, Matias; Bilousova, Ganna; Zaberezhnyy, Vadym; Higa, Kelly C.; Serkova, Natalie J.; Hansen, Kirk C.; D’Alessandro, Angelo; DeGregori, James

2017-01-01

While dietary folate deficiency is associated with increased risk for birth defects and other diseases, evidence suggests that supplementation with folic acid can contribute to predisposition to some diseases, including immune dysfunction and cancer. Herein, we show that diets supplemented with folic acid both below and above the recommended levels led to significantly altered metabolism in multiple tissues in mice. Surprisingly, both low and excessive dietary folate induced similar metabolic changes, which were particularly evident for nucleotide biosynthetic pathways in B-progenitor cells. Diet-induced metabolic changes in these cells partially phenocopied those observed in mice treated with anti-folate drugs, suggesting that both deficiency and excessive levels of dietary folic acid compromise folate-dependent biosynthetic pathways. Both folate deficiency and excessive dietary folate levels compromise hematopoiesis, resulting in defective cell cycle progression, persistent DNA damage, and impaired production of lymphocytes. These defects reduce the reconstitution potential in transplantation settings and increase radiation-induced mortality. We conclude that excessive folic acid supplementation can metabolically mimic dietary folate insufficiency, leading to similar functional impairment of hematopoiesis. PMID:28883079

Metabolic engineering in the biotechnological production of organic acids in the tricarboxylic acid cycle of microorganisms: Advances and prospects.

PubMed

Yin, Xian; Li, Jianghua; Shin, Hyun-Dong; Du, Guocheng; Liu, Long; Chen, Jian

2015-11-01

Organic acids, which are chemically synthesized, are also natural intermediates in the metabolic pathways of microorganisms, among which the tricarboxylic acid (TCA) cycle is the most crucial route existing in almost all living organisms. Organic acids in the TCA cycle include citric acid, α-ketoglutaric acid, succinic acid, fumaric acid, l-malic acid, and oxaloacetate, which are building-block chemicals with wide applications and huge markets. In this review, we summarize the synthesis pathways of these organic acids and review recent advances in metabolic engineering strategies that enhance organic acid production. We also propose further improvements for the production of organic acids with systems and synthetic biology-guided metabolic engineering strategies. Copyright © 2015 Elsevier Inc. All rights reserved.

Metabolomic analysis of amino acid and energy metabolism in rats supplemented with chlorogenic acid

PubMed Central

Ruan, Zheng; Yang, Yuhui; Zhou, Yan; Wen, Yanmei; Ding, Sheng; Liu, Gang; Wu, Xin; Deng, Zeyuan; Assaad, Houssein; Wu, Guoyao

2016-01-01

This study was conducted to investigate effects of chlorogenic acid (CGA) supplementation on serum and hepatic metabolomes in rats. Rats received daily intragastric administration of either CGA (60 mg/kg body weight) or distilled water (control) for 4 weeks. Growth performance, serum biochemical profiles, and hepatic morphology were measured. Additionally, serum and liver tissue extracts were analyzed for metabolomes by high-resolution 1H nuclear magnetic resonance-based metabolomics and multivariate statistics. CGA did not affect rat growth performance, serum biochemical profiles, or hepatic morphology. However, supplementation with CGA decreased serum concentrations of lactate, pyruvate, succinate, citrate, β-hydroxybutyrate and acetoacetate, while increasing serum concentrations of glycine and hepatic concentrations of glutathione. These results suggest that CGA supplementation results in perturbation of energy and amino acid metabolism in rats. We suggest that glycine and glutathione in serum may be useful biomarkers for biological properties of CGA on nitrogen metabolism in vivo. PMID:24927697

Metabolic engineering of Pichia pastoris to produce ricinoleic acid, a hydroxy fatty acid of industrial importance[S

PubMed Central

Meesapyodsuk, Dauenpen; Chen, Yan; Ng, Siew Hon; Chen, Jianan; Qiu, Xiao

2015-01-01

Ricinoleic acid (12-hydroxyoctadec-cis-9-enoic acid) has many specialized uses in bioproduct industries, while castor bean is currently the only commercial source for the fatty acid. This report describes metabolic engineering of a microbial system (Pichia pastoris) to produce ricinoleic acid using a “push” (synthesis) and “pull” (assembly) strategy. CpFAH, a fatty acid hydroxylase from Claviceps purpurea, was used for synthesis of ricinoleic acid, and CpDGAT1, a diacylglycerol acyl transferase for the triacylglycerol synthesis from the same species, was used for assembly of the fatty acid. Coexpression of CpFAH and CpDGAT1 produced higher lipid contents and ricinoleic acid levels than expression of CpFAH alone. Coexpression in a mutant haploid strain defective in the Δ12 desaturase activity resulted in a higher level of ricinoleic acid than that in the diploid strain. Intriguingly, the ricinoleic acid produced was mainly distributed in the neutral lipid fractions, particularly the free fatty acid form, but with little in the polar lipids. This work demonstrates the effectiveness of the metabolic engineering strategy and excellent capacity of the microbial system for production of ricinoleic acid as an alternative to plant sources for industrial uses. PMID:26323290

D-erythroascorbic acid: Its preparations, chemistry, and metabolism (fungi and plants)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loewus, F.A.; Seib, P.A.

1991-01-01

The origin of oxalate in plants has received considerable attention and glycolate metabolism has been generally regarded as a prime precursor candidate although studies on the metabolism of L-ascorbic acid single out that plant constituent as well. Experiments with oxalate-accumulating plants that contain little or no tartaric acid revealed the presence of a comparable L-ascorbic acid metabolism with the exception that the cleavage products were oxalic acid and L-threonic acid or products of L-threonic acid metabolism. A reasonable mechanism for cleavage of L-ascorbic acid at the endiolic bond is found in studies on the photooxygenation of L-ascorbic acid. Presumably, analogsmore » of L-ascorbic acid that differ only in the substituent at C4 also form a hydroperoxide in the presence of alkaline hydrogen peroxide and subsequently yield oxalic acid and the corresponding aldonic acid or its lactone. We became interested in such a possibility when we discovered that L-ascorbic acid was rare or absent in certain yeasts and fungi whereas a L-ascorbic acid analog, D-glycero-pent-2-enono- 1,4-lactone (D-erythroascorbic acid), was present. It has long been known that oxalate occurs in yeasts and fungi and its production plays a role in plant pathogenesis. As to the biosynthetic origin of fungal oxalic acid there is little information although it is generally assumed that oxaloacetate or possibly, glycolate, might be that precursor.« less

Metabolic Regulation of Manganese Superoxide Dismutase Expression via Essential Amino Acid Deprivation*

PubMed Central

Aiken, Kimberly J.; Bickford, Justin S.; Kilberg, Michael S.; Nick, Harry S.

2008-01-01

Organisms respond to available nutrient levels by rapidly adjusting metabolic flux, in part through changes in gene expression. A consequence of adaptations in metabolic rate is the production of mitochondria-derived reactive oxygen species. Therefore, we hypothesized that nutrient sensing could regulate the synthesis of the primary defense of the cell against superoxide radicals, manganese superoxide dismutase. Our data establish a novel nutrient-sensing pathway for manganese superoxide dismutase expression mediated through essential amino acid depletion concurrent with an increase in cellular viability. Most relevantly, our results are divergent from current mechanisms governing amino acid-dependent gene regulation. This pathway requires the presence of glutamine, signaling via the tricarboxylic acid cycle/electron transport chain, an intact mitochondrial membrane potential, and the activity of both the MEK/ERK and mammalian target of rapamycin kinases. Our results provide evidence for convergence of metabolic cues with nutrient control of antioxidant gene regulation, revealing a potential signaling strategy that impacts free radical-mediated mutations with implications in cancer and aging. PMID:18187411

Uric acid in metabolic syndrome: From an innocent bystander to a central player

PubMed Central

Kanbay, Mehmet; Jensen, Thomas; Solak, Yalcin; Le, Myphuong; Roncal-Jimenez, Carlos; Rivard, Chris; Lanaspa, Miguel A.; Nakagawa, Takahiko; Johnson, Richard J.

2016-01-01

Uric acid, once viewed as an inert metabolic end-product of purine metabolism, has been recently incriminated in a number of chronic disease states, including hypertension, metabolic syndrome, diabetes, non-alcoholic fatty liver disease, and chronic kidney disease. Several experimental and clinical studies support a role for uric acid as a contributory causal factor in these conditions. Here we discuss some of the major mechanisms linking uric acid to metabolic and cardiovascular diseases. At this time the key to understanding the importance of uric acid in these diseases will be the conduct of large clinical trials in which the effect of lowering uric acid on hard clinical outcomes is assessed. Elevated uric acid may turn out to be one of the more important remediable risk factors for metabolic and cardiovascular diseases. PMID:26703429

Fatty acid CoA ligase-4 gene polymorphism influences fatty acid metabolism in metabolic syndrome, but not in depression.

PubMed

Zeman, Miroslav; Vecka, Marek; Jáchymová, Marie; Jirák, Roman; Tvrzická, Eva; Stanková, Barbora; Zák, Ales

2009-04-01

The composition of polyunsaturated fatty acids (PUFAs) in cell membranes and body tissues is altered in metabolic syndrome (MetS) and depressive disorder (DD). Within the cell, fatty acid coenzyme A (CoA) ligases (FACLs) activate PUFAs by esterifying with CoA. The FACL4 isoform prefers PUFAs (arachidonic and eicosapentaenoic acid) as substrates, and the FACL4 gene is mapped to Xq23. We have analyzed the association between the common single nucleotide polymorphism (SNP) (rs1324805, C to T substitution) in the first intron of the FACL4 gene and MetS or DD. The study included 113 healthy subjects (54 Males/59 Females), 56 MetS patients (34M/22F) and 41 DD patients (7M/34F). In MetS group, T-carriers and patients with CC or C0 (CC/C0) genotype did not differ in the values of metabolic indices of MetS and M/F ratio. Nevertheless, in comparison with CC/C0, the T-allele carriers were characterized by enhanced unfavorable changes in fatty acid metabolism typical for MetS: higher content of dihomogammalinolenic acid (P < 0.05) and lower content of arachidonic acid in plasma phosphatidylcholine (PC) (P = 0.052), lower index of Delta5 desaturation (P < 0.01) and unsaturation index (UI) (P < 0.001). In contrast, DD patients had higher concentrations of plasma glucose, insulin, conjugated dienes and index of insulin resistance, but showed no significant association with the studied SNP. The present study shows that the common SNP (C to T substitution) in the first intron of the FACL4 gene is associated with altered FA composition of plasma phosphatidylcholines in patients with MetS.

ARISTOLOCHIC ACID I METABOLISM IN THE ISOLATED PERFUSED RAT KIDNEY

PubMed Central

Priestap, Horacio A.; Torres, M. Cecilia; Rieger, Robert A.; Dickman, Kathleen G.; Freshwater, Tomoko; Taft, David R.; Barbieri, Manuel A.; Iden, Charles R.

2012-01-01

Aristolochic acids are natural nitro-compounds found globally in the plant genus Aristolochia that have been implicated in the severe illness in humans termed aristolochic acid nephropathy (AAN). Aristolochic acids undergo nitroreduction, among other metabolic reactions, and active intermediates arise that are carcinogenic. Previous experiments with rats showed that aristolochic acid I (AA-I), after oral administration or injection, is subjected to detoxication reactions to give aristolochic acid Ia, aristolactam Ia, aristolactam I and their glucuronide and sulfate conjugates that can be found in urine and faeces. Results obtained with whole rats do not clearly define the role of liver and kidney in such metabolic transformation. In this study, in order to determine the specific role of the kidney on the renal disposition of AA-I and to study the biotransformations suffered by AA-I in this organ, isolated kidneys of rats were perfused with AA-I. AA-I and metabolite concentrations were determined in perfusates and urines using HPLC procedures. The isolated perfused rat kidney model showed that AA-I distributes rapidly and extensively in kidney tissues by uptake from the peritubular capillaries and the tubules. It was also established that the kidney is able to metabolize AA-I into aristolochic acid Ia, aristolochic acid Ia O-sulfate, aristolactam Ia, aristolactam I and aristolactam Ia O-glucuronide. Rapid demethylation and sulfation of AA-I in the kidney generate aristolochic acid Ia and its sulfate conjugate that are voided to the urine. Reduction reactions to give the aristolactam metabolites occur to a slower rate. Renal clearances showed that filtered AA-I is reabsorbed at the tubules whereas the metabolites are secreted. The unconjugated metabolites produced in the renal tissues are transported to both urine and perfusate whereas the conjugated metabolites are almost exclusively secreted to the urine. PMID:22118289

Perturbations in amino acids and metabolic pathways in osteoarthritis patients determined by targeted metabolomics analysis.

PubMed

Chen, Rui; Han, Su; Liu, Xuefeng; Wang, Kunpeng; Zhou, Yong; Yang, Chundong; Zhang, Xi

2018-05-15

Osteoarthritis (OA) is a degenerative synovial joint disease affecting people worldwide. However, the exact pathogenesis of OA remains unclear. Metabolomics analysis was performed to obtain insight into possible pathogenic mechanisms and diagnostic biomarkers of OA. Ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-TQ-MS), followed by multivariate statistical analysis, was used to determine the serum amino acid profiles of 32 OA patients and 35 healthy controls. Variable importance for project values and Student's t-test were used to determine the metabolic abnormalities in OA. Another 30 OA patients were used as independent samples to validate the alterations in amino acids. MetaboAnalyst was used to identify the key amino acid pathways and construct metabolic networks describing their relationships. A total of 25 amino acids and four biogenic amines were detected by UPLC-TQ-MS. Differences in amino acid profiles were found between the healthy controls and OA patients. Alanine, γ-aminobutyric acid and 4-hydroxy-l-proline were important biomarkers distinguishing OA patients from healthy controls. The metabolic pathways with the most significant effects were involved in metabolism of alanine, aspartate, glutamate, arginine and proline. The results of this study improve understanding of the amino acid metabolic abnormalities and pathogenic mechanisms of OA at the molecular level. The metabolic perturbations may be important for the diagnosis and prevention of OA. Copyright © 2018 Elsevier B.V. All rights reserved.

Light quality modulates metabolic synchronization over the diel phases of crassulacean acid metabolism

PubMed Central

Ceusters, Johan; Borland, Anne M.; Taybi, Tahar; Frans, Mario; Godts, Christof; De Proft, Maurice P.

2014-01-01

Temporal compartmentation of carboxylation processes is a defining feature of crassulacean acid metabolism and involves circadian control of key metabolic and transport steps that regulate the supply and demand for carbon over a 24h cycle. Recent insights on the molecular workings of the circadian clock and its connection with environmental inputs raise new questions on the importance of light quality and, by analogy, certain photoreceptors for synchronizing the metabolic components of CAM. The present work tested the hypothesis that optimal coupling of stomatal conductance, net CO2 uptake, and the reciprocal turnover of carbohydrates and organic acids over the diel CAM cycle requires both blue and red light input signals. Contrasting monochromatic wavelengths of blue, green, and red light (i.e. 475, 530, 630nm) with low fluence rates (10 μmol m–2 s–1) were administered for 16 hours each diel cycle for a total treatment time of 48 hours to the obligate CAM bromeliad, Aechmea ‘Maya’. Of the light treatments imposed, low-fluence blue light was a key determinant in regulating stomatal responses, organic acid mobilization from the vacuole, and daytime decarboxylation. However, the reciprocal relationship between starch and organic acid turnover that is typical for CAM was uncoupled under low-fluence blue light. Under low-fluence red or green light, the diel turnover of storage carbohydrates was orchestrated in line with the requirements of CAM, but a consistent delay in acid consumption at dawn compared with plants under white or low-fluence blue light was noted. Consistent with the acknowledged influences of both red and blue light as input signals for the circadian clock, the data stress the importance of both red and blue-light signalling pathways for synchronizing the metabolic and physiological components of CAM over the day/night cycle. PMID:24803500

Uric Acid Nephrolithiasis: A Systemic Metabolic Disorder

PubMed Central

Moe, Orson W.

2014-01-01

Uric acid nephrolithiasis is characteristically a manifestation of a systemic metabolic disorder. It has a prevalence of about 10% among all stone formers, the third most common type of kidney stone in the industrialized world. Uric acid stones form primarily due to an unduly acid urine; less deciding factors are hyperuricosuria and a low urine volume. The vast majority of uric acid stone formers have the metabolic syndrome, and not infrequently, clinical gout is present as well. A universal finding is a low baseline urine pH plus insufficient production of urinary ammonium buffer. Persons with gastrointestinal disorders, in particular chronic diarrhea or ostomies, and patients with malignancies with a large tumor mass and high cell turnover comprise a less common but nevertheless important subset. Pure uric acid stones are radiolucent but well visualized on renal ultrasound. A 24 h urine collection for stone risk analysis provides essential insight into the pathophysiology of stone formation and may guide therapy. Management includes a liberal fluid intake and dietary modification. Potassium citrate to alkalinize the urine to a goal pH between 6 and 6.5 is essential, as undissociated uric acid deprotonates into its much more soluble urate form. PMID:25045326

Down-regulated energy metabolism genes associated with mitochondria oxidative phosphorylation and fatty acid metabolism in viral cardiomyopathy mouse heart.

PubMed

Xu, Jing; Nie, Hong-gang; Zhang, Xiao-dong; Tian, Ye; Yu, Bo

2011-08-01

The majority of experimental and clinical studies indicates that the hypertrophied and failing myocardium are characterized by changes in energy and substrate metabolism that attributed to failing heart changes at the genomic level, in fact, heart failure is caused by various diseases, their energy metabolism and substrate are in different genetic variations, then the potential significance of the molecular mechanisms for the aetiology of heart failure is necessary to be evaluated. Persistent viral infection (especially coxsackievirus group B3) of the myocardium in viral myocarditis and viral dilated cardiomyopathy has never been neglected by experts. This study aimed to explore the role and regulatory mechanism of the altered gene expression for energy metabolism involved in mitochondrial oxidative phosphorylation, fatty acid metabolism in viral dilated cardiomyopathy. cDNA Microarray technology was used to evaluate the expression of >35,852 genes in a mice model of viral dilated cardiomyopathy. In total 1385 highly different genes expression, we analyzed 33 altered genes expression for energy metabolism involved in mitochondrial oxidative phosphorylation, fatty acid metabolism and further selected real-time-PCR for quantity one of regulatory mechanisms for energy including fatty acid metabolism-the UCP2 and assayed cytochrome C oxidase activity by Spectrophotometer to explore mitochondrial oxidative phosphorylation function. We found obviously different expression of 33 energy metabolism genes associated with mitochondria oxidative phosphorylation, fatty acid metabolism in cardiomyopathy mouse heart, the regulatory gene for energy metabolism: UCP2 was down-regulated and cytochrome C oxidase activity was decreased. Genes involved in both fatty acid metabolism and mitochondrial oxidative phosphorylation were down-regulated, mitochondrial uncoupling proteins (UCP2) expression did not increase but decrease which might be a kind of adaptive protection response to

Homocysteine regulates fatty acid and lipid metabolism in yeast.

PubMed

Visram, Myriam; Radulovic, Maja; Steiner, Sabine; Malanovic, Nermina; Eichmann, Thomas O; Wolinski, Heimo; Rechberger, Gerald N; Tehlivets, Oksana

2018-04-13

S -Adenosyl-l-homocysteine hydrolase (AdoHcy hydrolase; Sah1 in yeast/AHCY in mammals) degrades AdoHcy, a by-product and strong product inhibitor of S -adenosyl-l-methionine (AdoMet)-dependent methylation reactions, to adenosine and homocysteine (Hcy). This reaction is reversible, so any elevation of Hcy levels, such as in hyperhomocysteinemia (HHcy), drives the formation of AdoHcy, with detrimental consequences for cellular methylation reactions. HHcy, a pathological condition linked to cardiovascular and neurological disorders, as well as fatty liver among others, is associated with a deregulation of lipid metabolism. Here, we developed a yeast model of HHcy to identify mechanisms that dysregulate lipid metabolism. Hcy supplementation to wildtype cells up-regulated cellular fatty acid and triacylglycerol content and induced a shift in fatty acid composition, similar to changes observed in mutants lacking Sah1. Expression of the irreversible bacterial pathway for AdoHcy degradation in yeast allowed us to dissect the impact of AdoHcy accumulation on lipid metabolism from the impact of elevated Hcy. Expression of this pathway fully suppressed the growth deficit of sah1 mutants as well as the deregulation of lipid metabolism in both the sah1 mutant and Hcy-exposed wildtype, showing that AdoHcy accumulation mediates the deregulation of lipid metabolism in response to elevated Hcy in yeast. Furthermore, Hcy supplementation in yeast led to increased resistance to cerulenin, an inhibitor of fatty acid synthase, as well as to a concomitant decline of condensing enzymes involved in very long-chain fatty acid synthesis, in line with the observed shift in fatty acid content and composition. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Homocysteine regulates fatty acid and lipid metabolism in yeast

PubMed Central

Visram, Myriam; Radulovic, Maja; Steiner, Sabine; Malanovic, Nermina; Eichmann, Thomas O.; Wolinski, Heimo; Rechberger, Gerald N.; Tehlivets, Oksana

2018-01-01

S-Adenosyl-l-homocysteine hydrolase (AdoHcy hydrolase; Sah1 in yeast/AHCY in mammals) degrades AdoHcy, a by-product and strong product inhibitor of S-adenosyl-l-methionine (AdoMet)-dependent methylation reactions, to adenosine and homocysteine (Hcy). This reaction is reversible, so any elevation of Hcy levels, such as in hyperhomocysteinemia (HHcy), drives the formation of AdoHcy, with detrimental consequences for cellular methylation reactions. HHcy, a pathological condition linked to cardiovascular and neurological disorders, as well as fatty liver among others, is associated with a deregulation of lipid metabolism. Here, we developed a yeast model of HHcy to identify mechanisms that dysregulate lipid metabolism. Hcy supplementation to wildtype cells up-regulated cellular fatty acid and triacylglycerol content and induced a shift in fatty acid composition, similar to changes observed in mutants lacking Sah1. Expression of the irreversible bacterial pathway for AdoHcy degradation in yeast allowed us to dissect the impact of AdoHcy accumulation on lipid metabolism from the impact of elevated Hcy. Expression of this pathway fully suppressed the growth deficit of sah1 mutants as well as the deregulation of lipid metabolism in both the sah1 mutant and Hcy-exposed wildtype, showing that AdoHcy accumulation mediates the deregulation of lipid metabolism in response to elevated Hcy in yeast. Furthermore, Hcy supplementation in yeast led to increased resistance to cerulenin, an inhibitor of fatty acid synthase, as well as to a concomitant decline of condensing enzymes involved in very long-chain fatty acid synthesis, in line with the observed shift in fatty acid content and composition. PMID:29414770

Can valproic acid be an inducer of clozapine metabolism?

PubMed Central

Diaz, Francisco J.; Eap, Chin B.; Ansermot, Nicolas; Crettol, Severine; Spina, Edoardo; de Leon, Jose

2014-01-01

Introduction Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that 1) VPA is a net inducer of clozapine metabolism, and 2) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. Methods After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. Results VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14% to 39%) after controlling for confounding variables including smoking (35% lower, 28% to 56%). Discussion Prospective studies are needed to definitively establish that VPA may 1) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and 2) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism. PMID:24764199

Roles of renal ammonia metabolism other than in acid-base homeostasis

PubMed Central

Weiner, I. David

2016-01-01

The importance of renal ammonia metabolism in acid-base homeostasis is well known. However, the effects of renal ammonia metabolism other than in acid-base homeostasis are not as widely recognized. First, ammonia differs from almost all other solutes in the urine in that it does not result from arterial delivery. Instead, ammonia is produced by the kidney and only a portion of the ammonia produced is excreted in the urine. The remainder is returned to the systemic circulation through the renal veins. In normal individuals, systemic ammonia addition is metabolized efficiently by the liver, but in patients with either acute or chronic liver disease, conditions that increase renal ammonia addition to the systemic circulation can cause precipitation and/or worsening of hyperammonemia. Second, ammonia appears to serve as an intra-renal paracrine signaling molecule. Hypokalemia increases proximal tubule ammonia production and secretion and it increases reabsorption in the thick ascending limb of the loop of Henle, thereby increasing delivery to the renal interstitium and the collecting duct. In the collecting duct, ammonia decreases potassium secretion and stimulates potassium reabsorption, thereby decreasing urinary potassium excretion and enabling feedback correction of the initiating hypokalemia. Finally, hypokalemia’s stimulation of renal ammonia metabolism and hypokalemia contributes to development of metabolic alkalosis, which can stimulate NaCl reabsorption and thereby contribute to the intravascular volume expansion, increased blood pressure and diuretic resistance that can develop with hypokalemia. In this review, we discuss the evidence supporting these novel non-acid-base roles of renal ammonia metabolism. PMID:27169421

Hepatitis B virus X protein (HBx)-induced abnormalities of nucleic acid metabolism revealed by (1)H-NMR-based metabonomics.

PubMed

Dan Yue; Zhang, Yuwei; Cheng, Liuliu; Ma, Jinhu; Xi, Yufeng; Yang, Liping; Su, Chao; Shao, Bin; Huang, Anliang; Xiang, Rong; Cheng, Ping

2016-04-14

Hepatitis B virus X protein (HBx) plays an important role in HBV-related hepatocarcinogenesis; however, mechanisms underlying HBx-mediated carcinogenesis remain unclear. In this study, an NMR-based metabolomics approach was applied to systematically investigate the effects of HBx on cell metabolism. EdU incorporation assay was conducted to examine the effects of HBx on DNA synthesis, an important feature of nucleic acid metabolism. The results revealed that HBx disrupted metabolism of glucose, lipids, and amino acids, especially nucleic acids. To understand the potential mechanism of HBx-induced abnormalities of nucleic acid metabolism, gene expression profiles of HepG2 cells expressing HBx were investigated. The results showed that 29 genes involved in DNA damage and DNA repair were differentially expressed in HBx-expressing HepG2 cells. HBx-induced DNA damage was further demonstrated by karyotyping, comet assay, Western blotting, immunofluorescence and immunohistochemistry analyses. Many studies have previously reported that DNA damage can induce abnormalities of nucleic acid metabolism. Thus, our results implied that HBx initially induces DNA damage, and then disrupts nucleic acid metabolism, which in turn blocks DNA repair and induces the occurrence of hepatocellular carcinoma (HCC). These findings further contribute to our understanding of the occurrence of HCC.

Crassulacean acid metabolism in submerged aquatic plants

USGS Publications Warehouse

Keeley, Jon E.; Sybesme, C.

1984-01-01

CO2-fixation in the dark is known to occur in various organs of many plants. However, only in species possessing crassulacean acid metabolism (CAM) does dark CO2-fixation contribute substantially to the carbon economy of the plant. Until very recently CAM was known only from terrestrial species, largely drought adapted succulents. The discovery of CAM in the submerged aquatic fern ally Isoetes howellii (Isoetaceae)(Keeley 1981) adds a new dimension to our understanding of crassulacean acid metabolism. In this paper I will summarize 1) the evidence of CAM in Isoetes howellii, 2) the data on the distribution of CAM in aquatic species, and 3) the work to date on the functional significance of CAM in aquatic species.

Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart

PubMed Central

Desai, Moreshwar; Mathur, Bhoomika; Eblimit, Zeena; Vasquez, Hernan; Taegtmeyer, Heinrich; Karpen, Saul; Penny, Daniel J.; Moore, David D.; Anakk, Sayeepriyadarshini

2017-01-01

Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term Cholecardia. Fxr; Shp double knockout (DKO) mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, DKO mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of Pgc1α, a key regulator of fatty acid metabolism, and that Pgc1α overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the DKO mice. Conclusions Overall, we propose that decreased Pgc1α expression contributes to the metabolic dysfunction in Cholecardia, and that reducing serum bile acid concentrations will be beneficial against metabolic and pathological changes in the heart. PMID:27774647

Metabolic treatment of cancer: intermediate results of a prospective case series.

PubMed

Schwartz, Laurent; Buhler, Ludivine; Icard, Philippe; Lincet, Hubert; Steyaert, Jean-Marc

2014-02-01

The combination of hydroxycitrate and lipoic acid has been demonstrated by several laboratories to be effective in reducing murine cancer growth. All patients had failed standard chemotherapy and were offered only palliative care by their referring oncologist. Karnofsky status was between 50 and 80. Life expectancy was estimated to be between 2 and 6 months. Ten consecutive patients with chemoresistant advanced metastatic cancer were offered compassionate metabolic treatment. They were treated with a combination of lipoic acid at 600 mg i.v. (Thioctacid), hydroxycitrate at 500 mg t.i.d. (Solgar) and low-dose naltrexone at 5 mg (Revia) at bedtime. Primary sites were lung carcinoma (n=2), colonic carcinoma (n=2), ovarian carcinoma (n=1), esophageal carcinoma (n=1), uterine sarcoma (n=1), cholangiocarcinoma (n=1), parotid carcinoma (n=1) and unknown primary (n=1). The patients had been heavily pre-treated. One patient had received four lines of chemotherapy, four patients three lines, four patients two lines and one patient had received radiation therapy and chemotherapy. An eleventh patient with advanced prostate cancer resistant to hormonotherapy treated with hydroxycitrate, lipoic acid and anti-androgen is also reported. One patient was unable to receive i.v. lipoic acid and was switched to oral lipoic acid (Tiobec). Toxicity was limited to transient nausea and vomiting. Two patients died of progressive disease within two months. Two other patients had to be switched to conventional chemotherapy combined with metabolic treatment, one of when had a subsequent dramatic tumor response. Disease in the other patients was either stable or very slowly progressive. The patient with hormone-resistant prostate cancer had a dramatic fall in Prostate-Specific Antigen (90%), which is still decreasing. These very primary results suggest the lack of toxicity and the probable efficacy of metabolic treatment in chemoresistant advanced carcinoma. It is also probable that metabolic

Interaction of ethacrynic acid with control sites of renal glucose metabolism.

PubMed

Fúlgraff, G; Dingler-Núnemann, H

1975-01-01

Ethacrynic acid stimulates in vitro concentration dependent renal gluconeogenesis from substrates which enter the gluconeogenic pathway at the level of the triosephosphates like glycerol or fructose or from substrates which have to pass the oxaloacetate shuttle like pyruvate or from intermediary products of fatty acid oxydation or citrate cycle. Our results suggest that a site of action of ethacrynic acid in this metabolic aspect is the enzyme system fructose diphosphatase/frutose-6-phosphate kinase and eventually additionally pyruvate carboxylase.

Loss of macrophage fatty acid oxidation does not potentiate systemic metabolic dysfunction

PubMed Central

Gonzalez-Hurtado, Elsie; Lee, Jieun; Choi, Joseph; Selen Alpergin, Ebru S.; Collins, Samuel L.; Horton, Maureen R.

2017-01-01

Fatty acid oxidation in macrophages has been suggested to play a causative role in high-fat diet-induced metabolic dysfunction, particularly in the etiology of adipose-driven insulin resistance. To understand the contribution of macrophage fatty acid oxidation directly to metabolic dysfunction in high-fat diet-induced obesity, we generated mice with a myeloid-specific knockout of carnitine palmitoyltransferase II (CPT2 Mϕ-KO), an obligate step in mitochondrial long-chain fatty acid oxidation. While fatty acid oxidation was clearly induced upon IL-4 stimulation, fatty acid oxidation-deficient CPT2 Mϕ-KO bone marrow-derived macrophages displayed canonical markers of M2 polarization following IL-4 stimulation in vitro. In addition, loss of macrophage fatty acid oxidation in vivo did not alter the progression of high-fat diet-induced obesity, inflammation, macrophage polarization, oxidative stress, or glucose intolerance. These data suggest that although IL-4-stimulated alternatively activated macrophages upregulate fatty acid oxidation, fatty acid oxidation is dispensable for macrophage polarization and high-fat diet-induced metabolic dysfunction. Macrophage fatty acid oxidation likely plays a correlative, rather than causative, role in systemic metabolic dysfunction. PMID:28223293

The role of xanthine oxidoreductase and uric acid in metabolic syndrome.

PubMed

Battelli, Maria Giulia; Bortolotti, Massimo; Polito, Letizia; Bolognesi, Andrea

2018-08-01

Xanthine oxidoreductase (XOR) could contribute to the pathogenesis of metabolic syndrome through the oxidative stress and the inflammatory response induced by XOR-derived reactive oxygen species and uric acid. Hyperuricemia is strongly linked to hypertension, insulin resistance, obesity and hypertriglyceridemia. The serum level of XOR is correlated to triglyceride/high density lipoprotein cholesterol ratio, fasting glycemia, fasting insulinemia and insulin resistance index. Increased activity of endothelium-linked XOR may promote hypertension. In addition, XOR is implicated in pre-adipocyte differentiation and adipogenesis. XOR and uric acid play a role in cell transformation and proliferation as well as in the progression and metastatic process. Collected evidences confirm the contribution of XOR and uric acid in metabolic syndrome. However, in some circumstances XOR and uric acid may have anti-oxidant protective outcomes. The dual-face role of both XOR and uric acid explains the contradictory results obtained with XOR inhibitors and suggests caution in their therapeutic use. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Metabolism of nonesterified and esterified hydroxycinnamic acids in red wines by Brettanomyces bruxellensis.

PubMed

Schopp, Lauren M; Lee, Jungmin; Osborne, James P; Chescheir, Stuart C; Edwards, Charles G

2013-11-27

While Brettanomyces can metabolize nonesterified hydroxycinnamic acids found in grape musts/wines (caffeic, p-coumaric, and ferulic acids), it was not known whether this yeast could utilize the corresponding tartaric acid esters (caftaric, p-coutaric, and fertaric acids, respectively). Red wines from Washington and Oregon were inoculated with B. bruxellensis, while hydroxycinnamic acids were monitored by HPLC. Besides consuming p-coumaric and ferulic acids, strains I1a, B1b, and E1 isolated from Washington wines metabolized 40-50% of caffeic acid, a finding in contrast to strains obtained from California wines. Higher molar recoveries of 4-ethylphenol and 4-ethylguaiacol synthesized from p-coumaric and ferulic acids, respectively, were observed in Washington Cabernet Sauvignon and Syrah but not Merlot. This finding suggested that Brettanomyces either (a) utilized vinylphenols formed during processing of some wines or (b) metabolized other unidentified phenolic precursors. None of the strains of Brettanomyces studied metabolized caftaric or p-coutaric acids present in wines from Washington or Oregon.

CACODYLIC ACID (DMAV): METABOLISM AND ...

EPA Pesticide Factsheets

The cacodylic acid (DMAV) issue paper discusses the metabolism and pharmacokinetics of the various arsenical chemicals; evaluates the appropriate dataset to quantify the potential cancer risk to the organic arsenical herbicides; provides an evaluation of the mode of carcinogenic action (MOA) for DMAV including a consideration of the key events for bladder tumor formation in rats, other potential modes of action; and also considers the human relevance of the proposed animal MOA. As part of tolerance reassessment under the Food Quality Protection Act for the August 3, 2006 deadline, the hazard of cacodylic acid is being reassessed.

Insulin activation of plasma non-esterified fatty acid uptake in metabolic syndrome

PubMed Central

Ramos-Roman, Maria A.; Lapidot, Smadar A.; Phair, Robert D.; Parks, Elizabeth J.

2012-01-01

Objectives Insulin control of fatty acid metabolism has long been deemed dominated by suppression of adipose lipolysis. This study’s goal was to test the hypothesis that this single role of insulin is insufficient to explain observed fatty acid dynamics. Methods and Results Fatty acid kinetics were measured during a meal-tolerance test and insulin sensitivity assessed by IVGTT in overweight human subjects (n=15, BMI 35.8 ± 7.1 kg/m2). Non-steady state tracer kinetic models were formulated and tested using ProcessDB© software. Suppression of adipose release alone could not account for NEFA concentration changes postprandially, but when combined with insulin activation of fatty acid uptake was consistent with the NEFA data. The observed insulin Km for NEFA uptake was inversely correlated with both insulin sensitivity of glucose uptake (IVGTT Si) (r=−0.626, P=0.01), and whole body fat oxidation after the meal (r=−0.538, P=0.05). Conclusions These results support insulin regulation of fatty acid turnover by both release and uptake mechanisms. Activation of fatty acid uptake is consistent with the human data, has mechanistic precedent in cell culture, and highlights a new potential target for therapies aimed at improving the control of fatty acid metabolism in insulin-resistant disease states. PMID:22723441

Fatty acid regulation of hepatic lipid metabolism

PubMed Central

Jump, Donald B.

2012-01-01

Purpose of review To discuss transcriptional mechanisms regulating hepatic lipid metabolism. Recent findings Humans who are obese or have diabetes (NIDDM) or metabolic syndrome (MetS) have low blood and tissue levels of C20–22 polyunsaturated fatty acids (PUFAs). Although the impact of low C20–22 PUFAs on disease progression in humans is not fully understood, studies with mice have provided clues suggesting that impaired PUFA metabolism may contribute to the severity of risk factors associated with NIDDM and MetS. High fat diets promote hyperglycemia, insulin resistance and fatty liver in C57BL/6J mice, an effect that correlates with suppressed expression of enzymes involved in PUFA synthesis and decreased hepatic C20–22 PUFA content. A/J mice, in contrast, are resistant to diet-induced obesity and diabetes; these mice have elevated expression of hepatic enzymes involved in PUFA synthesis and C20–22 PUFA content. Moreover, loss-of-function and gain-of-function studies have identified fatty acid elongase (Elovl5), a key enzyme involved in PUFA synthesis, as a regulator of hepatic lipid and carbohydrate metabolism. Elovl5 activity regulates hepatic C20–22 PUFA content, signaling pathways (Akt and PP2A) and transcription factors (SREBP-1, PPARα, FoxO1 and PGC1α) that control fatty acid synthesis and gluconeogenesis. Summary These studies may help define novel strategies to control fatty liver and hyperglycemia associated with NIDDM and MetS. PMID:21178610

Evolution of amino acid metabolism inferred through cladistic analysis.

PubMed

Cunchillos, Chomin; Lecointre, Guillaume

2003-11-28

Because free amino acids were most probably available in primitive abiotic environments, their metabolism is likely to have provided some of the very first metabolic pathways of life. What were the first enzymatic reactions to emerge? A cladistic analysis of metabolic pathways of the 16 aliphatic amino acids and 2 portions of the Krebs cycle was performed using four criteria of homology. The analysis is not based on sequence comparisons but, rather, on coding similarities in enzyme properties. The properties used are shared specific enzymatic activity, shared enzymatic function without substrate specificity, shared coenzymes, and shared functional family. The tree shows that the earliest pathways to emerge are not portions of the Krebs cycle but metabolisms of aspartate, asparagine, glutamate, and glutamine. The views of Horowitz (Horowitz, N. H. (1945) Proc. Natl. Acad. Sci. U. S. A. 31, 153-157) and Cordón (Cordón, F. (1990) Tratado Evolucionista de Biologia, Aguilar, Madrid, Spain), according to which the upstream reactions in the catabolic pathways and the downstream reactions in the anabolic pathways are the earliest in evolution, are globally corroborated; however, with some exceptions. These are due to later opportunistic connections of pathways (actually already suggested by these authors). Earliest enzymatic functions are mostly catabolic; they were deaminations, transaminations, and decarboxylations. From the consensus tree we extracted four time spans for amino acid metabolism development. For some amino acids catabolism and biosynthesis occurred at the same time (Asp, Glu, Lys, Leu, Ala, Val, Ile, Pro, Arg). For others ultimate reactions that use amino acids as a substrate or as a product are distinct in time, with catabolism preceding anabolism for Asn, Gln, and Cys and anabolism preceding catabolism for Ser, Met, and Thr. Cladistic analysis of the structure of biochemical pathways makes hypotheses in biochemical evolution explicit and parsimonious.

Cancer metabolism: fatty acid oxidation in the limelight

PubMed Central

Carracedo, Arkaitz; Cantley, Lewis C.; Pandolfi, Pier Paolo

2013-01-01

Warburg suggested that the alterations in metabolism that he observed in cancer cells were due to the malfunction of mitochondria. In the past decade, we have revisited this idea and reached a better understanding of the ‘metabolic switch’ in cancer cells, including the intimate and causal relationship between cancer genes and metabolic alterations, and their potential to be targeted for cancer treatment. However, the vast majority of the research into cancer metabolism has been limited to a handful of metabolic pathways, while other pathways have remained in the dark. This Progress article brings to light the important contribution of fatty acid oxidation to cancer cell function. PMID:23446547

Acyl Coenzyme A Thioesterase 7 Regulates Neuronal Fatty Acid Metabolism To Prevent Neurotoxicity

PubMed Central

Ellis, Jessica M.; Wong, G. William

2013-01-01

Numerous neurological diseases are associated with dysregulated lipid metabolism; however, the basic metabolic control of fatty acid metabolism in neurons remains enigmatic. Here we have shown that neurons have abundant expression and activity of the long-chain cytoplasmic acyl coenzyme A (acyl-CoA) thioesterase 7 (ACOT7) to regulate lipid retention and metabolism. Unbiased and targeted metabolomic analysis of fasted mice with a conditional knockout of ACOT7 in the nervous system, Acot7N−/−, revealed increased fatty acid flux into multiple long-chain acyl-CoA-dependent pathways. The alterations in brain fatty acid metabolism were concomitant with a loss of lean mass, hypermetabolism, hepatic steatosis, dyslipidemia, and behavioral hyperexcitability in Acot7N−/− mice. These failures in adaptive energy metabolism are common in neurodegenerative diseases. In agreement, Acot7N−/− mice exhibit neurological dysfunction and neurodegeneration. These data show that ACOT7 counterregulates fatty acid metabolism in neurons and protects against neurotoxicity. PMID:23459938

Acyl coenzyme A thioesterase 7 regulates neuronal fatty acid metabolism to prevent neurotoxicity.

PubMed

Ellis, Jessica M; Wong, G William; Wolfgang, Michael J

2013-05-01

Numerous neurological diseases are associated with dysregulated lipid metabolism; however, the basic metabolic control of fatty acid metabolism in neurons remains enigmatic. Here we have shown that neurons have abundant expression and activity of the long-chain cytoplasmic acyl coenzyme A (acyl-CoA) thioesterase 7 (ACOT7) to regulate lipid retention and metabolism. Unbiased and targeted metabolomic analysis of fasted mice with a conditional knockout of ACOT7 in the nervous system, Acot7(N-/-), revealed increased fatty acid flux into multiple long-chain acyl-CoA-dependent pathways. The alterations in brain fatty acid metabolism were concomitant with a loss of lean mass, hypermetabolism, hepatic steatosis, dyslipidemia, and behavioral hyperexcitability in Acot7(N-/-) mice. These failures in adaptive energy metabolism are common in neurodegenerative diseases. In agreement, Acot7(N-/-) mice exhibit neurological dysfunction and neurodegeneration. These data show that ACOT7 counterregulates fatty acid metabolism in neurons and protects against neurotoxicity.

Retrobiosynthetic nuclear magnetic resonance analysis of amino acid biosynthesis and intermediary metabolism. Metabolic flux in developing maize kernels.

PubMed

Glawischnig, E; Gierl, A; Tomas, A; Bacher, A; Eisenreich, W

2001-03-01

Information on metabolic networks could provide the basis for the design of targets for metabolic engineering. To study metabolic flux in cereals, developing maize (Zea mays) kernels were grown in sterile culture on medium containing [U-(13)C(6)]glucose or [1,2-(13)C(2)]acetate. After growth, amino acids, lipids, and sitosterol were isolated from kernels as well as from the cobs, and their (13)C isotopomer compositions were determined by quantitative nuclear magnetic resonance spectroscopy. The highly specific labeling patterns were used to analyze the metabolic pathways leading to amino acids and the triterpene on a quantitative basis. The data show that serine is generated from phosphoglycerate, as well as from glycine. Lysine is formed entirely via the diaminopimelate pathway and sitosterol is synthesized entirely via the mevalonate route. The labeling data of amino acids and sitosterol were used to reconstruct the labeling patterns of key metabolic intermediates (e.g. acetyl-coenzyme A, pyruvate, phosphoenolpyruvate, erythrose 4-phosphate, and Rib 5-phosphate) that revealed quantitative information about carbon flux in the intermediary metabolism of developing maize kernels. Exogenous acetate served as an efficient precursor of sitosterol, as well as of amino acids of the aspartate and glutamate family; in comparison, metabolites formed in the plastidic compartments showed low acetate incorporation.

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

Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism.

PubMed

Lerin, Carles; Goldfine, Allison B; Boes, Tanner; Liu, Manway; Kasif, Simon; Dreyfuss, Jonathan M; De Sousa-Coelho, Ana Luisa; Daher, Grace; Manoli, Irini; Sysol, Justin R; Isganaitis, Elvira; Jessen, Niels; Goodyear, Laurie J; Beebe, Kirk; Gall, Walt; Venditti, Charles P; Patti, Mary-Elizabeth

2016-10-01

Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear. To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis. Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding. Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D.

Pathological hypertrophy and cardiac dysfunction are linked to aberrant endogenous unsaturated fatty acid metabolism

PubMed Central

Salomé Campos, Dijon Henrique; Grippa Sant’Ana, Paula; Okoshi, Katashi; Padovani, Carlos Roberto; Masahiro Murata, Gilson; Nguyen, Son; Kolwicz, Stephen C.; Cicogna, Antonio Carlos

2018-01-01

Pathological cardiac hypertrophy leads to derangements in lipid metabolism that may contribute to the development of cardiac dysfunction. Since previous studies, using high saturated fat diets, have yielded inconclusive results, we investigated whether provision of a high-unsaturated fatty acid (HUFA) diet was sufficient to restore impaired lipid metabolism and normalize diastolic dysfunction in the pathologically hypertrophied heart. Male, Wistar rats were subjected to supra-valvar aortic stenosis (SVAS) or sham surgery. After 6 weeks, diastolic dysfunction and pathological hypertrophy was confirmed and both sham and SVAS rats were treated with either normolipidic or HUFA diet. At 18 weeks post-surgery, the HUFA diet failed to normalize decreased E/A ratios or attenuate measures of cardiac hypertrophy in SVAS animals. Enzymatic activity assays and gene expression analysis showed that both normolipidic and HUFA-fed hypertrophied hearts had similar increases in glycolytic enzyme activity and down-regulation of fatty acid oxidation genes. Mass spectrometry analysis revealed depletion of unsaturated fatty acids, primarily linoleate and oleate, within the endogenous lipid pools of normolipidic SVAS hearts. The HUFA diet did not restore linoleate or oleate in the cardiac lipid pools, but did maintain body weight and adipose mass in SVAS animals. Overall, these results suggest that, in addition to decreased fatty acid oxidation, aberrant unsaturated fatty acid metabolism may be a maladaptive signature of the pathologically hypertrophied heart. The HUFA diet is insufficient to reverse metabolic remodeling, diastolic dysfunction, or pathologically hypertrophy, possibly do to preferentially partitioning of unsaturated fatty acids to adipose tissue. PMID:29494668

Natural toxins that affect plant amino acid metabolism

USDA-ARS?s Scientific Manuscript database

A diverse range of natural compounds interfere with the synthesis and other aspects of amino acid metabolism. Some are amino acid analogues, but most are not. This review covers a number of specific natural phytotoxic compounds by molecular target site. Inhibition of glutamine synthetase is of part...

Obesity and Cancer Progression: Is There a Role of Fatty Acid Metabolism?

PubMed Central

Balaban, Seher; Lee, Lisa S.; Schreuder, Mark; Hoy, Andrew J.

2015-01-01

Currently, there is renewed interest in elucidating the metabolic characteristics of cancer and how these characteristics may be exploited as therapeutic targets. Much attention has centered on glucose, glutamine and de novo lipogenesis, yet the metabolism of fatty acids that arise from extracellular, as well as intracellular, stores as triacylglycerol has received much less attention. This review focuses on the key pathways of fatty acid metabolism, including uptake, esterification, lipolysis, and mitochondrial oxidation, and how the regulators of these pathways are altered in cancer. Additionally, we discuss the potential link that fatty acid metabolism may serve between obesity and changes in cancer progression. PMID:25866768

[Percentage of uric acid calculus and its metabolic character in Dongjiang River valley].

PubMed

Chong, Hong-Heng; An, Geng

2009-02-15

To study the percentage of uric acid calculus in uroliths and its metabolic character in Dongjiang River valley. To analyze the chemical composition of 290 urinary stones by infrared (IR) spectroscopy and study the ratio changes of uric acid calculus. Uric acid calculus patients and healthy people were studied. Personal characteristics, dietary habits were collected. Conditional logistic regression was used for data analysis and studied the dietary risk factors of uric acid calculus. Patients with uric acid calculus, calcium oxalate and those without urinary calculus were undergone metabolic evaluation analysis. The results of uric acid calculus patients compared to another two groups to analysis the relations between the formation of uric acid calculus and metabolism factors. Uric acid calculi were found in 53 cases (18.3%). The multiple logistic regression analysis suggested that low daily water intake, eating more salted and animal food, less vegetable were very closely associated with uric acid calculus. Comparing to calcium oxalate patients, the urine volume, the value of pH, urine calcium, urine oxalic acid were lower, but uric acid was higher than it. The value of pH, urine oxalic acid and citric acid were lower than them, but uric acid and urine calcium were higher than none urinary calculus peoples. Blood potassium and magnesium were lower than them. The percentage of uric acid stones had obvious advanced. Less daily water intake, eating salted food, eating more animal food, less vegetables and daily orange juice intake, eating sea food are the mainly dietary risk factors to the formation of uric acid calculus. Urine volume, the value of pH, citric acid, urine calcium, urine uric acid and the blood natrium, potassium, magnesium, calcium, uric acid have significant influence to the information of uric acid stones.

A causal role for uric acid in fructose-induced metabolic syndrome.

PubMed

Nakagawa, Takahiko; Hu, Hanbo; Zharikov, Sergey; Tuttle, Katherine R; Short, Robert A; Glushakova, Olena; Ouyang, Xiaosen; Feig, Daniel I; Block, Edward R; Herrera-Acosta, Jaime; Patel, Jawaharlal M; Johnson, Richard J

2006-03-01

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.

Branched Chain Amino Acids: Beyond Nutrition Metabolism.

PubMed

Nie, Cunxi; He, Ting; Zhang, Wenju; Zhang, Guolong; Ma, Xi

2018-03-23

Branched chain amino acids (BCAAs), including leucine (Leu), isoleucine (Ile), and valine (Val), play critical roles in the regulation of energy homeostasis, nutrition metabolism, gut health, immunity and disease in humans and animals. As the most abundant of essential amino acids (EAAs), BCAAs are not only the substrates for synthesis of nitrogenous compounds, they also serve as signaling molecules regulating metabolism of glucose, lipid, and protein synthesis, intestinal health, and immunity via special signaling network, especially phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway. Current evidence supports BCAAs and their derivatives as the potential biomarkers of diseases such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), cancer, and cardiovascular diseases (CVDs). These diseases are closely associated with catabolism and balance of BCAAs. Hence, optimizing dietary BCAA levels should have a positive effect on the parameters associated with health and diseases. This review focuses on recent findings of BCAAs in metabolic pathways and regulation, and underlying the relationship of BCAAs to related disease processes.

Branched Chain Amino Acids: Beyond Nutrition Metabolism

PubMed Central

2018-01-01

Branched chain amino acids (BCAAs), including leucine (Leu), isoleucine (Ile), and valine (Val), play critical roles in the regulation of energy homeostasis, nutrition metabolism, gut health, immunity and disease in humans and animals. As the most abundant of essential amino acids (EAAs), BCAAs are not only the substrates for synthesis of nitrogenous compounds, they also serve as signaling molecules regulating metabolism of glucose, lipid, and protein synthesis, intestinal health, and immunity via special signaling network, especially phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway. Current evidence supports BCAAs and their derivatives as the potential biomarkers of diseases such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), cancer, and cardiovascular diseases (CVDs). These diseases are closely associated with catabolism and balance of BCAAs. Hence, optimizing dietary BCAA levels should have a positive effect on the parameters associated with health and diseases. This review focuses on recent findings of BCAAs in metabolic pathways and regulation, and underlying the relationship of BCAAs to related disease processes. PMID:29570613

Alteration of metabolomic markers of amino-acid metabolism in piglets with in-feed antibiotics.

PubMed

Mu, Chunlong; Yang, Yuxiang; Yu, Kaifan; Yu, Miao; Zhang, Chuanjian; Su, Yong; Zhu, Weiyun

2017-04-01

In-feed antibiotics have been used to promote growth in piglets, but its impact on metabolomics profiles associated with host metabolism is largely unknown. In this study, to test the hypothesis that antibiotic treatment may affect metabolite composition both in the gut and host biofluids, metabolomics profiles were analyzed in antibiotic-treated piglets. Piglets were fed a corn-soy basal diet with or without in-feed antibiotics from postnatal day 7 to day 42. The serum biochemical parameters, metabolomics profiles of the serum, urine, and jejunal digesta, and indicators of microbial metabolism (short-chain fatty acids and biogenic amines) were analyzed. Compared to the control group, antibiotics treatment did not have significant effects on serum biochemical parameters except that it increased (P < 0.05) the concentration of urea. Antibiotics treatment increased the relative concentrations of metabolites involved in amino-acid metabolism in the serum, while decreased the relative concentrations of most amino acids in the jejunal content. Antibiotics reduced urinary 2-ketoisocaproate and hippurate. Furthermore, antibiotics decreased (P < 0.05) the concentrations of propionate and butyrate in the feces. Antibiotics significantly affected the concentrations of biogenic amines, which are derived from microbial amino-acid metabolism. The three major amines, putrescine, cadaverine, and spermidine, were all increased (P < 0.05) in the large intestine of antibiotics-treated piglets. These results identified the phenomena that in-feed antibiotics may have significant impact on the metabolomic markers of amino-acid metabolism in piglets.

Altered Cholesterol and Fatty Acid Metabolism in Huntington Disease

PubMed Central

Block, Robert C.; Dorsey, E. Ray; Beck, Christopher A.; Brenna, J. Thomas; Shoulson, Ira

2010-01-01

Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease. PMID:20802793

Glucose metabolic flux distribution of Lactobacillus amylophilus during lactic acid production using kitchen waste saccharified solution.

PubMed

Liu, Jianguo; Wang, Qunhui; Zou, Hui; Liu, Yingying; Wang, Juan; Gan, Kemin; Xiang, Juan

2013-11-01

The (13) C isotope tracer method was used to investigate the glucose metabolic flux distribution and regulation in Lactobacillus amylophilus to improve lactic acid production using kitchen waste saccharified solution (KWSS). The results demonstrate that L. amylophilus is a homofermentative bacterium. In synthetic medium, 60.6% of the glucose entered the Embden-Meyerhof-Parnas (EMP) to produce lactic acid, whereas 36.4% of the glucose entered the pentose phosphate metabolic pathway (HMP). After solid-liquid separation of the KWSS, the addition of Fe(3+) during fermentation enhanced the NADPH production efficiency and increased the NADH content. The flux to the EMP was also effectively increased. Compared with the control (60.6% flux to EMP without Fe(3+) addition), the flux to the EMP with the addition of Fe(3+) (74.3%) increased by 23.8%. In the subsequent pyruvate metabolism, Fe(3+) also increased lactate dehydrogenase activity, and inhibited alcohol dehydrogenase, pyruvate dehydrogenase and pyruvate carboxylase, thereby increasing the lactic acid production to 9.03 g l(-1) , an increase of 8% compared with the control. All other organic acid by-products were lower than in the control. However, the addition of Zn(2+) showed an opposite effect, decreasing the lactic acid production. In conclusion it is feasible and effective means using GC-MS, isotope experiment and MATLAB software to integrate research the metabolic flux distribution of lactic acid bacteria, and the results provide the theoretical foundation for similar metabolic flux distribution. © 2013 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

L-Lactic acid production from glycerol coupled with acetic acid metabolism by Enterococcus faecalis without carbon loss.

PubMed

Murakami, Nao; Oba, Mana; Iwamoto, Mariko; Tashiro, Yukihiro; Noguchi, Takuya; Bonkohara, Kaori; Abdel-Rahman, Mohamed Ali; Zendo, Takeshi; Shimoda, Mitsuya; Sakai, Kenji; Sonomoto, Kenji

2016-01-01

Glycerol is a by-product in the biodiesel production process and considered as one of the prospective carbon sources for microbial fermentation including lactic acid fermentation, which has received considerable interest due to its potential application. Enterococcus faecalis isolated in our laboratory produced optically pure L-lactic acid from glycerol in the presence of acetic acid. Gas chromatography-mass spectrometry analysis using [1, 2-(13)C2] acetic acid proved that the E. faecalis strain QU 11 was capable of converting acetic acid to ethanol during lactic acid fermentation of glycerol. This indicated that strain QU 11 restored the redox balance by oxidizing excess NADH though acetic acid metabolism, during ethanol production, which resulted in lactic acid production from glycerol. The effects of pH control and substrate concentration on lactic acid fermentation were also investigated. Glycerol and acetic acid concentrations of 30 g/L and 10 g/L, respectively, were expected to be appropriate for lactic acid fermentation of glycerol by strain QU 11 at a pH of 6.5. Furthermore, fed-batch fermentation with 30 g/L glycerol and 10 g/L acetic acid wholly exhibited the best performance including lactic acid production (55.3 g/L), lactic acid yield (0.991 mol-lactic acid/mol-glycerol), total yield [1.08 mol-(lactic acid and ethanol)]/mol-(glycerol and acetic acid)], and total carbon yield [1.06 C-mol-(lactic acid and ethanol)/C-mol-(glycerol and acetic acid)] of lactic acid and ethanol. In summary, the strain QU 11 successfully produced lactic acid from glycerol with acetic acid metabolism, and an efficient fermentation system was established without carbon loss. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

In vitro colonic metabolism of coffee and chlorogenic acid results in selective changes in human faecal microbiota growth.

PubMed

Mills, Charlotte E; Tzounis, Xenofon; Oruna-Concha, Maria-Jose; Mottram, Don S; Gibson, Glenn R; Spencer, Jeremy P E

2015-04-28

Coffee is a relatively rich source of chlorogenic acids (CGA), which, as other polyphenols, have been postulated to exert preventive effects against CVD and type 2 diabetes. As a considerable proportion of ingested CGA reaches the large intestine, CGA may be capable of exerting beneficial effects in the large gut. Here, we utilise a stirred, anaerobic, pH-controlled, batch culture fermentation model of the distal region of the colon in order to investigate the impact of coffee and CGA on the growth of the human faecal microbiota. Incubation of coffee samples with the human faecal microbiota led to the rapid metabolism of CGA (4 h) and the production of dihydrocaffeic acid and dihydroferulic acid, while caffeine remained unmetabolised. The coffee with the highest levels of CGA (P<0·05, relative to the other coffees) induced a significant increase in the growth of Bifidobacterium spp. relative to the control vessel at 10 h after exposure (P<0·05). Similarly, an equivalent quantity of CGA (80·8 mg, matched with that in high-CGA coffee) induced a significant increase in the growth of Bifidobacterium spp. (P<0·05). CGA alone also induced a significant increase in the growth of the Clostridium coccoides-Eubacterium rectale group (P<0·05). This selective metabolism and subsequent amplification of specific bacterial populations could be beneficial to host health.

Integrated Transcriptome and Metabolic Analyses Reveals Novel Insights into Free Amino Acid Metabolism in Huangjinya Tea Cultivar

PubMed Central

Zhang, Qunfeng; Liu, Meiya; Ruan, Jianyun

2017-01-01

The chlorotic tea variety Huangjinya, a natural mutant, contains enhanced levels of free amino acids in its leaves, which improves the drinking quality of its brewed tea. Consequently, this chlorotic mutant has a higher economic value than the non-chlorotic varieties. However, the molecular mechanisms behind the increased levels of free amino acids in this mutant are mostly unknown, as are the possible effects of this mutation on the overall metabolome and biosynthetic pathways in tea leaves. To gain further insight into the effects of chlorosis on the global metabolome and biosynthetic pathways in this mutant, Huangjinya plants were grown under normal and reduced sunlight, resulting in chlorotic and non-chlorotic leaves, respectively; their leaves were analyzed using transcriptomics as well as targeted and untargeted metabolomics. Approximately 5,000 genes (8.5% of the total analyzed) and ca. 300 metabolites (14.5% of the total detected) were significantly differentially regulated, thus indicating the occurrence of marked effects of light on the biosynthetic pathways in this mutant plant. Considering primary metabolism, including that of sugars, amino acids, and organic acids, significant changes were observed in the expression of genes involved in both nitrogen (N) and carbon metabolism. The suite of changes not only generated an increase in amino acids, including glutamic acid, glutamine, and theanine, but it also elevated the levels of free ammonium, citrate, and α-ketoglutarate, and lowered the levels of mono- and di-saccharides and of caffeine as compared with the non-chlorotic leaves. Taken together, our results suggest that the increased levels of amino acids in the chlorotic vs. non-chlorotic leaves are likely due to increased protein catabolism and/or decreased glycolysis and diminished biosynthesis of nitrogen-containing compounds other than amino acids, including chlorophyll, purines, nucleotides, and alkaloids. PMID:28321230

Effect of obesity and metabolic syndrome on plasma oxysterols and fatty acids in human.

PubMed

Tremblay-Franco, Marie; Zerbinati, Chiara; Pacelli, Antonio; Palmaccio, Giuseppina; Lubrano, Carla; Ducheix, Simon; Guillou, Hervé; Iuliano, Luigi

2015-07-01

Obesity and the related entity metabolic syndrome are characterized by altered lipid metabolism and associated with increased morbidity risk for cardiovascular disease and cancer. Oxysterols belong to a large family of cholesterol-derived molecules known to play crucial role in many signaling pathways underlying several diseases. Little is known on the potential effect of obesity and metabolic syndrome on oxysterols in human. In this work, we questioned whether circulating oxysterols might be significantly altered in obese patients and in patients with metabolic syndrome. We also tested the potential correlation between circulating oxysterols and fatty acids. 60 obese patients and 75 patients with metabolic syndrome were enrolled in the study along with 210 age- and sex-matched healthy subjects, used as control group. Plasma oxysterols were analyzed by isotope dilution GC/MS, and plasma fatty acids profiling was assessed by gas chromatography coupled with flame ionization detection. We found considerable differences in oxysterols profiling in the two disease groups that were gender-related. Compared to controls, males showed significant differences only in 4α- and 4β-hydroxycholesterol levels in obese and metabolic syndrome patients. In contrast, females showed consistent differences in 7-oxocholesterol, 4α-hydroxycholesterol, 25-hydroxycholesterol and triol. Concerning fatty acids, we found minor differences in the levels of these variables in males of the three groups. Significant changes were observed in plasma fatty acid profile of female patients with obesity or metabolic syndrome. We found significant correlations between various oxysterols and fatty acids. In particular, 4β-hydroxycholesterol, which is reduced in obesity and metabolic syndrome, correlated with a number of saturated and mono-unsaturated fatty acids that are end-products of de novo lipogenesis. Our data provide the first evidence that obesity and metabolic syndrome are associated with

Uric Acid Levels Can Predict Metabolic Syndrome and Hypertension in Adolescents: A 10-Year Longitudinal Study.

PubMed

Sun, Hai-Lun; Pei, Dee; Lue, Ko-Huang; Chen, Yen-Lin

2015-01-01

The relationships between uric acid and chronic disease risk factors such as metabolic syndrome, type 2 diabetes mellitus, and hypertension have been studied in adults. However, whether these relationships exist in adolescents is unknown. We randomly selected 8,005 subjects who were between 10 to 15 years old at baseline. Measurements of uric acid were used to predict the future occurrence of metabolic syndrome, hypertension, and type 2 diabetes. In total, 5,748 adolescents were enrolled and followed for a median of 7.2 years. Using cutoff points of uric acid for males and females (7.3 and 6.2 mg/dl, respectively), a high level of uric acid was either the second or third best predictor for hypertension in both genders (hazard ratio: 2.920 for males, 5.222 for females; p<0.05). However, uric acid levels failed to predict type 2 diabetes mellitus, and only predicted metabolic syndrome in males (hazard ratio: 1.658; p<0.05). The same results were found in multivariate adjusted analysis. In conclusion, a high level of uric acid indicated a higher likelihood of developing hypertension in both genders and metabolic syndrome in males after 10 years of follow-up. However, uric acid levels did not affect the occurrence of type 2 diabetes in both genders.

Metabolism of Mevalonic Acid in Vegetative and Induced Plants of Xanthium strumarium.

PubMed

Bledsoe, C S

1978-11-01

The metabolism of mevalonic acid in Xanthium strumarium L. Chicago plants was studied to determine how mevalonate was metabolized and whether metabolism was related to induction of flowering. Leaves of vegetative, photoperiodically induced, and chemically inhibited cocklebur plants were supplied with [(14)C]mevalonic acid prior to or during a 16-hour inductive dark period. Vegetative, induced, and Tris(2-diethylaminoethyl)phosphate trihydrochloride-treated plants did not differ significantly in the amount of [(14)C]mevalonic acid they absorbed, nor in the distribution of radioactivity among the leaf blade (97%), petiole (2.3%), or shoot tip (0.7%). [(14)C]Mevalonic acid was rapidly metabolized and transported out of the leaves. Possible metabolites of mevalonate were mevalonic acid phosphates and sterols. No detectable (14)C was found in gibberellins, carotenoids, or the phytol alcohol of chlorophyll. Chemically inhibited plants accumulated (14)C compounds not found in vegetative or induced plants. When ethanol extracts of leaves, petioles, and buds were chromatographed, comparisons of chromatographic patterns did not show significant differences between vegetative and induced treatments.

Metabolism of Sialic Acid by Bifidobacterium breve UCC2003

PubMed Central

Egan, Muireann; O'Connell Motherway, Mary; Ventura, Marco

2014-01-01

Bifidobacteria constitute a specific group of commensal bacteria that inhabit the gastrointestinal tracts of humans and other mammals. Bifidobacterium breve UCC2003 has previously been shown to utilize several plant-derived carbohydrates that include cellodextrins, starch, and galactan. In the present study, we investigated the ability of this strain to utilize the mucin- and human milk oligosaccharide (HMO)-derived carbohydrate sialic acid. Using a combination of transcriptomic and functional genomic approaches, we identified a gene cluster dedicated to the uptake and metabolism of sialic acid. Furthermore, we demonstrate that B. breve UCC2003 can cross feed on sialic acid derived from the metabolism of 3′-sialyllactose, an abundant HMO, by another infant gut bifidobacterial strain, Bifidobacterium bifidum PRL2010. PMID:24814790

D-erythroascorbic acid: Its preparations, chemistry, and metabolism (fungi and plants). Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loewus, F.A.; Seib, P.A.

1991-12-31

The origin of oxalate in plants has received considerable attention and glycolate metabolism has been generally regarded as a prime precursor candidate although studies on the metabolism of L-ascorbic acid single out that plant constituent as well. Experiments with oxalate-accumulating plants that contain little or no tartaric acid revealed the presence of a comparable L-ascorbic acid metabolism with the exception that the cleavage products were oxalic acid and L-threonic acid or products of L-threonic acid metabolism. A reasonable mechanism for cleavage of L-ascorbic acid at the endiolic bond is found in studies on the photooxygenation of L-ascorbic acid. Presumably, analogsmore » of L-ascorbic acid that differ only in the substituent at C4 also form a hydroperoxide in the presence of alkaline hydrogen peroxide and subsequently yield oxalic acid and the corresponding aldonic acid or its lactone. We became interested in such a possibility when we discovered that L-ascorbic acid was rare or absent in certain yeasts and fungi whereas a L-ascorbic acid analog, D-glycero-pent-2-enono- 1,4-lactone (D-erythroascorbic acid), was present. It has long been known that oxalate occurs in yeasts and fungi and its production plays a role in plant pathogenesis. As to the biosynthetic origin of fungal oxalic acid there is little information although it is generally assumed that oxaloacetate or possibly, glycolate, might be that precursor.« less

Fatty Acids Consumption: The Role Metabolic Aspects Involved in Obesity and Its Associated Disorders

PubMed Central

Carla Inada, Aline; Marcelino, Gabriela; Maiara Lopes Cardozo, Carla; de Cássia Freitas, Karine; de Cássia Avellaneda Guimarães, Rita; Pereira de Castro, Alinne; Aragão do Nascimento, Valter; Aiko Hiane, Priscila

2017-01-01

Obesity and its associated disorders, such as insulin resistance, dyslipidemia, metabolic inflammation, dysbiosis, and non-alcoholic hepatic steatosis, are involved in several molecular and inflammatory mechanisms that alter the metabolism. Food habit changes, such as the quality of fatty acids in the diet, are proposed to treat and prevent these disorders. Some studies demonstrated that saturated fatty acids (SFA) are considered detrimental for treating these disorders. A high fat diet rich in palmitic acid, a SFA, is associated with lower insulin sensitivity and it may also increase atherosclerosis parameters. On the other hand, a high intake of eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids may promote positive effects, especially on triglyceride levels and increased high-density lipoprotein (HDL) levels. Moreover, polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs) are effective at limiting the hepatic steatosis process through a series of biochemical events, such as reducing the markers of non-alcoholic hepatic steatosis, increasing the gene expression of lipid metabolism, decreasing lipogenic activity, and releasing adiponectin. This current review shows that the consumption of unsaturated fatty acids, MUFA, and PUFA, and especially EPA and DHA, which can be applied as food supplements, may promote effects on glucose and lipid metabolism, as well as on metabolic inflammation, gut microbiota, and hepatic metabolism. PMID:29065507

Amino acid metabolism in tumour-bearing mice.

PubMed Central

Rivera, S; Azcón-Bieto, J; López-Soriano, F J; Miralpeix, M; Argilés, J M

1988-01-01

Mice bearing the Lewis lung carcinoma showed a high tumour glutaminase activity and significantly higher concentrations of most amino acids than in both the liver and the skeletal muscle of the host. Tumour tissue slices showed a marked preference for glutamine, especially for oxidation of its skeleton to CO2. It is proposed that the metabolism of this particular carcinoma is focused on amino acid degradation, glutamine being its preferred substrate. PMID:3342022

Effect of Selection for High Activity-Related Metabolism on Membrane Phospholipid Fatty Acid Composition in Bank Voles.

PubMed

Stawski, Clare; Valencak, Teresa G; Ruf, Thomas; Sadowska, Edyta T; Dheyongera, Geoffrey; Rudolf, Agata; Maiti, Uttaran; Koteja, Paweł

2015-01-01

Endothermy, high basal metabolic rates (BMRs), and high locomotor-related metabolism were important steps in the evolution of mammals. It has been proposed that the composition of membrane phospholipid fatty acids plays an important role in energy metabolism and exercise muscle physiology. In particular, the membrane pacemaker theory of metabolism suggests that an increase in cell membrane fatty acid unsaturation would result in an increase in BMR. We aimed to determine whether membrane phospholipid fatty acid composition of heart, liver, and gastrocnemius muscles differed between lines of bank voles selected for high swim-induced aerobic metabolism-which also evolved an increased BMR-and unselected control lines. Proportions of fatty acids significantly differed among the organs: liver was the least unsaturated, whereas the gastrocnemius muscles were most unsaturated. However, fatty acid proportions of the heart and liver did not differ significantly between selected and control lines. In gastrocnemius muscles, significant differences between selection directions were found: compared to control lines, membranes of selected voles were richer in saturated C18:0 and unsaturated C18:2n-6 and C18:3n-3, whereas the pattern was reversed for saturated C16:0 and unsaturated C20:4n-6. Neither unsaturation index nor other combined indexes of fatty acid proportions differed between lines. Thus, our results do not support the membrane pacemaker hypothesis. However, the differences between selected and control lines in gastrocnemius muscles reflect chain lengths rather than number of double bonds and are probably related to differences in locomotor activity per se rather than to differences in the basal or routine metabolic rate.

Metabolism of uniformly labeled 13C-eicosapentaenoic acid and 13C-arachidonic acid in young and old men.

PubMed

Léveillé, Pauline; Chouinard-Watkins, Raphaël; Windust, Anthony; Lawrence, Peter; Cunnane, Stephen C; Brenna, J Thomas; Plourde, Mélanie

2017-08-01

Background: Plasma eicosapentaenoic acid (EPA) and arachidonic acid (AA) concentrations increase with age. Objective: The aim of this study was to evaluate EPA and AA metabolism in young and old men by using uniformly labeled carbon-13 ( 13 C) fatty acids. Design: Six young (∼25 y old) and 6 old (∼75 y old) healthy men were recruited. Each participant consumed a single oral dose of 35 mg 13 C-EPA and its metabolism was followed in the course of 14 d in the plasma and 28 d in the breath. After the washout period of ≥28 d, the same participants consumed a single oral dose of 50 mg 13 C-AA and its metabolism was followed for 28 d in plasma and breath. Results: There was a time × age interaction for 13 C-EPA ( P time × age = 0.008), and the shape of the postprandial curves was different between young and old men. The 13 C-EPA plasma half-life was ∼2 d for both young and old men ( P = 0.485). The percentage dose recovered of 13 C-EPA per hour as 13 CO 2 and the cumulative β-oxidation of 13 C-EPA did not differ between young and old men. At 7 d, however, old men had a >2.2-fold higher plasma 13 C-DHA concentration synthesized from 13 C-EPA compared with young men ( P age = 0.03). 13 C-AA metabolism was not different between young and old men. The 13 C-AA plasma half-life was ∼4.4 d in both young and old participants ( P = 0.589). Conclusions: The metabolism of 13 C-AA was not modified by age, whereas 13 C-EPA metabolism was slightly but significantly different in old compared with young men. The higher plasma 13 C-DHA seen in old men may be a result of slower plasma DHA clearance with age. This trial was registered at clinicaltrials.gov as NCT02957188. © 2017 American Society for Nutrition.

Systems metabolic engineering strategies for the production of amino acids.

PubMed

Ma, Qian; Zhang, Quanwei; Xu, Qingyang; Zhang, Chenglin; Li, Yanjun; Fan, Xiaoguang; Xie, Xixian; Chen, Ning

2017-06-01

Systems metabolic engineering is a multidisciplinary area that integrates systems biology, synthetic biology and evolutionary engineering. It is an efficient approach for strain improvement and process optimization, and has been successfully applied in the microbial production of various chemicals including amino acids. In this review, systems metabolic engineering strategies including pathway-focused approaches, systems biology-based approaches, evolutionary approaches and their applications in two major amino acid producing microorganisms: Corynebacterium glutamicum and Escherichia coli, are summarized.

Biomechanism of chlorogenic acid complex mediated plasma free fatty acid metabolism in rat liver.

PubMed

H V, Sudeep; K, Venkatakrishna; Patel, Dipak; K, Shyamprasad

2016-08-05

Plasma free fatty acids (FFA) are involved in blood lipid metabolism as well as many health complications. The present study was conducted to evaluate the potential role of chlorogenic acid complex from green coffee bean (CGA7) on FFA metabolism in high fat diet fed rats. Hyperlipidemia was induced in Wistar rats using high-fat diet. The animals were given CGA7/orlistat concurrently for 42 days. The parameters analysed during the study include plasma and liver total cholesterol (TC), Triglycerides (TG) and FFA. AMPK activation in the liver was analysed through ELISA. The multiple factors involved in AMPK mediated FFA metabolism were analysed using western blotting. CGA7 (50, 100, 150 mg/kg BW) decreased triglycerides (TG) and FFA levels in plasma and liver. CGA7 administration led to the activation of AMP-activated protein kinase (AMPK) and a subsequent increase in the levels of carnitine palmitoyltransferase 1 (CPT-1). There was a decrease in acetyl-CoA carboxylase (ACC) activity as evident by the increase in its phosphorylation level. Chlorogenic acids improved the blood lipid metabolism in rats by alleviating the levels of FFA and TG, modulating the multiple factors in liver through AMPK pathway. The study concludes that CGA7 complex can be promoted as an active ingredient in nutrition for obesity management.

Metabolism of hydroxycinnamic acids and their tartaric acid esters by Brettanomyces and Pediococcus in red wines.

USDA-ARS?s Scientific Manuscript database

Caffeic, p-coumaric, and ferulic acids and their corresponding tartaric acid esters (caftaric, coutaric, and fertaric, respectively) are found in wines in varying concentrations. While Brettanomyces and Pediococcus can utilize the free acids, it is not known whether they can metabolize the correspon...

Metabolism of sialic acid by Bifidobacterium breve UCC2003.

PubMed

Egan, Muireann; O'Connell Motherway, Mary; Ventura, Marco; van Sinderen, Douwe

2014-07-01

Bifidobacteria constitute a specific group of commensal bacteria that inhabit the gastrointestinal tracts of humans and other mammals. Bifidobacterium breve UCC2003 has previously been shown to utilize several plant-derived carbohydrates that include cellodextrins, starch, and galactan. In the present study, we investigated the ability of this strain to utilize the mucin- and human milk oligosaccharide (HMO)-derived carbohydrate sialic acid. Using a combination of transcriptomic and functional genomic approaches, we identified a gene cluster dedicated to the uptake and metabolism of sialic acid. Furthermore, we demonstrate that B. breve UCC2003 can cross feed on sialic acid derived from the metabolism of 3'-sialyllactose, an abundant HMO, by another infant gut bifidobacterial strain, Bifidobacterium bifidum PRL2010. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Metabolic Conversion of l-Ascorbic Acid to Oxalic Acid in Oxalate-accumulating Plants 1

PubMed Central

Yang, Joan C.; Loewus, Frank A.

1975-01-01

l-Ascorbic acid-1-14C and its oxidation product, dehydro-l-ascorbic acid, produced labeled oxalic acid in oxalate-accumulating plants such as spinach seedlings (Spinacia oleracea) and the detached leaves of woodsorrel (Oxalis stricta and O. oregana), shamrock (Oxalis adenopylla), and begonia (Begonia evansiana). In O. oregana, conversion occurred equally well in the presence or absence of light. This relationship between l-ascorbic acid metabolism and oxalic acid formation must be given careful consideration in attempts to explain oxalic accumulation in plants. PMID:16659288

Postillumination burst of carbon dioxide in crassalacean Acid metabolism plants.

PubMed

Crews, C E; Vines, H M; Black, C C

1975-04-01

Immediately following exposure to light, a postillumination burst of CO(2) has been detected in Crassulacean acid metabolism plants. A detailed study with pineapple (Ananas comosus) leaves indicates that the postillumination burst changes its amplitude and kinetics during the course of a day. In air, the postillumination burst in pineapple leaves generally is exhibited as two peaks. The postillumination burst is sensitive to atmospheric CO(2) and O(2) concentrations as well as to the light intensity under which plants are grown. We propose that the CO(2) released in the first postillumination burst peak is indicative of photorespiration since it is sensitive to either O(2) or CO(2) concentration while the second CO(2) evolution peak is likely due to decarboxylation of organic acids involved in Crassulacean acid metabolism.In marked contrast to other higher plants, the postillumination burst in Crassulacean acid metabolism plants can be equal to or greater than the rate of photosynthesis. Photosynthesis in pineapple leaves also varies throughout a day. Both photosynthesis and the postillumination burst have a daily variation which apparently is a complex function of degree of leaf acidity, growth light intensity, ambient gas phase, and the time a plant has been exposed to a given gas.

Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity.

PubMed

Mueller, Michaela; Thorell, Anders; Claudel, Thierry; Jha, Pooja; Koefeler, Harald; Lackner, Carolin; Hoesel, Bastian; Fauler, Guenter; Stojakovic, Tatjana; Einarsson, Curt; Marschall, Hanns-Ulrich; Trauner, Michael

2015-06-01

Bile acids (BAs) are major regulators of hepatic BA and lipid metabolism but their mechanisms of action in non-alcoholic fatty liver disease (NAFLD) are still poorly understood. Here we aimed to explore the molecular and biochemical mechanisms of ursodeoxycholic acid (UDCA) in modulating the cross-talk between liver and visceral white adipose tissue (vWAT) regarding BA and cholesterol metabolism and fatty acid/lipid partitioning in morbidly obese NAFLD patients. In this randomized controlled pharmacodynamic study, we analyzed serum, liver and vWAT samples from 40 well-matched morbidly obese patients receiving UDCA (20 mg/kg/day) or no treatment three weeks prior to bariatric surgery. Short term UDCA administration stimulated BA synthesis by reducing circulating fibroblast growth factor 19 and farnesoid X receptor (FXR) activation, resulting in cholesterol 7α-hydroxylase induction mirrored by elevated C4 and 7α-hydroxycholesterol. Enhanced BA formation depleted hepatic and LDL-cholesterol with subsequent activation of the key enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl-CoA reductase. Blunted FXR anti-lipogenic effects induced lipogenic stearoyl-CoA desaturase (SCD) in the liver, thereby increasing hepatic triglyceride content. In addition, induced SCD activity in vWAT shifted vWAT lipid metabolism towards generation of less toxic and more lipogenic monounsaturated fatty acids such as oleic acid. These data demonstrate that by exerting FXR-antagonistic effects, UDCA treatment in NAFLD patients strongly impacts on cholesterol and BA synthesis and induces neutral lipid accumulation in both liver and vWAT. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Value of acid metabolic products in identification of certain corynebacteria.

PubMed Central

Reddy, C A; Kao, M

1978-01-01

Acid metabolic products of 23 strains of human and animal pathogenic corynebacteria, representing eight different species, were determined by gas chromatography. The results showed that the species examined were metabolically heterogeneous and could be presumptively identified based on the acid products produced. Corynebacterium equi did not produce any acids; C. renale produced lactate; and C. pyogenes produced major amounts of lactate, variable amounts of acetate, and minor amounts of succinate and pyruvate. C. kutscheri produced propionate and lactate as major products and pyruvate and oxalacetate as minor products. C. diphtheriae and C. pseudotuberculosis produced major amounts of propionate, acetate, and formate. In addition, C. pseudotuberculosis produced major amounts of pyruvate and minor amounts of succinate, lactate, and oxalacetate, whereas C. diphtheriae strains produced minor but variable amounts of lactate, succinate, fumarate, pyruvate, and oxalacetate. C. bovis produced aicd products similar to those of C. pyogenes but was readily distinguishable from the latter by the lack of hemolysis on blood agar, colony morphology, catalase reaction, and biochemicals. C. suis characteristically produced major amounts of ethanol, acetate, and formate and minor amounts of lactate and succinate but no propionate. PMID:96126

Metabolic Engineering of Actinobacillus succinogenes Provides Insights into Succinic Acid Biosynthesis

PubMed Central

Guarnieri, Michael T.; Chou, Yat-Chen; Salvachúa, Davinia; Mohagheghi, Ali; St. John, Peter C.; Peterson, Darren J.; Bomble, Yannick J.

2017-01-01

ABSTRACT Actinobacillus succinogenes, a Gram-negative facultative anaerobe, exhibits the native capacity to convert pentose and hexose sugars to succinic acid (SA) with high yield as a tricarboxylic acid (TCA) cycle intermediate. In addition, A. succinogenes is capnophilic, incorporating CO2 into SA, making this organism an ideal candidate host for conversion of lignocellulosic sugars and CO2 to an emerging commodity bioproduct sourced from renewable feedstocks. In this work, we report the development of facile metabolic engineering capabilities in A. succinogenes, enabling examination of SA flux determinants via knockout of the primary competing pathways—namely, acetate and formate production—and overexpression of the key enzymes in the reductive branch of the TCA cycle leading to SA. Batch fermentation experiments with the wild-type and engineered strains using pentose-rich sugar streams demonstrate that the overexpression of the SA biosynthetic machinery (in particular, the enzyme malate dehydrogenase) enhances flux to SA. Additionally, removal of competitive carbon pathways leads to higher-purity SA but also triggers the generation of by-products not previously described from this organism (e.g., lactic acid). The resultant engineered strains also lend insight into energetic and redox balance and elucidate mechanisms governing organic acid biosynthesis in this important natural SA-producing microbe. IMPORTANCE Succinic acid production from lignocellulosic residues is a potential route for enhancing the economic feasibility of modern biorefineries. Here, we employ facile genetic tools to systematically manipulate competing acid production pathways and overexpress the succinic acid-producing machinery in Actinobacillus succinogenes. Furthermore, the resulting strains are evaluated via fermentation on relevant pentose-rich sugar streams representative of those from corn stover. Overall, this work demonstrates genetic modifications that can lead to succinic

Metabolic Engineering of Actinobacillus succinogenes Provides Insights into Succinic Acid Biosynthesis.

PubMed

Guarnieri, Michael T; Chou, Yat-Chen; Salvachúa, Davinia; Mohagheghi, Ali; St John, Peter C; Peterson, Darren J; Bomble, Yannick J; Beckham, Gregg T

2017-09-01

Actinobacillus succinogenes , a Gram-negative facultative anaerobe, exhibits the native capacity to convert pentose and hexose sugars to succinic acid (SA) with high yield as a tricarboxylic acid (TCA) cycle intermediate. In addition, A. succinogenes is capnophilic, incorporating CO 2 into SA, making this organism an ideal candidate host for conversion of lignocellulosic sugars and CO 2 to an emerging commodity bioproduct sourced from renewable feedstocks. In this work, we report the development of facile metabolic engineering capabilities in A. succinogenes , enabling examination of SA flux determinants via knockout of the primary competing pathways-namely, acetate and formate production-and overexpression of the key enzymes in the reductive branch of the TCA cycle leading to SA. Batch fermentation experiments with the wild-type and engineered strains using pentose-rich sugar streams demonstrate that the overexpression of the SA biosynthetic machinery (in particular, the enzyme malate dehydrogenase) enhances flux to SA. Additionally, removal of competitive carbon pathways leads to higher-purity SA but also triggers the generation of by-products not previously described from this organism (e.g., lactic acid). The resultant engineered strains also lend insight into energetic and redox balance and elucidate mechanisms governing organic acid biosynthesis in this important natural SA-producing microbe. IMPORTANCE Succinic acid production from lignocellulosic residues is a potential route for enhancing the economic feasibility of modern biorefineries. Here, we employ facile genetic tools to systematically manipulate competing acid production pathways and overexpress the succinic acid-producing machinery in Actinobacillus succinogenes Furthermore, the resulting strains are evaluated via fermentation on relevant pentose-rich sugar streams representative of those from corn stover. Overall, this work demonstrates genetic modifications that can lead to succinic acid

Metabolic Engineering of Actinobacillus succinogenes Provides Insights into Succinic Acid Biosynthesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guarnieri, Michael T.; Chou, Yat -Chen; Salvachua, Davinia Rodriquez

Actinobacillus succinogenes, a Gram-negative facultative anaerobe, exhibits the native capacity to convert pentose and hexose sugars to succinic acid (SA) with high yield as a tricarboxylic acid (TCA) cycle intermediate. In addition, A. succinogenes is capnophilic, incorporating CO 2 into SA, making this organism an ideal candidate host for conversion of lignocellulosic sugars and CO 2 to an emerging commodity bioproduct sourced from renewable feedstocks. In this work, we report the development of facile metabolic engineering capabilities in A. succinogenes, enabling examination of SA flux determinants via knockout of the primary competing pathways—namely, acetate and formate production—and overexpression of themore » key enzymes in the reductive branch of the TCA cycle leading to SA. Batch fermentation experiments with the wild-type and engineered strains using pentose-rich sugar streams demonstrate that the overexpression of the SA biosynthetic machinery (in particular, the enzyme malate dehydrogenase) enhances flux to SA. Additionally, removal of competitive carbon pathways leads to higher-purity SA but also triggers the generation of by-products not previously described from this organism (e.g., lactic acid). The resultant engineered strains also lend insight into energetic and redox balance and elucidate mechanisms governing organic acid biosynthesis in this important natural SA-producing microbe. IMPORTANCE Succinic acid production from lignocellulosic residues is a potential route for enhancing the economic feasibility of modern biorefineries. Here, we employ facile genetic tools to systematically manipulate competing acid production pathways and overexpress the succinic acid-producing machinery in Actinobacillus succinogenes. Furthermore, the resulting strains are evaluated via fermentation on relevant pentose-rich sugar streams representative of those from corn stover. Altogether, this work demonstrates genetic modifications that can lead to succinic

Metabolic Engineering of Actinobacillus succinogenes Provides Insights into Succinic Acid Biosynthesis

DOE PAGES

Guarnieri, Michael T.; Chou, Yat -Chen; Salvachua, Davinia Rodriquez; ...

2017-06-16

Actinobacillus succinogenes, a Gram-negative facultative anaerobe, exhibits the native capacity to convert pentose and hexose sugars to succinic acid (SA) with high yield as a tricarboxylic acid (TCA) cycle intermediate. In addition, A. succinogenes is capnophilic, incorporating CO 2 into SA, making this organism an ideal candidate host for conversion of lignocellulosic sugars and CO 2 to an emerging commodity bioproduct sourced from renewable feedstocks. In this work, we report the development of facile metabolic engineering capabilities in A. succinogenes, enabling examination of SA flux determinants via knockout of the primary competing pathways—namely, acetate and formate production—and overexpression of themore » key enzymes in the reductive branch of the TCA cycle leading to SA. Batch fermentation experiments with the wild-type and engineered strains using pentose-rich sugar streams demonstrate that the overexpression of the SA biosynthetic machinery (in particular, the enzyme malate dehydrogenase) enhances flux to SA. Additionally, removal of competitive carbon pathways leads to higher-purity SA but also triggers the generation of by-products not previously described from this organism (e.g., lactic acid). The resultant engineered strains also lend insight into energetic and redox balance and elucidate mechanisms governing organic acid biosynthesis in this important natural SA-producing microbe. IMPORTANCE Succinic acid production from lignocellulosic residues is a potential route for enhancing the economic feasibility of modern biorefineries. Here, we employ facile genetic tools to systematically manipulate competing acid production pathways and overexpress the succinic acid-producing machinery in Actinobacillus succinogenes. Furthermore, the resulting strains are evaluated via fermentation on relevant pentose-rich sugar streams representative of those from corn stover. Altogether, this work demonstrates genetic modifications that can lead to succinic

Carbon Source-Dependent Inducible Metabolism of Veratryl Alcohol and Ferulic Acid in Pseudomonas putida CSV86

PubMed Central

Mohan, Karishma

2017-01-01

ABSTRACT Pseudomonas putida CSV86 degrades lignin-derived metabolic intermediates, viz., veratryl alcohol, ferulic acid, vanillin, and vanillic acid, as the sole sources of carbon and energy. Strain CSV86 also degraded lignin sulfonate. Cell respiration, enzyme activity, biotransformation, and high-pressure liquid chromatography (HPLC) analyses suggest that veratryl alcohol and ferulic acid are metabolized to vanillic acid by two distinct carbon source-dependent inducible pathways. Vanillic acid was further metabolized to protocatechuic acid and entered the central carbon pathway via the β-ketoadipate route after ortho ring cleavage. Genes encoding putative enzymes involved in the degradation were found to be present at fer, ver, and van loci. The transcriptional analysis suggests a carbon source-dependent cotranscription of these loci, substantiating the metabolic studies. Biochemical and quantitative real-time (qRT)-PCR studies revealed the presence of two distinct O-demethylases, viz., VerAB and VanAB, involved in the oxidative demethylation of veratric acid and vanillic acid, respectively. This report describes the various steps involved in metabolizing lignin-derived aromatic compounds at the biochemical level and identifies the genes involved in degrading veratric acid and the arrangement of phenylpropanoid metabolic genes as three distinct inducible transcription units/operons. This study provides insight into the bacterial degradation of lignin-derived aromatics and the potential of P. putida CSV86 as a suitable candidate for producing valuable products. IMPORTANCE Pseudomonas putida CSV86 metabolizes lignin and its metabolic intermediates as a carbon source. Strain CSV86 displays a unique property of preferential utilization of aromatics, including for phenylpropanoids over glucose. This report unravels veratryl alcohol metabolism and genes encoding veratric acid O-demethylase, hitherto unknown in pseudomonads, thereby providing new insight into the

Bile acids modulate glucocorticoid metabolism and the hypothalamic–pituitary–adrenal axis in obstructive jaundice☆

PubMed Central

McNeilly, Alison D.; Macfarlane, David P.; O’Flaherty, Emmett; Livingstone, Dawn E.; Mitić, Tijana; McConnell, Kirsty M.; McKenzie, Scott M.; Davies, Eleanor; Reynolds, Rebecca M.; Thiesson, Helle C.; Skøtt, Ole; Walker, Brian R.; Andrew, Ruth

2010-01-01

Background & Aims Suppression of the hypothalamic–pituitary–adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5β-reductase. Methods The effect of bile acids on glucocorticoid metabolism was studied in vitro in hepatic subcellular fractions and hepatoma cells, allowing quantitation of the kinetics and transcript abundance of 5β-reductase. Metabolism was subsequently examined in vivo in rats following dietary manipulation or bile duct ligation. Finally, glucocorticoid metabolism was assessed in humans with obstructive jaundice. Results In rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5β-reductase (Ki 9.19 ± 0.40 μM) and reduced its transcript abundance (in H4iiE cells) and promoter activity (reporter system, HepG2 cells). In Wistar rats, dietary chenodeoxycholic acid (1% w/w chow) inhibited hepatic 5β-reductase activity, reduced urinary excretion of 3α,5β-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5β-reductase activity, supplementation of the fat-free diet with CDCA reduced 5β-reductase activity, and urinary 3α,5β-reduced corticosterone. Cholestasis in rats suppressed hepatic 5β-reductase activity and transcript abundance. In eight women with obstructive jaundice, relative urinary excretion of 3α,5β-tetrahydrocortisol was significantly lower than in healthy controls. Conclusion These data suggest a novel role for bile acids in inhibiting hepatic glucocorticoid clearance, of sufficient magnitude to suppress hypothalamic–pituitary–adrenal axis activity. Elevated hepatic bile acids may account for adrenal insufficiency in liver disease. PMID:20347173

Nitrogen isotopes provide clues to amino acid metabolism in human colorectal cancer cells.

PubMed

Krishnamurthy, R V; Suryawanshi, Yogesh R; Essani, Karim

2017-05-31

Glutamic acid and alanine make up more than 60 per cent of the total amino acids in the human body. Glutamine is a significant source of energy for cells and also a prime donor of nitrogen in the biosynthesis of many amino acids. Several studies have advocated the role of glutamic acid in cancer therapy. Identification of metabolic signatures in cancer cells will be crucial for advancement of cancer therapies based on the cell's metabolic state. Stable nitrogen isotope ratios ( 15 N/ 14 N, δ 15 N) are of particular advantage to understand the metabolic state of cancer cells, since most biochemical reactions involve transfer of nitrogen. In our study, we used the natural abundances of nitrogen isotopes (δ 15 N values) of individual amino acids from human colorectal cancer cell lines to investigate isotope discrimination among amino acids. Significant effects were noticed in the case of glutamic acid, alanine, aspartic acid and proline between cancer and healthy cells. The data suggest that glutamic acid is a nitrogen acceptor while alanine, aspartic acid and proline are nitrogen donors in cancerous cells. One plausible explanation is the transamination of the three acids to produce glutamic acid in cancerous cells.

Urea application promotes amino acid metabolism and membrane lipid peroxidation in Azolla.

PubMed

Chen, Jiana; Huang, Min; Cao, Fangbo; Pardha-Saradhi, P; Zou, Yingbin

2017-01-01

A pot experiment was conducted to evaluate the effect of urea on nitrogen metabolism and membrane lipid peroxidation in Azolla pinnata. Compared to controls, the application of urea to A. pinnata resulted in a 44% decrease in nitrogenase activity, no significant change in glutamine synthetase activity, 660% higher glutamic-pyruvic transaminase, 39% increase in free amino acid levels, 22% increase in malondialdehyde levels, 21% increase in Na+/K+- levels, 16% increase in Ca2+/Mg2+-ATPase levels, and 11% decrease in superoxide dismutase activity. In terms of H2O2 detoxifying enzymes, peroxidase activity did not change and catalase activity increased by 64% in urea-treated A. pinnata. These findings suggest that urea application promotes amino acid metabolism and membrane lipid peroxidation in A. pinnata.

13C Metabolic Flux Analysis for Systematic Metabolic Engineering of S. cerevisiae for Overproduction of Fatty Acids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghosh, Amit; Ando, David; Gin, Jennifer

Efficient redirection of microbial metabolism into the abundant production of desired bioproducts remains non-trivial. Here, we used flux-based modeling approaches to improve yields of fatty acids in Saccharomyces cerevisiae. We combined 13C labeling data with comprehensive genome-scale models to shed light onto microbial metabolism and improve metabolic engineering efforts. We concentrated on studying the balance of acetyl-CoA, a precursor metabolite for the biosynthesis of fatty acids. A genome-wide acetyl-CoA balance study showed ATP citrate lyase from Yarrowia lipolytica as a robust source of cytoplasmic acetyl-CoA and malate synthase as a desirable target for downregulation in terms of acetyl-CoA consumption. Thesemore » genetic modifications were applied to S. cerevisiae WRY2, a strain that is capable of producing 460 mg/L of free fatty acids. With the addition of ATP citrate lyase and downregulation of malate synthase, the engineered strain produced 26% more free fatty acids. Further increases in free fatty acid production of 33% were obtained by knocking out the cytoplasmic glycerol-3-phosphate dehydrogenase, which flux analysis had shown was competing for carbon flux upstream with the carbon flux through the acetyl-CoA production pathway in the cytoplasm. In total, the genetic interventions applied in this work increased fatty acid production by ~70%.« less

13C Metabolic Flux Analysis for Systematic Metabolic Engineering of S. cerevisiae for Overproduction of Fatty Acids

DOE PAGES

Ghosh, Amit; Ando, David; Gin, Jennifer; ...

2016-10-05

Efficient redirection of microbial metabolism into the abundant production of desired bioproducts remains non-trivial. Here, we used flux-based modeling approaches to improve yields of fatty acids in Saccharomyces cerevisiae. We combined 13C labeling data with comprehensive genome-scale models to shed light onto microbial metabolism and improve metabolic engineering efforts. We concentrated on studying the balance of acetyl-CoA, a precursor metabolite for the biosynthesis of fatty acids. A genome-wide acetyl-CoA balance study showed ATP citrate lyase from Yarrowia lipolytica as a robust source of cytoplasmic acetyl-CoA and malate synthase as a desirable target for downregulation in terms of acetyl-CoA consumption. Thesemore » genetic modifications were applied to S. cerevisiae WRY2, a strain that is capable of producing 460 mg/L of free fatty acids. With the addition of ATP citrate lyase and downregulation of malate synthase, the engineered strain produced 26% more free fatty acids. Further increases in free fatty acid production of 33% were obtained by knocking out the cytoplasmic glycerol-3-phosphate dehydrogenase, which flux analysis had shown was competing for carbon flux upstream with the carbon flux through the acetyl-CoA production pathway in the cytoplasm. In total, the genetic interventions applied in this work increased fatty acid production by ~70%.« less

Sites of abscisic acid synthesis and metabolism in Ricinus communis L

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeevaart, J.A.D.

1977-05-01

The sites of abscisic acid (ABA) synthesis and metabolism in Ricinus communis L. were investigated by analyzing the levels of ABA and its two metabolites phaseic acid (PA) and dihydrophaseic acid (DPA) in the shoot tips, mature leaves, and phloem sap of stressed and nonstressed plants. Water stress increased the concentration of ABA, PA, and DPA in phloem exudate and also increased the levels of all three compounds in mature leaves and in shoot tips. The latter had a very high DPA content (18.7 ..mu..g/g fresh weight) even in plants not subjected to water stress. When young and mature leavesmore » were excised and allowed to wilt, the level of ABA increased in both, demonstrating that leaves at an early stage of development have the capacity to produce ABA. These results have been interpreted to mean that in mature leaves of nonstressed Ricinus plants, ABA is synthesized and metabolized, and that ABA itself, as well as its metabolites, are translocated in the phloem to the shoot tips (sinks). Since DPA, but not ABA, accumulates in the shoot tips, it follows that ABA is metabolized rapidly in the apical region. To what extent ABA present in young leaves of nonstressed plants is the consequence of synthesis in situ and of import from older leaves remains to be determined.« less

Salicylic Acid Biosynthesis and Metabolism

PubMed Central

Dempsey, D'Maris Amick; Vlot, A. Corina; Wildermuth, Mary C.; Klessig, Daniel F.

2011-01-01

Salicylic acid (SA) has been shown to regulate various aspects of growth and development; it also serves as a critical signal for activating disease resistance in Arabidopsis thaliana and other plant species. This review surveys the mechanisms involved in the biosynthesis and metabolism of this critical plant hormone. While a complete biosynthetic route has yet to be established, stressed Arabidopsis appear to synthesize SA primarily via an isochorismate-utilizing pathway in the chloroplast. A distinct pathway utilizing phenylalanine as the substrate also may contribute to SA accumulation, although to a much lesser extent. Once synthesized, free SA levels can be regulated by a variety of chemical modifications. Many of these modifications inactivate SA; however, some confer novel properties that may aid in long distance SA transport or the activation of stress responses complementary to those induced by free SA. In addition, a number of factors that directly or indirectly regulate the expression of SA biosynthetic genes or that influence the rate of SA catabolism have been identified. An integrated model, encompassing current knowledge of SA metabolism in Arabidopsis, as well as the influence other plant hormones exert on SA metabolism, is presented. PMID:22303280

Progress of succinic acid production from renewable resources: Metabolic and fermentative strategies.

PubMed

Jiang, Min; Ma, Jiangfeng; Wu, Mingke; Liu, Rongming; Liang, Liya; Xin, Fengxue; Zhang, Wenming; Jia, Honghua; Dong, Weiliang

2017-12-01

Succinic acid is a four-carbon dicarboxylic acid, which has attracted much interest due to its abroad usage as a precursor of many industrially important chemicals in the food, chemicals, and pharmaceutical industries. Facing the shortage of crude oil supply and demand of sustainable development, biological production of succinic acid from renewable resources has become a topic of worldwide interest. In recent decades, robust producing strain selection, metabolic engineering of model strains, and process optimization for succinic acid production have been developed. This review provides an overview of succinic acid producers and cultivation technology, highlight some of the successful metabolic engineering approaches. Copyright © 2017 Elsevier Ltd. All rights reserved.

Metabolism of hydroxycinnamic acids and esters by Brettanomyces in different red wines

USDA-ARS?s Scientific Manuscript database

Depending on the cultivars and other factors, differing concentrations of hydroxycinnamic acids (caffeic, p-coumaric, and ferulic acids) and their corresponding tartaric acid esters (caftaric, coutaric, and fertaric acid, respectively) are found in red wines. Hydroxycinnamic acids are metabolized by...

Effect of Ursolic Acid on Metabolic Syndrome, Insulin Sensitivity, and Inflammation.

PubMed

Ramírez-Rodríguez, Alejandra M; González-Ortiz, Manuel; Martínez-Abundis, Esperanza; Acuña Ortega, Natalhie

2017-09-01

To evaluate the effect of ursolic acid on metabolic syndrome, insulin sensitivity, and inflammation, a randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients (30-60 years) with a diagnosis of metabolic syndrome without treatment. They were randomly assigned to two groups of 12 patients, each to receive orally 150 mg of ursolic acid or homologated placebo once a day for 12 weeks. Before and after the intervention, the components of metabolic syndrome, insulin sensitivity (Matsuda index), and inflammation profile (interleukin-6 and C-reactive protein) were evaluated. After ursolic acid administration, the remission of metabolic syndrome occurred in 50% of patients (P = .005) with significant differences in body weight (75.7 ± 11.5 vs. 71 ± 11 kg, P = .002), body mass index (BMI) (29.9 + 3.6 vs. 24.9 ± 1.2 kg/m 2 , P = .049), waist circumference (93 ± 8.9 vs. 83 + 8.6 cm, P = .008), fasting glucose (6.0 ± 0.5 vs. 4.7 ± 0.4 mmol/L, P = .002), and insulin sensitivity (3.1 ± 1.1 vs. 4.2 ± 1.2, P = .003). Ursolic acid administration leads to transient remission of metabolic syndrome, reducing body weight, BMI, waist circumference and fasting glucose, as well as increasing insulin sensitivity.

Uric Acid Stimulates Fructokinase and Accelerates Fructose Metabolism in the Development of Fatty Liver

PubMed Central

Lanaspa, Miguel A.; Sanchez-Lozada, Laura G.; Cicerchi, Christina; Li, Nanxing; Roncal-Jimenez, Carlos A.; Ishimoto, Takuji; Le, Myphuong; Garcia, Gabriela E.; Thomas, Jeffrey B.; Rivard, Christopher J.; Andres-Hernando, Ana; Hunter, Brandi; Schreiner, George; Rodriguez-Iturbe, Bernardo; Sautin, Yuri Y.; Johnson, Richard J.

2012-01-01

Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver. PMID:23112875

Transcriptome and Proteome Expression Analysis of the Metabolism of Amino Acids by the Fungus Aspergillus oryzae in Fermented Soy Sauce

PubMed Central

Zhao, Guozhong; Yao, Yunping; Wang, Chunling; Tian, Fengwei; Liu, Xiaoming; Hou, Lihua; Yang, Zhen; Zhao, Jianxin; Zhang, Hao

2015-01-01

Amino acids comprise the majority of the flavor compounds in soy sauce. A portion of these amino acids are formed from the biosynthesis and metabolism of the fungus Aspergillus oryzae; however, the metabolic pathways leading to the formation of these amino acids in A. oryzae remain largely unknown. We sequenced the transcriptomes of A. oryzae 100-8 and A. oryzae 3.042 under similar soy sauce fermentation conditions. 2D gel electrophoresis was also used to find some differences in protein expression. We found that many amino acid hydrolases (endopeptidases, aminopeptidases, and X-pro-dipeptidyl aminopeptidase) were expressed at much higher levels (mostly greater than double) in A. oryzae 100-8 than in A. oryzae 3.042. Our results indicated that glutamate dehydrogenase may activate the metabolism of amino acids. We also found that the expression levels of some genes changed simultaneously in the metabolic pathways of tyrosine and leucine and that these conserved genes may modulate the function of the metabolic pathway. Such variation in the metabolic pathways of amino acids is important as it can significantly alter the flavor of fermented soy sauce. PMID:25945335

Transcriptome and Proteome Expression Analysis of the Metabolism of Amino Acids by the Fungus Aspergillus oryzae in Fermented Soy Sauce.

PubMed

Zhao, Guozhong; Yao, Yunping; Wang, Chunling; Tian, Fengwei; Liu, Xiaoming; Hou, Lihua; Yang, Zhen; Zhao, Jianxin; Zhang, Hao; Cao, Xiaohong

2015-01-01

Amino acids comprise the majority of the flavor compounds in soy sauce. A portion of these amino acids are formed from the biosynthesis and metabolism of the fungus Aspergillus oryzae; however, the metabolic pathways leading to the formation of these amino acids in A. oryzae remain largely unknown. We sequenced the transcriptomes of A. oryzae 100-8 and A. oryzae 3.042 under similar soy sauce fermentation conditions. 2D gel electrophoresis was also used to find some differences in protein expression. We found that many amino acid hydrolases (endopeptidases, aminopeptidases, and X-pro-dipeptidyl aminopeptidase) were expressed at much higher levels (mostly greater than double) in A. oryzae 100-8 than in A. oryzae 3.042. Our results indicated that glutamate dehydrogenase may activate the metabolism of amino acids. We also found that the expression levels of some genes changed simultaneously in the metabolic pathways of tyrosine and leucine and that these conserved genes may modulate the function of the metabolic pathway. Such variation in the metabolic pathways of amino acids is important as it can significantly alter the flavor of fermented soy sauce.

Metabolism of Mevalonic Acid in Vegetative and Induced Plants of Xanthium strumarium 1

PubMed Central

Bledsoe, Caroline S.; Ross, Cleon W.

1978-01-01

The metabolism of mevalonic acid in Xanthium strumarium L. Chicago plants was studied to determine how mevalonate was metabolized and whether metabolism was related to induction of flowering. Leaves of vegetative, photoperiodically induced, and chemically inhibited cocklebur plants were supplied with [14C]mevalonic acid prior to or during a 16-hour inductive dark period. Vegetative, induced, and Tris(2-diethylaminoethyl)phosphate trihydrochloride-treated plants did not differ significantly in the amount of [14C]mevalonic acid they absorbed, nor in the distribution of radioactivity among the leaf blade (97%), petiole (2.3%), or shoot tip (0.7%). [14C]Mevalonic acid was rapidly metabolized and transported out of the leaves. Possible metabolites of mevalonate were mevalonic acid phosphates and sterols. No detectable 14C was found in gibberellins, carotenoids, or the phytol alcohol of chlorophyll. Chemically inhibited plants accumulated 14C compounds not found in vegetative or induced plants. When ethanol extracts of leaves, petioles, and buds were chromatographed, comparisons of chromatographic patterns did not show significant differences between vegetative and induced treatments. ImagesFig. 1 PMID:16660583

Protein Analysis of Sapienic Acid-Treated Porphyromonas gingivalis Suggests Differential Regulation of Multiple Metabolic Pathways.

PubMed

Fischer, Carol L; Dawson, Deborah V; Blanchette, Derek R; Drake, David R; Wertz, Philip W; Brogden, Kim A

2016-01-01

Lipids endogenous to skin and mucosal surfaces exhibit potent antimicrobial activity against Porphyromonas gingivalis, an important colonizer of the oral cavity implicated in periodontitis. Our previous work demonstrated the antimicrobial activity of the fatty acid sapienic acid (C(16:1Δ6)) against P. gingivalis and found that sapienic acid treatment alters both protein and lipid composition from those in controls. In this study, we further examined whole-cell protein differences between sapienic acid-treated bacteria and untreated controls, and we utilized open-source functional association and annotation programs to explore potential mechanisms for the antimicrobial activity of sapienic acid. Our analyses indicated that sapienic acid treatment induces a unique stress response in P. gingivalis resulting in differential expression of proteins involved in a variety of metabolic pathways. This network of differentially regulated proteins was enriched in protein-protein interactions (P = 2.98 × 10(-8)), including six KEGG pathways (P value ranges, 2.30 × 10(-5) to 0.05) and four Gene Ontology (GO) molecular functions (P value ranges, 0.02 to 0.04), with multiple suggestive enriched relationships in KEGG pathways and GO molecular functions. Upregulated metabolic pathways suggest increases in energy production, lipid metabolism, iron acquisition and processing, and respiration. Combined with a suggested preferential metabolism of serine, which is necessary for fatty acid biosynthesis, these data support our previous findings that the site of sapienic acid antimicrobial activity is likely at the bacterial membrane. P. gingivalis is an important opportunistic pathogen implicated in periodontitis. Affecting nearly 50% of the population, periodontitis is treatable, but the resulting damage is irreversible and eventually progresses to tooth loss. There is a great need for natural products that can be used to treat and/or prevent the overgrowth of periodontal pathogens and

Combined effect of sesamin and α-lipoic acid on hepatic fatty acid metabolism in rats.

PubMed

Ide, Takashi; Azechi, Ayana; Kitade, Sayaka; Kunimatsu, Yoko; Suzuki, Natsuko; Nakajima, Chihiro

2013-04-01

Dietary sesamin (1:1 mixture of sesamin and episesamin) decreases fatty acid synthesis but increases fatty acid oxidation in rat liver. Dietary α-lipoic acid lowers hepatic fatty acid synthesis. These changes can account for the serum lipid-lowering effect of sesamin and α-lipoic acid. It is expected that the combination of these compounds in the diet potentially ameliorates lipid metabolism more than the individual compounds. We therefore studied the combined effect of sesamin and α-lipoic acid on lipid metabolism in rats. Male Sprague-Dawley rats were fed diets supplemented with 0 or 2 g/kg sesamin and containing 0 or 2.5 g/kg α-lipoic acid for 22 days. Sesamin and α-lipoic acid decreased serum lipid concentrations and the combination of these compounds further decreased the parameters in an additive fashion. These compounds reduced the hepatic concentration of triacylglycerol, the lignan being less effective in decreasing this value. The combination failed to cause a stronger decrease in hepatic triacylglycerol concentration. The combination of sesamin and α-lipoic acid decreased the activity and mRNA levels of hepatic lipogenic enzymes in an additive fashion. Sesamin strongly increased the parameters of hepatic fatty acid oxidation enzymes. α-Lipoic acid antagonized the stimulating effect of sesamin of fatty acid oxidation through reductions in the activity of some fatty acid oxidation enzymes and carnitine concentration in the liver. This may account for the failure to observe strong reductions in hepatic triacylglycerol concentration in rats given a diet containing both sesamin and α-lipoic acid.

Branched short-chain fatty acids modulate glucose and lipid metabolism in primary adipocytes

PubMed Central

Heimann, Emilia; Nyman, Margareta; Pålbrink, Ann-Ki; Lindkvist-Petersson, Karin; Degerman, Eva

2016-01-01

ABSTRACT Short-chain fatty acids (SCFAs), e.g. acetic acid, propionic acid and butyric acid, generated through colonic fermentation of dietary fibers, have been shown to reach the systemic circulation at micromolar concentrations. Moreover, SCFAs have been conferred anti-obesity properties in both animal models and human subjects. Branched SCFAs (BSCFAs), e.g., isobutyric and isovaleric acid, are generated by fermentation of branched amino acids, generated from undigested protein reaching colon. However, BSCFAs have been sparsely investigated when referring to effects on energy metabolism. Here we primarily investigate the effects of isobutyric acid and isovaleric acid on glucose and lipid metabolism in primary rat and human adipocytes. BSCFAs inhibited both cAMP-mediated lipolysis and insulin-stimulated de novo lipogenesis at 10 mM, whereas isobutyric acid potentiated insulin-stimulated glucose uptake by all concentrations (1, 3 and 10 mM) in rat adipocytes. For human adipocytes, only SCFAs inhibited lipolysis at 10 mM. In both in vitro models, BSCFAs and SCFAs reduced phosphorylation of hormone sensitive lipase, a rate limiting enzyme in lipolysis. In addition, BSCFAs and SCFAs, in contrast to insulin, inhibited lipolysis in the presence of wortmannin, a phosphatidylinositide 3-kinase inhibitor and OPC3911, a phosphodiesterase 3 inhibitor in rat adipocytes. Furthermore, BSCFAs and SCFAs reduced insulin-mediated phosphorylation of protein kinase B. To conclude, BSCFAs have effects on adipocyte lipid and glucose metabolism that can contribute to improved insulin sensitivity in individuals with disturbed metabolism. PMID:27994949

The influence of placental metabolism on fatty acid transfer to the fetus[S

PubMed Central

Perazzolo, Simone; Hirschmugl, Birgit; Wadsack, Christian; Desoye, Gernot; Lewis, Rohan M.; Sengers, Bram G.

2017-01-01

The factors determining fatty acid transfer across the placenta are not fully understood. This study used a combined experimental and computational modeling approach to explore placental transfer of nonesterified fatty acids and identify the rate-determining processes. Isolated perfused human placenta was used to study the uptake and transfer of 13C-fatty acids and the release of endogenous fatty acids. Only 6.2 ± 0.8% of the maternal 13C-fatty acids taken up by the placenta was delivered to the fetal circulation. Of the unlabeled fatty acids released from endogenous lipid pools, 78 ± 5% was recovered in the maternal circulation and 22 ± 5% in the fetal circulation. Computational modeling indicated that fatty acid metabolism was necessary to explain the discrepancy between uptake and delivery of 13C-fatty acids. Without metabolism, the model overpredicts the fetal delivery of 13C-fatty acids 15-fold. Metabolic rate was predicted to be the main determinant of uptake from the maternal circulation. The microvillous membrane had a greater fatty acid transport capacity than the basal membrane. This study suggests that incorporation of fatty acids into placental lipid pools may modulate their transfer to the fetus. Future work needs to focus on the factors regulating fatty acid incorporation into lipid pools. PMID:27913585

Enhanced d-lactic acid production by recombinant Saccharomyces cerevisiae following optimization of the global metabolic pathway.

PubMed

Yamada, Ryosuke; Wakita, Kazuki; Mitsui, Ryosuke; Ogino, Hiroyasu

2017-09-01

Utilization of renewable feedstocks for the production of bio-based chemicals such as d-lactic acid by engineering metabolic pathways in the yeast Saccharomyces cerevisiae has recently become an attractive option. In this study, to realize efficient d-lactic acid production by S. cerevisiae, the expression of 12 glycolysis-related genes and the Leuconostoc mesenteroides d-LDH gene was optimized using a previously developed global metabolic engineering strategy, and repeated batch fermentation was carried out using the resultant strain YPH499/dPdA3-34/DLDH/1-18. Stable d-lactic acid production through 10 repeated batch fermentations was achieved using YPH499/dPdA3-34/DLDH/1-18. The average d-lactic acid production, productivity, and yield with 10 repeated batch fermentations were 60.3 g/L, 2.80 g/L/h, and 0.646, respectively. The present study is the first report of the application of a global metabolic engineering strategy for bio-based chemical production, and it shows the potential for efficient production of such chemicals by global metabolic engineering of the yeast S. cerevisiae. Biotechnol. Bioeng. 2017;114: 2075-2084. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets.

PubMed

Shin, John J; Aftab, Qurratulain; Austin, Pamela; McQueen, Jennifer A; Poon, Tak; Li, Shu Chen; Young, Barry P; Roskelley, Calvin D; Loewen, Christopher J R

2016-09-01

A hallmark of all primary and metastatic tumours is their high rate of glucose uptake and glycolysis. A consequence of the glycolytic phenotype is the accumulation of metabolic acid; hence, tumour cells experience considerable intracellular acid stress. To compensate, tumour cells upregulate acid pumps, which expel the metabolic acid into the surrounding tumour environment, resulting in alkalization of intracellular pH and acidification of the tumour microenvironment. Nevertheless, we have only a limited understanding of the consequences of altered intracellular pH on cell physiology, or of the genes and pathways that respond to metabolic acid stress. We have used yeast as a genetic model for metabolic acid stress with the rationale that the metabolic changes that occur in cancer that lead to intracellular acid stress are likely fundamental. Using a quantitative systems biology approach we identified 129 genes required for optimal growth under conditions of metabolic acid stress. We identified six highly conserved protein complexes with functions related to oxidative phosphorylation (mitochondrial respiratory chain complex III and IV), mitochondrial tRNA biosynthesis [glutamyl-tRNA(Gln) amidotransferase complex], histone methylation (Set1C-COMPASS), lysosome biogenesis (AP-3 adapter complex), and mRNA processing and P-body formation (PAN complex). We tested roles for two of these, AP-3 adapter complex and PAN deadenylase complex, in resistance to acid stress using a myeloid leukaemia-derived human cell line that we determined to be acid stress resistant. Loss of either complex inhibited growth of Hap1 cells at neutral pH and caused sensitivity to acid stress, indicating that AP-3 and PAN complexes are promising new targets in the treatment of cancer. Additionally, our data suggests that tumours may be genetically sensitized to acid stress and hence susceptible to acid stress-directed therapies, as many tumours accumulate mutations in mitochondrial respiratory chain

Urea application promotes amino acid metabolism and membrane lipid peroxidation in Azolla

PubMed Central

Chen, Jiana; Cao, Fangbo; Pardha-Saradhi, P.; Zou, Yingbin

2017-01-01

A pot experiment was conducted to evaluate the effect of urea on nitrogen metabolism and membrane lipid peroxidation in Azolla pinnata. Compared to controls, the application of urea to A. pinnata resulted in a 44% decrease in nitrogenase activity, no significant change in glutamine synthetase activity, 660% higher glutamic-pyruvic transaminase, 39% increase in free amino acid levels, 22% increase in malondialdehyde levels, 21% increase in Na+/K+- levels, 16% increase in Ca2+/Mg2+-ATPase levels, and 11% decrease in superoxide dismutase activity. In terms of H2O2 detoxifying enzymes, peroxidase activity did not change and catalase activity increased by 64% in urea-treated A. pinnata. These findings suggest that urea application promotes amino acid metabolism and membrane lipid peroxidation in A. pinnata. PMID:28945775

Metabolic syndrome and uric acid nephrolithiasis: insulin resistance in focus.

PubMed

Spatola, Leonardo; Ferraro, Pietro Manuel; Gambaro, Giovanni; Badalamenti, Salvatore; Dauriz, Marco

2018-06-01

Uric acid nephrolithiasis (UAN) is an increasingly common disease in ethnically diverse populations and constitutes about 10% of all kidney stones. Metabolic syndrome and diabetes mellitus are accounted among the major risk factors for UAN, together with environmental exposure, individual lifestyle habits and genetic predisposition. The development and overt manifestation of UAN appears to stem on the background of insulin resistance, which acts at the kidney level by reducing urinary pH, thus hampering the ability of the kidney to generate renal ammonium in response to an acid load. Unduly acidic urinary pH and overt UAN are both considered renal manifestations of insulin resistance. The mechanisms underlying increased endogenous acid production and/or defective ammonium excretion are yet to be completely understood. Although the development of UAN and, more in general, of kidney stones largely recognizes modifiable individual determining factors, the rising prevalence of diabetes, obesity and accompanying metabolic disorders calls for the identification of novel therapeutic approaches and intervention targets. This review aims at providing an updated picture of existing evidence on the relationship between insulin resistance and UAN in the context of metabolic syndrome and in light of the most recent advancements in our understanding of its genetic signature. Copyright © 2018. Published by Elsevier Inc.

Composition of fatty acids in plasma and erythrocytes and eicosanoids level in patients with metabolic syndrome

PubMed Central

2011-01-01

Background Disturbances of the fatty acids composition in plasma and red blood cells and eicosanoid synthesis play an important role in the metabolic syndrome (MS) formation. Methods The observation group included 61 people with metabolic syndrome (30 patients with MS and normal levels of insulin, 31 people with MS and insulin resistance - IR). The parameters of carbohydrate and lipid metabolism in blood serum were examined. The composition of nonesterified fatty acids (NEFA), fatty acid (FA) of red blood cells lipids was analyzed by gas-liquid chromatography. Eicosanoids level in MS patients blood serum was studied by enzyme immunoassay. Results In MS patients in the absence of glucose-insulin homeostasis disturbances and in patients with IR the accumulation of polyunsaturated fatty acids (18:2 n6, 18:3 n3, 22:4 n6) and lower pool of saturated FA (12:0, 14:0, 16: 0, 17:0) in plasma were discovered. A deficit of polyunsaturated FA (18:3 n3, 20:4 n6) with a predominance of on-saturated FA (14:0, 18:0) in erythrocyte membranes was revealed. In MS patients regardless of the carbohydrate metabolism status high levels of leukotriene B4 and 6-keto-prostaglandin-F1α in serum were found. The development of IR in MS patients leads to increased synthesis of thromboxane A2. Conclusion The results revealed a disturbance in nonesterified fatty acids of plasma lipids and red blood cells, eicosanoid synthesis in MS patients. The breach of the plasma and cell membranes fatty acids compositions, synthesis of vasoactive and proinflammatory eicosanoids is an important pathogenetic part of the MS development. PMID:21595891

Metabolic Diet App Suite for inborn errors of amino acid metabolism.

PubMed

Ho, Gloria; Ueda, Keiko; Houben, Roderick F A; Joa, Jeff; Giezen, Alette; Cheng, Barbara; van Karnebeek, Clara D M

2016-03-01

An increasing number of rare inborn errors of metabolism (IEMs) are amenable to targeted metabolic nutrition therapy. Daily adherence is important to attain metabolic control and prevent organ damage. This is challenging however, given the lack of information of disorder specific nutrient content of foods, the limited availability and cost of specialty products as well as difficulties in reliable calculation and tracking of dietary intake and targets. To develop apps for all inborn errors of amino acid metabolism for which the mainstay of treatment is a medical diet, and obtain patient and family feedback throughout the process to incorporate this into subsequent versions. The Metabolic Diet App Suite was created with input from health care professionals as a free, user-friendly, online tool for both mobile devices and desktop computers (http://www.metabolicdietapp.org) for 15 different IEMs. General information is provided for each IEM with links to useful online resources. Nutrient information is based on the MetabolicPro™, a North American food database compiled by the Genetic Metabolic Dietitians International (GMDI) Technology committee. After user registration, a personalized dashboard and management plan including specific nutrient goals are created. Each Diet App has a user-friendly interface and the functions include: nutrient intake counts, adding your own foods and homemade recipes and, managing a daily food diary. Patient and family feedback was overall positive and specific suggestions were used to further improve the App Suite. The Metabolic Diet App Suite aids individuals affected by IEMs to track and plan their meals. Future research should evaluate its impact on patient adherence, metabolic control, quality of life and health-related outcomes. The Suite will be updated and expanded to Apps for other categories of IEMs. Finally, this Suite is a support tool only, and does not replace medical/metabolic nutrition professional advice. Copyright �

Metabolism of the 18O-methoxy substituent of 3-methoxybenzoic acid and other unlabeled methoxybenzoic acids by anaerobic bacteria.

PubMed Central

DeWeerd, K A; Saxena, A; Nagle, D P; Suflita, J M

1988-01-01

O-methyl substituents of aromatic compounds can provide C1 growth substrates for facultative and strict anaerobic bacteria isolated from diverse environments. The mechanism of the bioconversion of methoxylated benzoic acids to the hydroxylated derivatives was investigated with a model substrate and cultures of one anaerobic consortium, eight strict anaerobic bacteria, and one facultative anaerobic microorganism. Using high-pressure liquid chromatography and gas chromatography-mass spectral analysis, we found that a haloaromatic dehalogenating consortium, a dehalogenating isolate from that consortium, Eubacterium limosum, and a strain of Acetobacterium woodii metabolized 3-[methoxy-18O]methoxybenzoic acid (3-anisic acid) to 3-[hydroxy-18O]hydroxybenzoic acid stoichiometrically at rates of 1.5, 3.2, 52.4, and 36.7 nmol/min per mg of protein, respectively. A different strain of Acetobacterium and strains of Syntrophococcus, Clostridium, Desulfotomaculum, Enterobacter, and an anaerobic bacterium, strain TH-001, were unable to transform this compound. The O-demethylating ability of E. limosum was induced only with appropriate methoxylated benzoates but not with D-glucose, lactate, isoleucine, or methanol. Cross-acclimation and growth experiments with E. limosum showed a rate of metabolism that was an order of magnitude slower and showed no growth with either 4-methoxysalicylic acid (2-hydroxy-4-methoxybenzoic acid) or 4-anisic acid (4-methoxybenzoic acid) when adapted to 3-anisic acid. However, A. woodii NZva-16 showed slower rates and no growth with 3- or 4-methoxysalicylic acid when adapted to 3-anisic acid in similar experiments. The results clearly indicate a methyl rather than methoxy group removal mechanism for such reactions. PMID:3389815

Hepatic Metabolism of Perfluorinated Carboxylic Acids and Polycholorotrifluoroethylene: A Nuclear Magnetic Resonance Investigation in Vivo

DTIC Science & Technology

1993-01-14

13. ABSTRACT (Maximum 200 words) This report describes our studies of the effects of perfluorooctanoic acid ( PFOA ) and perfluorodecanolc acid ( PFDA ) on... perfluorooctanole acid ( PFOA ) and perfluorodecanoic acid ( PFDA ) in rats has been the primary focus of our research efforts. During the past year our... PERFLUOROCARBOXYLIC ACIDS ON CARBOHYDRATE METABOLISM We have been actively investigating the hepatic metabolic consequences of PFOA and PFDA exposure

Harmful effects of usnic acid on hepatic metabolism.

PubMed

Moreira, Caroline T; Oliveira, Andrea L; Comar, Jurandir F; Peralta, Rosane M; Bracht, A

2013-04-25

Usnic acid is a naturally occurring dibenzofuran derivative found in several lichen species. The compound has been marketed as an ingredient of food supplements for weight reduction. There is evidence that the compound acts as an uncoupler of mitochondrial oxidative phosphorylation and it is also clear that consumption of the drug can lead to severe hepatotoxicity depending on the doses. Based on these and other ideas the objective of the present work was to investigate the possible effects of usnic acid on liver metabolism. Livers of male Wistar rats were perfused in a non-recirculating system. Usnic acid stimulated oxygen consumption at low concentrations, diminished the cellular ATP levels, increased the cytosolic but diminished the mitochondrial NADH/NAD(+) ratio, strongly inhibited gluconeogenesis from three different substrates (IC(50) between 1.33 and 3.61 μM), stimulated glycolysis, fructolysis, glycogenolysis and ammoniagenesis and inhibited ureogenesis. The (14)CO(2) production from [1-(14)C]octanoate and [1-(14)C]oleate was increased by usnic acid, but ketogenesis from octanoate was diminished and that from oleate was not affected. It may be concluded that the effects of usnic acid up to 2.5 μM reflect predominantly its activity as an uncoupler. At higher concentrations, however, several other effects may become significant, including inhibition of mitochondrial electron flow and inhibition of medium-chain fatty acid oxidation. In metabolic terms, toxicity of usnic acid can be predicted to be especially dangerous in the fasted state due to the combination of several deleterius events such as diminished hepatic glucose and ketone bodies output to the brain and increased ammonia production. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Bile acid metabolism and signaling in cholestasis, inflammation and cancer

PubMed Central

Apte, Udayan

2015-01-01

Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid soluble vitamins. Bile acid synthesis, transport and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration and carcinogenesis. PMID:26233910

Interaction of Gut Microbiota with Bile Acid Metabolism and its Influence on Disease States

PubMed Central

Staley, Christopher; Weingarden, Alexa R.

2016-01-01

Primary bile acids serve important roles in cholesterol metabolism, lipid digestion, host-microbe interactions, and regulatory pathways in the human host. While most bile acids are reabsorbed and recycled via enterohepatic cycling, ~5% serve as substrates for bacterial biotransformation in the colon. Enzymes involved in various transformations have been characterized from cultured gut bacteria and reveal taxa-specific distribution. More recently, bioinformatic approaches have revealed greater diversity in isoforms of these enzymes, and the microbial species in which they are found. Thus, the functional roles played by the bile acid-transforming gut microbiota and the distribution of resulting secondary bile acids, in the bile acid pool, may be profoundly affected by microbial community structure and function. Bile acids and the composition of the bile acid pool have historically been hypothesized to be associated with several disease states, including recurrent Clostridium difficile infection, inflammatory bowel diseases, metabolic syndrome, and several cancers. Recently, however, emphasis has been placed on how microbial communities in the dysbiotic gut may alter the bile acid pool to potentially cause or mitigate disease onset. This review highlights the current understanding of the interactions between the gut microbial community, bile acid biotransformation, and disease states, and addresses future directions to better understand these complex associations. PMID:27888332

Metabolic pathways regulated by γ-aminobutyric acid (GABA) contributing to heat tolerance in creeping bentgrass (Agrostis stolonifera)

PubMed Central

Li, Zhou; Yu, Jingjin; Peng, Yan; Huang, Bingru

2016-01-01

γ-Aminobutyric acid is a non-protein amino acid involved in various metabolic processes. The objectives of this study were to examine whether increased GABA could improve heat tolerance in cool-season creeping bentgrass through physiological analysis, and to determine major metabolic pathways regulated by GABA through metabolic profiling. Plants were pretreated with 0.5 mM GABA or water before exposed to non-stressed condition (21/19 °C) or heat stress (35/30 °C) in controlled growth chambers for 35 d. The growth and physiological analysis demonstrated that exogenous GABA application significantly improved heat tolerance of creeping bentgrass. Metabolic profiling found that exogenous application of GABA led to increases in accumulations of amino acids (glutamic acid, aspartic acid, alanine, threonine, serine, and valine), organic acids (aconitic acid, malic acid, succinic acid, oxalic acid, and threonic acid), sugars (sucrose, fructose, glucose, galactose, and maltose), and sugar alcohols (mannitol and myo-inositol). These findings suggest that GABA-induced heat tolerance in creeping bentgrass could involve the enhancement of photosynthesis and ascorbate-glutathione cycle, the maintenance of osmotic adjustment, and the increase in GABA shunt. The increased GABA shunt could be the supply of intermediates to feed the tricarboxylic acid cycle of respiration metabolism during a long-term heat stress, thereby maintaining metabolic homeostasis. PMID:27455877

Attenuation of abnormalities in the lipid metabolism during experimental myocardial infarction induced by isoproterenol in rats: beneficial effect of ferulic acid and ascorbic acid.

PubMed

Yogeeta, Surinder Kumar; Hanumantra, Rao Balaji Raghavendran; Gnanapragasam, Arunachalam; Senthilkumar, Subramanian; Subhashini, Rajakannu; Devaki, Thiruvengadam

2006-05-01

The present study aims at evaluating the effect of the combination of ferulic acid and ascorbic acid on isoproterenol-induced abnormalities in lipid metabolism. The rats were divided into eight groups: Control, isoproterenol, ferulic acid alone, ascorbic acid alone, ferulic acid+ascorbic acid, ferulic acid+isoproterenol, ascorbic acid+isoproterenol and ferulic acid+ascorbic acid+isoproterenol. Ferulic acid (20 mg/kg b.w.t.) and ascorbic acid (80 mg/kg b.w.t.) both alone and in combination was administered orally for 6 days and on the fifth and the sixth day, isoproterenol (150 mg/kg b.w.t.) was injected intraperitoneally to induce myocardial injury to rats. Induction of rats with isoproterenol resulted in a significant increase in the levels of triglycerides, total cholesterol, free fatty acids, free and ester cholesterol in both serum and cardiac tissue. A rise in the levels of phospholipids, lipid peroxides, low density lipoprotein and very low density lipoprotein-cholesterol was also observed in the serum of isoproterenol-intoxicated rats. Further, a decrease in the level of high density lipoprotein in serum and in the phospholipid levels, in the heart of isoproterenol-intoxicated rats was observed, which was paralleled by abnormal activities of lipid metabolizing enzymes: total lipase, cholesterol ester synthase, lipoprotein lipase and lecithin: cholesterol acyl transferase. Pre-cotreatment with the combination of ferulic acid and ascorbic acid significantly attenuated these alterations and restored the levels to near normal when compared to individual treatment groups. Histopathological observations were also in correlation with the biochemical parameters. These findings indicate the synergistic protective effect of ferulic acid and ascorbic acid on isoproterenol-induced abnormalities in lipid metabolism.

Amino acid levels in nascent metabolic syndrome: A contributor to the pro-inflammatory burden.

PubMed

Reddy, Priya; Leong, Joseph; Jialal, Ishwarlal

2018-05-01

Metabolic Syndrome (MetS) is a cluster of cardio-metabolic risk factors characterized by low-grade inflammation which confers an increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Prior studies have linked elevated branched chain amino acids (BCAA) and aromatic amino acids (AAA) with T2DM and CVD. Due to the paucity of data in MetS, the aim of this study was to investigate the status of amino acids as early biomarkers of nascent MetS patients without T2DM and CVD or smoking. Healthy controls (n = 20) and MetS (n = 29) patients were recruited for the study. MetS was defined by criteria of National Cholesterol Education Program Adult Treatment Panel III of having at least 3 risk factors. Urinary amino acids were quantified by gas chromatography time-of-flight mass spectrometry at the Western NIH Metabolomics Center as expressed to urinary creatinine. Tyrosine and Isoleucine levels were significantly elevated in MetS patients. Isoleucine positively correlated with salient cardio-metabolic features and inflammatory biomarkers. Lysine and Methionine levels were decreased in MetS patients. Lysine correlated negatively with cardio-metabolic features and inflammatory bimarkers. Methionine also correlated negatively with blood pressure and certain inflammatory biomarkers. Our novel results suggest that with regards to the cardio-metabolic risk factors and pro-inflammatory features of MetS, isoleucine (BCAA) demonstrated a positive correlation while lysine demonstrated a negative correlation. Thus, increased levels of isoleucine and decreased levels of lysine could be potential early biomarkers of MetS. Copyright © 2018. Published by Elsevier Inc.

Dietary phenolic acids reverse insulin resistance, hyperglycaemia, dyslipidaemia, inflammation and oxidative stress in high-fructose diet-induced metabolic syndrome rats.

PubMed

Ibitoye, Oluwayemisi B; Ajiboye, Taofeek O

2017-12-20

This study investigated the influence of caffeic, ferulic, gallic and protocatechuic acids on high-fructose diet-induced metabolic syndrome in rats. Oral administration of the phenolic acids significantly reversed high-fructose diet-mediated increase in body mass index and blood glucose. Furthermore, phenolic acids restored high-fructose diet-mediated alterations in metabolic hormones (insulin, leptin and adiponectin). Similarly, elevated tumour necrosis factor-α, interleukin-6 and -8 were significantly lowered. Administration of phenolic acids restored High-fructose diet-mediated increase in the levels of lipid parameters and indices of atherosclerosis, cardiac and cardiovascular diseases. High-fructose diet-mediated decrease in activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase) and increase in oxidative stress biomarkers (reduced glutathione, lipid peroxidation products, protein oxidation and fragmented DNA) were significantly restored by the phenolic acids. The result of this study shows protective influence of caffeic acid, ferulic acid, gallic acid and protocatechuic acid in high-fructose diet-induced metabolic syndrome.

Metabolomic Profiling of Fatty Acid and Amino Acid Metabolism in Youth With Obesity and Type 2 Diabetes

PubMed Central

Mihalik, Stephanie J.; Michaliszyn, Sara F.; de las Heras, Javier; Bacha, Fida; Lee, SoJung; Chace, Donald H.; DeJesus, Victor R.; Vockley, Jerry; Arslanian, Silva A.

2012-01-01

OBJECTIVE We compared acylcarnitine (AcylCN) species, common amino acid and fat oxidation (FOX) byproducts, and plasma amino acids in normal weight (NW; n = 39), obese (OB; n = 64), and type 2 diabetic (n = 17) adolescents. RESEARCH DESIGN AND METHODS Fasting plasma was analyzed by tandem mass spectrometry, body composition by dual energy X-ray absorptiometry and computed tomography, and total-body lipolysis and substrate oxidation by [2H5]glycerol and indirect calorimetry, respectively. In vivo insulin sensitivity (IS) was assessed with a 3-h hyperinsulinemic-euglycemic clamp. RESULTS Long-chain AcylCNs (C18:2-CN to C14:0-CN) were similar among the three groups. Medium- to short-chain AcylCNs (except C8 and C10) were significantly lower in type 2 diabetes compared with NW, and when compared with OB, C2-, C6-, and C10-CN were lower. Amino acid concentrations were lower in type 2 diabetes compared with NW. Fasting lipolysis and FOX were higher in OB and type 2 diabetes compared with NW, and the negative association of FOX to C10:1 disappeared after controlling for adiposity, Tanner stage, and sex. IS was lower in OB and type 2 diabetes with positive associations between IS and arginine, histidine, and serine after adjusting for adiposity, Tanner stage, and sex. CONCLUSIONS These metabolomics results, together with the increased rates of in vivo FOX, are not supportive of defective fatty acid or amino acid metabolism in obesity and type 2 diabetes in youth. Such observations are consistent with early adaptive metabolic plasticity in youth, which over time—with continued obesity and aging—may become dysfunctional, as observed in adults. PMID:22266733

Potential of nor-Ursodeoxycholic Acid in Cholestatic and Metabolic Disorders.

PubMed

Trauner, Michael; Halilbasic, Emina; Claudel, Thierry; Steinacher, Daniel; Fuchs, Claudia; Moustafa, Tarek; Pollheimer, Marion; Krones, Elisabeth; Kienbacher, Christian; Traussnigg, Stefan; Kazemi-Shirazi, Lili; Munda, Petra; Hofer, Harald; Fickert, Peter; Paumgartner, Gustav

2015-01-01

24-nor-ursodeoxycholic acid (norUDCA) is a side-chain shortened derivate of ursodeoxycholic acid (UDCA). Since norUDCA is only ineffectively conjugated with glycine or taurine, it has specific physicochemical and therapeutic properties distinct from UDCA. Nonamidated norUDCA undergoes cholehepatic shunting enabling 'ductular targeting' and inducing a bicarbonate-rich hypercholeresis, with cholangioprotective effects. At the same time it has direct anti-inflammatory, antilipotoxic, anti fibrotic, and antiproliferative properties targeting various liver cell populations. norUDCA appears to be one of the most promising novel treatment approaches targeting the liver and the bile duct system at multifactorial and multicellular levels. This review article is a summary of a lecture given at the XXIII International Bile Acid Meeting (Falk Symposium 194) on 'Bile Acids as Signal Integrators and Metabolic Modulators' held in Freiburg, October 8-9, 2014, and summarizes the recent progress with norUDCA as a novel therapeutic approach in cholestatic and metabolic (liver) disorders. 2015 S. Karger AG, Basel.

Short-Chain Fatty Acids Enhance the Lipid Accumulation of 3T3-L1 Cells by Modulating the Expression of Enzymes of Fatty Acid Metabolism.

PubMed

Yu, Haining; Li, Ran; Huang, Haiyong; Yao, Ru; Shen, Shengrong

2018-01-01

Short-chain fatty acids (SCFA) such as acetic acid, propionic acid, and butyric acid are produced by fermentation by gut microbiota. In this paper, we investigate the effects of SCFA on 3T3-L1 cells and the underlying molecular mechanisms. The cells were treated with acetic acid, propionic acid, or butyric acid when cells were induced to differentiate into adipocytes. MTT assay was employed to detect the viability of 3T3-L1 cells. Oil Red O staining was used to visualize the lipid content in 3T3-L1 cells. A triglyceride assay kit was used to detect the triacylglycerol content in 3T3-L1 cells. qRT-PCR and Western blot were used to evaluate the expression of metabolic enzymes. MTT results showed that safe concentrations of acetic acid, propionic acid, and butyric acid were less than 6.4, 3.2, and 0.8 mM, respectively. Oil Red O staining and triacylglycerols detection results showed that treatment with acetic acid, propionic acid, and butyric acid accelerated the 3T3-L1 adipocyte differentiation. qRT-PCR and Western blot results showed that the expressions of lipoprotein lipase (LPL), adipocyte fatty acid binding protein 4 (FABP4), fatty acid transporter protein 4 (FATP4), and fatty acid synthase (FAS) were significantly increased by acetic acid, propionic acid, and butyric acid treatment during adipose differentiation (p < 0.05). In conclusion, SCFA promoted lipid accumulation by modulating the expression of enzymes of fatty acid metabolism. © 2018 AOCS.

Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels.

PubMed

Herman, Mark A; She, Pengxiang; Peroni, Odile D; Lynch, Christopher J; Kahn, Barbara B

2010-04-09

Whereas the role of adipose tissue in glucose and lipid homeostasis is widely recognized, its role in systemic protein and amino acid metabolism is less well-appreciated. In vitro and ex vivo experiments suggest that adipose tissue can metabolize substantial amounts of branched chain amino acids (BCAAs). However, the role of adipose tissue in regulating BCAA metabolism in vivo is controversial. Interest in the contribution of adipose tissue to BCAA metabolism has been renewed with recent observations demonstrating down-regulation of BCAA oxidation enzymes in adipose tissue in obese and insulin-resistant humans. Using gene set enrichment analysis, we observe alterations in adipose-tissue BCAA enzyme expression caused by adipose-selective genetic alterations in the GLUT4 glucose-transporter expression. We show that the rate of adipose tissue BCAA oxidation per mg of tissue from normal mice is higher than in skeletal muscle. In mice overexpressing GLUT4 specifically in adipose tissue, we observe coordinate down-regulation of BCAA metabolizing enzymes selectively in adipose tissue. This decreases BCAA oxidation rates in adipose tissue, but not in muscle, in association with increased circulating BCAA levels. To confirm the capacity of adipose tissue to modulate circulating BCAA levels in vivo, we demonstrate that transplantation of normal adipose tissue into mice that are globally defective in peripheral BCAA metabolism reduces circulating BCAA levels by 30% (fasting)-50% (fed state). These results demonstrate for the first time the capacity of adipose tissue to catabolize circulating BCAAs in vivo and that coordinate regulation of adipose-tissue BCAA enzymes may modulate circulating BCAA levels.

New insights into the metabolism of aspartate-family amino acids in plant seeds.

PubMed

Wang, Wenyi; Xu, Mengyun; Wang, Guoping; Galili, Gad

2018-02-05

Aspartate-family amino acids. Aspartate (Asp)-family pathway, via several metabolic branches, leads to four key essential amino acids: Lys, Met, Thr, and Ile. Among these, Lys and Met have received the most attention, as they are the most limiting amino acid in cereals and legumes crops, respectively. The metabolic pathways of these four essential amino acids and their interactions with regulatory networks have been well characterized. Using this knowledge, extensive efforts have been devoted to augmenting the levels of these amino acids in various plant organs, especially seeds, which serve as the main source of human food and livestock feed. Seeds store a number of storage proteins, which are utilized as nutrient and energy resources. Storage proteins are composed of amino acids, to guarantee the continuation of plant progeny. Thus, understanding the seed metabolism, especially with respect to the accumulation of aspartate-derived amino acids Lys and Met, is a crucial factor for sustainable agriculture. In this review, we summarized the Asp-family pathway, with some new examples of accumulated Asp-family amino acids, particularly Lys and Met, in plant seeds. We also discuss the recent advances in understanding the roles of Asp-family amino acids during seed development.

Citric Acid Metabolism in Resistant Hypertension: Underlying Mechanisms and Metabolic Prediction of Treatment Response.

PubMed

Martin-Lorenzo, Marta; Martinez, Paula J; Baldan-Martin, Montserrat; Ruiz-Hurtado, Gema; Prado, Jose Carlos; Segura, Julian; de la Cuesta, Fernando; Barderas, Maria G; Vivanco, Fernando; Ruilope, Luis Miguel; Alvarez-Llamas, Gloria

2017-11-01

Resistant hypertension (RH) affects 9% to 12% of hypertensive adults. Prolonged exposure to suboptimal blood pressure control results in end-organ damage and cardiovascular risk. Spironolactone is the most effective drug for treatment, but not all patients respond and side effects are not negligible. Little is known on the mechanisms responsible for RH. We aimed to identify metabolic alterations in urine. In addition, a potential capacity of metabolites to predict response to spironolactone was investigated. Urine was collected from 29 patients with RH and from a group of 13 subjects with pseudo-RH. For patients, samples were collected before and after spironolactone administration and were classified in responders (n=19) and nonresponders (n=10). Nuclear magnetic resonance was applied to identify altered metabolites and pathways. Metabolites were confirmed by liquid chromatography-mass spectrometry. Citric acid cycle was the pathway most significantly altered ( P <0.0001). Metabolic concentrations were quantified and ranged from ng/mL malate to μg/mL citrate. Citrate and oxaloacetate increased in RH versus pseudoresistant. Together with α-ketoglutarate and malate, they were able to discriminate between responders and nonresponders, being the 4 metabolites increased in nonresponders. Combined as a prediction panel, they showed receiver operating characteristiccurve with area under the curve of 0.96. We show that citric acid cycle and deregulation of reactive oxygen species homeostasis control continue its activation after hypertension was developed. A metabolic panel showing alteration before spironolactone treatment and predicting future response of patients is shown. These molecular indicators will contribute optimizing the rate of control of RH patients with spironolactone. © 2017 American Heart Association, Inc.

Comparative effects of high oleic acid vs high mixed saturated fatty acid obesogenic diets upon PUFA metabolism in mice

USDA-ARS?s Scientific Manuscript database

Emerging evidence indicates that the fatty acid composition of obesogenic diets influences physiologic outcomes. There are scant data regarding how the content of non-essential fatty acids like monounsaturated fatty acids (MUFA) and saturated fatty acids (SFAs) impact the metabolism of polyunsaturat...

Oleic acid blocks EGF-induced [Ca2+]i release without altering cellular metabolism in fibroblast EGFR T17.

PubMed

Zugaza, J L; Casabiell, X A; Bokser, L; Casanueva, F F

1995-02-06

EGFR-T17 cells were pretreated with oleic acid and 5-10 minutes later stimulated with EGF, to study if early ionic signals are instrumental in inducing metabolic cellular response. Oleic acid blocks EGF-induced [Ca2+]i rise and Ca2+ influx without altering 2-deoxyglucose and 2-aminobutiryc acid uptake nor acute, nor chronically. Oleic acid it is shown, in the first minutes favors the entrance of both molecules to modify the physico-chemical membrane state. On the other hand, oleic acid is unable to block protein synthesis. The results suggest that EGF-induced Ins(1,4,5)P3/Ca2+ pathway does not seem to be decisive in the control of cellular metabolic activity.

Anaerobic organic acid metabolism of Candida zemplinina in comparison with Saccharomyces wine yeasts.

PubMed

Magyar, Ildikó; Nyitrai-Sárdy, Diána; Leskó, Annamária; Pomázi, Andrea; Kállay, Miklós

2014-05-16

Organic acid production under oxygen-limited conditions has been thoroughly studied in the Saccharomyces species, but practically never investigated in Candida zemplinina, which seems to be an acidogenic species under oxidative laboratory conditions. In this study, several strains of C. zemplinina were tested for organic acid metabolism, in comparison with Saccharomyces cerevisiae, Saccharomyces uvarum and Candida stellata, under fermentative conditions. Only C. stellata produced significantly higher acidity in simple minimal media (SM) with low sugar content and two different nitrogen sources (ammonia or glutamic acid) at low level. However, the acid profile differed largely between the Saccharomyces and Candida species and showed inverse types of N-dependence in some cases. Succinic acid production was strongly enhanced on glutamic acid in Saccharomyces species, but not in Candida species. 2-oxoglutarate production was strongly supported on ammonium nitrogen in Candida species, but remained low in Saccharomyces. Candida species, C. stellata in particular, produced more pyruvic acid regardless of N-sources. From the results, we concluded that the anaerobic organic acid metabolisms of C. zemplinina and C. stellata are different from each other and also from that of the Saccharomyces species. In the formation of succinic acid, the oxidative pathway from glutamic acid seems to play little or no role in C. zemplinina. The reductive branch of the TCA cycle, however, produces acidic intermediates (malic, fumaric, and succinic acid) in a level comparable with the production of the Saccharomyces species. An unidentified organic acid, which was produced on glutamic acid only by the Candida species, needs further investigation. Copyright © 2014 Elsevier B.V. All rights reserved.

Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice.

PubMed

Loftus, Róisín M; Assmann, Nadine; Kedia-Mehta, Nidhi; O'Brien, Katie L; Garcia, Arianne; Gillespie, Conor; Hukelmann, Jens L; Oefner, Peter J; Lamond, Angus I; Gardiner, Clair M; Dettmer, Katja; Cantrell, Doreen A; Sinclair, Linda V; Finlay, David K

2018-06-14

Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cytokine activation of NK cell glycolysis and oxidative phosphorylation (OXPHOS) are essential for robust NK cell responses. However, the mechanisms leading to this metabolic phenotype are unclear. Here we show that the transcription factor cMyc is essential for IL-2/IL-12-induced metabolic and functional responses in mice. cMyc protein levels are acutely regulated by amino acids; cMyc protein is lost rapidly when glutamine is withdrawn or when system L-amino acid transport is blocked. We identify SLC7A5 as the predominant system L-amino acid transporter in activated NK cells. Unlike other lymphocyte subsets, glutaminolysis and the tricarboxylic acid cycle do not sustain OXPHOS in activated NK cells. Glutamine withdrawal, but not the inhibition of glutaminolysis, results in the loss of cMyc protein, reduced cell growth and impaired NK cell responses. These data identify an essential role for amino acid-controlled cMyc for NK cell metabolism and function.

Discriminating gastric cancer and gastric ulcer using human plasma amino acid metabolic profile.

PubMed

Jing, Fangyu; Hu, Xin; Cao, Yunfeng; Xu, Minghao; Wang, Yuanyuan; Jing, Yu; Hu, Xiaodan; Gao, Yu; Zhu, Zhitu

2018-06-01

Patients with gastric ulcer (GU) have a significantly higher risk of developing gastric cancer (GC), especially within 2 years after diagnosis. The main way to improve the prognosis of GC is to predict the tumorigenesis and metastasis in the early stage. The objective of this study was to demonstrate the ability of human plasma amino acid metabolic profile for discriminating GC and GU. In this study, we first used liquid chromatography-tandem mass spectrometry technique to characterize the plasma amino acid metabolism in GC and GU patients. Plasma samples were collected from 84 GC patients and 82 GU patients, and 22 amino acids were detected in each patient. Partial least squares-discriminant analysis model was performed to analyze the data of these amino acids. We observed seven differential amino acids between GC and GU. A regression analysis model was established using these seven amino acids. Finally, a panel of five differential amino acids, including glutamine, ornithine, histidine, arginine and tryptophan, was identified for discriminating GC and GU with good specificity and sensitivity. The receiver operating characteristic curve was used to evaluate diagnostic ability of the regression model and area under the curve was 0.922. In conclusion, this study demonstrated the potential values of plasma amino acid metabolic profile and metabolomic analysis technique in assisting diagnosis of GC. More studies are needed to highlight the theoretical strengths of metabolomics to understand the potential metabolic mechanisms in GC. © 2018 IUBMB Life, 70(6):553-562, 2018. © 2018 International Union of Biochemistry and Molecular Biology.

Short- and medium-chain fatty acids in energy metabolism: the cellular perspective

PubMed Central

Schönfeld, Peter; Wojtczak, Lech

2016-01-01

Short- and medium-chain fatty acids (SCFAs and MCFAs), independently of their cellular signaling functions, are important substrates of the energy metabolism and anabolic processes in mammals. SCFAs are mostly generated by colonic bacteria and are predominantly metabolized by enterocytes and liver, whereas MCFAs arise mostly from dietary triglycerides, among them milk and dairy products. A common feature of SCFAs and MCFAs is their carnitine-independent uptake and intramitochondrial activation to acyl-CoA thioesters. Contrary to long-chain fatty acids, the cellular metabolism of SCFAs and MCFAs depends to a lesser extent on fatty acid-binding proteins. SCFAs and MCFAs modulate tissue metabolism of carbohydrates and lipids, as manifested by a mostly inhibitory effect on glycolysis and stimulation of lipogenesis or gluconeogenesis. SCFAs and MCFAs exert no or only weak protonophoric and lytic activities in mitochondria and do not significantly impair the electron transport in the respiratory chain. SCFAs and MCFAs modulate mitochondrial energy production by two mechanisms: they provide reducing equivalents to the respiratory chain and partly decrease efficacy of oxidative ATP synthesis. PMID:27080715

Potential use of carbon-11 labeled alpha-aminoisobutyric acid (AIB) as an in vivo tracer of amino acid uptake in differing metabolic states

DOE Office of Scientific and Technical Information (OSTI.GOV)

Conti, P.S.; Starnes, H.F.; Brennan, M.F.

1986-05-01

AIB has been used as a model amino acid for the evaluation of alanine-preferring amino acid transport. Hormonal factors and starvation alter the tissue distribution of amino acids, particularly in liver and muscle. With positron emission tomography and labeling of biochemical tracers with C-11, (t1/2=20.4 min), it is now possible to study amino acid kinetics in vivo using external imaging. In order to investigate the utility of C-11 AIB as an in vivo tracer of altered tissue metabolism, C-14 AIB was studied in groups of rats with either streptozotocin-induced diabetes, insulin-induced hypoglycemia or starvation. The data suggest an increased aminomore » acid uptake in liver in starvation, an increased uptake in muscle in response to insulin and associated hypoglycemia and decreased transport in muscle in starvation, as seen by other investigators. These results suggest that C-11 AIB may be useful as an in vivo monitor of metabolic changes in body tissues.« less

Effects of dietary vitamin B6 supplementation on fillet fatty acid composition and fatty acid metabolism of rainbow trout fed vegetable oil based diets.

PubMed

Senadheera, Shyamalie D; Turchini, Giovanni M; Thanuthong, Thanongsak; Francis, David S

2012-03-07

Fish oil replacement in aquaculture feeds results in major modifications to the fatty acid makeup of cultured fish. Therefore, in vivo fatty acid biosynthesis has been a topic of considerable research interest. Evidence suggests that pyridoxine (vitamin B(6)) plays a role in fatty acid metabolism, and in particular, the biosynthesis of LC-PUFA has been demonstrated in mammals. However, there is little information on the effects of dietary pyridoxine availability in fish fed diets lacking LC-PUFA. This study demonstrates a relationship between dietary pyridoxine supplementation and fatty acid metabolism in rainbow trout. In particular, the dietary pyridoxine level was shown to modulate and positively stimulate the activity of the fatty acid elongase and Δ-6 and Δ-5 desaturase enzymes, deduced by the whole-body fatty acid balance method. This activity was insufficient to compensate for a diet lacking in LC-PUFA but does highlight potential strategies to maximize this activity in cultured fish, especially when fish oil is replaced with vegetable oils.

Energetic and metabolic transient response of Saccharomyces cerevisiae to benzoic acid.

PubMed

Kresnowati, M T A P; van Winden, W A; van Gulik, W M; Heijnen, J J

2008-11-01

Saccharomyces cerevisiae is known to be able to adapt to the presence of the commonly used food preservative benzoic acid with a large energy expenditure. Some mechanisms for the adaptation process have been suggested, but its quantitative energetic and metabolic aspects have rarely been discussed. This study discusses use of the stimulus response approach to quantitatively study the energetic and metabolic aspects of the transient adaptation of S. cerevisiae to a shift in benzoic acid concentration, from 0 to 0.8 mM. The information obtained also serves as the basis for further utilization of benzoic acid as a tool for targeted perturbation of the energy system, which is important in studying the kinetics and regulation of central carbon metabolism in S. cerevisiae. Using this experimental set-up, we found significant fast-transient (< 3000 s) increases in O(2) consumption and CO(2) production rates, of approximately 50%, which reflect a high energy requirement for the adaptation process. We also found that with a longer exposure time to benzoic acid, S. cerevisiae decreases the cell membrane permeability for this weak acid by a factor of 10 and decreases the cell size to approximately 80% of the initial value. The intracellular metabolite profile in the new steady-state indicates increases in the glycolytic and tricarboxylic acid cycle fluxes, which are in agreement with the observed increases in specific glucose and O(2) uptake rates.

The gut microbiota modulates host amino acid and glutathione metabolism in mice

PubMed Central

Mardinoglu, Adil; Shoaie, Saeed; Bergentall, Mattias; Ghaffari, Pouyan; Zhang, Cheng; Larsson, Erik; Bäckhed, Fredrik; Nielsen, Jens

2015-01-01

The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV-R) and germ-free (GF) mice using gene expression data and tissue-specific genome-scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue-specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV-R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N-acetylated AAs in the hepatic portal vein of CONV-R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV-R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice. PMID:26475342

Metabolic interaction between urea cycle and citric acid cycle shunt: A guided approach.

PubMed

Pesi, Rossana; Balestri, Francesco; Ipata, Piero L

2018-03-01

This article is a guided pedagogical approach, devoted to postgraduate students specializing in biochemistry, aimed at presenting all single reactions and overall equations leading to the metabolic interaction between ureagenesis and citric acid cycle to be incorporated into a two-three lecture series about the interaction of urea cycle with other metabolic pathways. We emphasize that citrate synthetase, aconitase, and isocitrate dehydrogenase, three enzymes of the citric acid cycle are not involved, thus creating a shunt in citric acid cycle. In contrast, the glutamic-oxaloacetate transaminase, which does not belong to citric acid cycle, has a paramount importance in the metabolic interaction of the two cycles, because it generates aspartate, one of the two fuel molecules of urea cycle, and a-ketoglutarate, an intermediate of the citric acid cycle. Finally, students should appreciate that balancing equations for all atoms and charges is not only a stoichiometric task, but strongly facilitates the discussion of the physiological roles of metabolic pathways. Indeed, this exercise has been used in the classroom, to encourage a deeper level of understanding of an important biochemical issue. © 2017 by The International Union of Biochemistry and Molecular Biology, 46(2):182-185, 2018. © 2017 The International Union of Biochemistry and Molecular Biology.

Dietary taurine alters ascorbic acid metabolism in rats fed diets containing polychlorinated biphenyls.

PubMed

Mochizuki, H; Oda, H; Yokogoshi, H

2000-04-01

The effect of dietary taurine on ascorbic acid metabolism and hepatic drug-metabolizing enzymes was investigated in rats fed diets containing polychlorinated biphenyls (PCB) to determine whether taurine has an adaptive and protective function in xenobiotic-treated animals. Young male Wistar rats (60 g) were fed diets containing 0 or 0.2 g/kg diet PCB with or without 30 g/kg diet of taurine for 14 d. The rats fed the PCB-containing diets had greater liver weight, higher ascorbic acid concentrations in the liver and spleen and greater hepatic cytochrome P-450 contents than control rats that were not treated with PCB (P < 0.01). In PCB-fed rats, urinary ascorbic acid excretion was enhanced, and serum cholesterol concentration (especially HDL-cholesterol) was significantly elevated compared with those in control rats. Dietary taurine significantly potentiated the increases in the urinary excretion of ascorbic acid and the rise in the levels of cytochrome P-450 which were caused by PCB treatment. On the other hand, the supplementation of taurine to control diet did not alter these variables. Taurine may enhance the hepatic drug-metabolizing systems, leading to the stimulation of the ascorbic acid metabolism in rats fed diets containing PCB.

Potential Antagonist of Folic Acid Metabolism as Malarial Drugs,

DTIC Science & Technology

1982-09-01

which sen.irited from the hydrocloric acid was filtered and then washed with water (25 ml). The reaction gave 2.3 g of the product which melted be...neutralized with cold dilute hydrocloric acid and evaporated to dryness. The residue was then extracted with methylene chloride filtered, and again...FhGh6/15hEE 1281 12.5 ~I1.50 IIA 132ii MJCRc)tll I’RE SOLU i UN ltIS CHiARI AD FINAL REPORT POTENTIAL ANTAGONIST OF FOLIC ACID METABOLISM AS MALARIAL

A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia.

PubMed

Kaliannan, Kanakaraju; Wang, Bin; Li, Xiang-Yong; Kim, Kui-Jin; Kang, Jing X

2015-06-11

Metabolic endotoxemia, commonly derived from gut dysbiosis, is a primary cause of chronic low grade inflammation that underlies many chronic diseases. Here we show that mice fed a diet high in omega-6 fatty acids exhibit higher levels of metabolic endotoxemia and systemic low-grade inflammation, while transgenic conversion of tissue omega-6 to omega-3 fatty acids dramatically reduces endotoxemic and inflammatory status. These opposing effects of tissue omega-6 and omega-3 fatty acids can be eliminated by antibiotic treatment and animal co-housing, suggesting the involvement of the gut microbiota. Analysis of gut microbiota and fecal transfer revealed that elevated tissue omega-3 fatty acids enhance intestinal production and secretion of intestinal alkaline phosphatase (IAP), which induces changes in the gut bacteria composition resulting in decreased lipopolysaccharide production and gut permeability, and ultimately, reduced metabolic endotoxemia and inflammation. Our findings uncover an interaction between host tissue fatty acid composition and gut microbiota as a novel mechanism for the anti-inflammatory effect of omega-3 fatty acids. Given the excess of omega-6 and deficiency of omega-3 in the modern Western diet, the differential effects of tissue omega-6 and omega-3 fatty acids on gut microbiota and metabolic endotoxemia provide insight into the etiology and management of today's health epidemics.

Ellagic acid attenuates high-carbohydrate, high-fat diet-induced metabolic syndrome in rats.

PubMed

Panchal, Sunil K; Ward, Leigh; Brown, Lindsay

2013-03-01

Fruits and nuts may prevent or reverse common human health conditions such as obesity, diabetes and hypertension; together, these conditions are referred to as metabolic syndrome, an increasing problem. This study has investigated the responses to ellagic acid, present in many fruits and nuts, in a diet-induced rat model of metabolic syndrome. Eight- to nine-week-old male Wistar rats were divided into four groups for 16-week feeding with cornstarch diet (C), cornstarch diet supplemented with ellagic acid (CE), high-carbohydrate, high-fat diet (H) and high-carbohydrate, high-fat diet supplemented with ellagic acid (HE). CE and HE rats were given 0.8 g/kg ellagic acid in food from week 8 to 16 only. At the end of 16 weeks, cardiovascular, hepatic and metabolic parameters along with protein levels of Nrf2, NF-κB and CPT1 in the heart and the liver were characterised. High-carbohydrate, high-fat diet-fed rats developed cardiovascular remodelling, impaired ventricular function, impaired glucose tolerance, non-alcoholic fatty liver disease with increased protein levels of NF-κB and decreased protein levels of Nrf2 and CPT1 in the heart and the liver. Ellagic acid attenuated these diet-induced symptoms of metabolic syndrome with normalisation of protein levels of Nrf2, NF-κB and CPT1. Ellagic acid derived from nuts and fruits such as raspberries and pomegranates may provide a useful dietary supplement to decrease the characteristic changes in metabolism and in cardiac and hepatic structure and function induced by a high-carbohydrate, high-fat diet by suppressing oxidative stress and inflammation.

Skeletal Muscle Acute and Chronic Metabolic Response to Essential Amino Acid Supplementation in Hypertriglyceridemic Older Adults

PubMed Central

Marquis, Bryce J; Hurren, Nicholas M; Carvalho, Eugenia; Kim, Il-Young; Schutzler, Scott; Azhar, Gohar; Wolfe, Robert R; Børsheim, Elisabet

2017-01-01

Abstract Background: Supplementation with essential amino acids (EAAs) + arginine is a promising nutritional approach to decrease plasma triglyceride (TG) concentrations, which are an independent risk factor for ischemic heart disease. Objective: The objective of this study was to examine the effects of 8 wk of EAA supplementation on skeletal muscle basal metabolite concentrations and changes in metabolic response to acute EAA intake, with an emphasis on mitochondrial metabolism, in adults with elevated TGs to better understand the mechanisms of lowering plasma TGs. Methods: Older adults with elevated plasma TG concentrations were given 22 g EAAs to ingest acutely before and after an 8-wk EAA supplementation period. Skeletal muscle biopsy samples were collected before and after acute EAA intake, both pre- and postsupplementation (4 biopsy samples), and targeted metabolomic analyses of organic acids and acylcarnitines were conducted on the specimens. Results: Acute EAA intake resulted in increased skeletal muscle acylcarnitine concentrations associated with oxidative catabolism of the supplement components, with the largest increases found in acylcarnitines of branched-chain amino acid oxidative catabolism, including isovaleryl-carnitine (2200%) and 2-methylbutyryl-carnitine (2400%). The chronic EAA supplementation resulted in a 19% decrease in plasma TGs along with accumulation of long-chain acylcarnitines myristoyl- (90%) and stearoyl- (120%) carnitine in skeletal muscle and increases in succinyl-carnitine (250%) and the late-stage tricarboxylic acid cycle intermediates fumarate (44%) and malate (110%). Conclusions: Supplementation with EAAs shows promise as an approach for moderate reduction in plasma TGs. Changes in skeletal muscle metabolites suggest incomplete fatty acid oxidation and increased anaplerosis, which suggests a potential bottleneck in fatty acid metabolism.

Engineering microbial fatty acid metabolism for biofuels and biochemicals.

PubMed

Marella, Eko Roy; Holkenbrink, Carina; Siewers, Verena; Borodina, Irina

2018-04-01

Traditional oleochemical industry chemically processes animal fats and plant oils to produce detergents, lubricants, biodiesel, plastics, coatings, and other products. Biotechnology offers an alternative process, where the same oleochemicals can be produced from abundant biomass feedstocks using microbial catalysis. This review summarizes the recent advances in the engineering of microbial metabolism for production of fatty acid-derived products. We highlight the efforts in engineering the central carbon metabolism, redox metabolism, controlling the chain length of the products, and obtaining metabolites with different functionalities. The prospects of commercializing microbial oleochemicals are also discussed. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Soybean Aphid Infestation Induces Changes in Fatty Acid Metabolism in Soybean

PubMed Central

Kanobe, Charles; McCarville, Michael T.; O’Neal, Matthew E.; Tylka, Gregory L.; MacIntosh, Gustavo C.

2015-01-01

The soybean aphid (Aphis glycines Matsumura) is one of the most important insect pests of soybeans in the North-central region of the US. It has been hypothesized that aphids avoid effective defenses by inhibition of jasmonate-regulated plant responses. Given the role fatty acids play in jasmonate-induced plant defenses, we analyzed the fatty acid profile of soybean leaves and seeds from aphid-infested plants. Aphid infestation reduced levels of polyunsaturated fatty acids in leaves with a concomitant increase in palmitic acid. In seeds, a reduction in polyunsaturated fatty acids was associated with an increase in stearic acid and oleic acid. Soybean plants challenged with the brown stem rot fungus or with soybean cyst nematodes did not present changes in fatty acid levels in leaves or seeds, indicating that the changes induced by aphids are not a general response to pests. One of the polyunsaturated fatty acids, linolenic acid, is the precursor of jasmonate; thus, these changes in fatty acid metabolism may be examples of “metabolic hijacking” by the aphid to avoid the induction of effective defenses. Based on the changes in fatty acid levels observed in seeds and leaves, we hypothesize that aphids potentially induce interference in the fatty acid desaturation pathway, likely reducing FAD2 and FAD6 activity that leads to a reduction in polyunsaturated fatty acids. Our data support the idea that aphids block jasmonate-dependent defenses by reduction of the hormone precursor. PMID:26684003

Nutritional Regulation of Bile Acid Metabolism Is Associated with Improved Pathological Characteristics of the Metabolic Syndrome*

PubMed Central

Liaset, Bjørn; Hao, Qin; Jørgensen, Henry; Hallenborg, Philip; Du, Zhen-Yu; Ma, Tao; Marschall, Hanns-Ulrich; Kruhøffer, Mogens; Li, Ruiqiang; Li, Qibin; Yde, Christian Clement; Criales, Gabriel; Bertram, Hanne C.; Mellgren, Gunnar; Øfjord, Erik Snorre; Lock, Erik-Jan; Espe, Marit; Frøyland, Livar; Madsen, Lise; Kristiansen, Karsten

2011-01-01

Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH). Importantly, the SPH-treated rats were resistant to diet-induced obesity. SPH-treated rats had reduced fed state plasma glucose and TAG levels and lower TAG in liver. The elevated plasma BA concentration was associated with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1α, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited increased whole body energy expenditure and heat dissipation. In skeletal muscle, expressions of the peroxisome proliferator-activated receptor β/δ target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5 weight % cholestyramine to the high fat SPH diet attenuated the reduction in abdominal obesity, the reduction in liver TAG, and the decrease in nonfasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome. PMID:21680746

Bile Acids and Tryptophan Metabolism Are Novel Pathways Involved in Metabolic Abnormalities in BPA-Exposed Pregnant Mice and Male Offspring.

PubMed

Susiarjo, Martha; Xin, Frances; Stefaniak, Martha; Mesaros, Clementina; Simmons, Rebecca A; Bartolomei, Marisa S

2017-08-01

Increasing evidence has demonstrated that exposure to endocrine-disrupting chemicals impacts maternal and fetal health, but the underlying mechanisms are still unclear. We previously showed that dietary exposure to 10 µg/kg body weight (bw)/d and 10 mg/kg bw/d of bisphenol A (BPA) during pregnancy induced metabolic abnormalities in F1 male offspring and gestational glucose intolerance in F0 pregnant mice. The aim of this study was to elucidate the underlying etiologies of BPA exposure-induced metabolic disease by analyzing the male fetal liver metabolome. Using the Metabolon Discover HD4 Platform, our laboratory identified metabolic pathways that were altered by BPA exposure, including biochemicals in lipid and amino acid metabolism. Specifically, primary and secondary bile acids were increased in liver from BPA-exposed embryonic day 18.5 male fetuses. We subsequently showed that increased bile acid was associated with a defective farnesoid X receptor-dependent negative feedback mechanism in BPA-exposed fetuses. In addition, through metabolomics, we observed that BPA-exposed fetuses had elevated tryptophan levels. Independent liquid chromatography and mass spectrometry measurement revealed that BPA-exposed dams also had increased tryptophan levels relative to those of controls. Because several key enzymes in tryptophan catabolism are vitamin B6 dependent and vitamin B6 deficiencies have been linked to gestational diabetes, we tested the impact of vitamin B6 supplementation and showed that it rescued gestational glucose intolerance in BPA-exposed pregnant mice. Our study has therefore identified two pathways (bile acid and tryptophan metabolism) that potentially underlie BPA-induced maternal and fetal metabolic disease. Copyright © 2017 Endocrine Society.

Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a High-throughput Targeted Metabolomics Approach

NASA Astrophysics Data System (ADS)

Yu, Nanyang; Wei, Si; Li, Meiying; Yang, Jingping; Li, Kan; Jin, Ling; Xie, Yuwei; Giesy, John P.; Zhang, Xiaowei; Yu, Hongxia

2016-04-01

Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.

Amino acid metabolism in maize earshoots. Implications for assimilate preconditioning and nitrogen signaling.

PubMed

Seebauer, Juliann R; Moose, Stephen P; Fabbri, Bradon J; Crossland, Lyle D; Below, Frederick E

2004-12-01

Nitrogen (N) is an essential requirement for kernel growth in maize (Zea mays); however, little is known about how N assimilates are metabolized in young earshoots during seed development. The objective of this study was to assess amino acid metabolism in cob and spikelet tissues during the critical 2 weeks following silking. Two maize hybrids were grown in the field for 2 years at two levels of supplemental N fertilizer (0 and 168 kg N/ha). The effects of the reproductive sink on cob N metabolism were examined by comparing pollinated to unpollinated earshoots. Earshoots were sampled at 2, 8, 14, and 18 d after silking; dissected into cob, spikelet, and/or pedicel and kernel fractions; then analyzed for amino acid profiles and key enzyme activities associated with amino acid metabolism. Major amino acids in the cob were glutamine (Gln), aspartic acid (Asp), asparagine (Asn), glutamate, and alanine. Gln concentrations dropped dramatically from 2 to 14 d after silking in both pollinated and unpollinated cobs, whereas all other measured amino acids accumulated over time in unpollinated spikelets and cobs, especially Asn. N supply had a variable effect on individual amino acid levels in young cobs and spikelets, with Asn being the most notably enhanced. We found that the cob performs significant enzymatic interconversions among Gln, alanine, Asp, and Asn during early reproductive development, which may precondition the N assimilate supply for sustained kernel growth. The measured amino acid profiles and enzymatic activities suggest that the Asn to Gln ratio in cobs may be part of a signal transduction pathway involving aspartate aminotransferase, Gln synthetase, and Asn synthetase to indicate plant N status for kernel development.

Fatty acids in energy metabolism of the central nervous system.

PubMed

Panov, Alexander; Orynbayeva, Zulfiya; Vavilin, Valentin; Lyakhovich, Vyacheslav

2014-01-01

In this review, we analyze the current hypotheses regarding energy metabolism in the neurons and astroglia. Recently, it was shown that up to 20% of the total brain's energy is provided by mitochondrial oxidation of fatty acids. However, the existing hypotheses consider glucose, or its derivative lactate, as the only main energy substrate for the brain. Astroglia metabolically supports the neurons by providing lactate as a substrate for neuronal mitochondria. In addition, a significant amount of neuromediators, glutamate and GABA, is transported into neurons and also serves as substrates for mitochondria. Thus, neuronal mitochondria may simultaneously oxidize several substrates. Astrocytes have to replenish the pool of neuromediators by synthesis de novo, which requires large amounts of energy. In this review, we made an attempt to reconcile β-oxidation of fatty acids by astrocytic mitochondria with the existing hypothesis on regulation of aerobic glycolysis. We suggest that, under condition of neuronal excitation, both metabolic pathways may exist simultaneously. We provide experimental evidence that isolated neuronal mitochondria may oxidize palmitoyl carnitine in the presence of other mitochondrial substrates. We also suggest that variations in the brain mitochondrial metabolic phenotype may be associated with different mtDNA haplogroups.

Fatty Acids in Energy Metabolism of the Central Nervous System

PubMed Central

Orynbayeva, Zulfiya; Vavilin, Valentin; Lyakhovich, Vyacheslav

2014-01-01

In this review, we analyze the current hypotheses regarding energy metabolism in the neurons and astroglia. Recently, it was shown that up to 20% of the total brain's energy is provided by mitochondrial oxidation of fatty acids. However, the existing hypotheses consider glucose, or its derivative lactate, as the only main energy substrate for the brain. Astroglia metabolically supports the neurons by providing lactate as a substrate for neuronal mitochondria. In addition, a significant amount of neuromediators, glutamate and GABA, is transported into neurons and also serves as substrates for mitochondria. Thus, neuronal mitochondria may simultaneously oxidize several substrates. Astrocytes have to replenish the pool of neuromediators by synthesis de novo, which requires large amounts of energy. In this review, we made an attempt to reconcile β-oxidation of fatty acids by astrocytic mitochondria with the existing hypothesis on regulation of aerobic glycolysis. We suggest that, under condition of neuronal excitation, both metabolic pathways may exist simultaneously. We provide experimental evidence that isolated neuronal mitochondria may oxidize palmitoyl carnitine in the presence of other mitochondrial substrates. We also suggest that variations in the brain mitochondrial metabolic phenotype may be associated with different mtDNA haplogroups. PMID:24883315

Metabolism of nonesterified and esterified hydroxycinnamic acids in red wines by Brettanomyces bruxellensis

USDA-ARS?s Scientific Manuscript database

While Brettanomyces can metabolize non–esterified hydroxycinnamic acids found in grape musts/wines (caffeic, p–coumaric, and ferulic acids), it was not known whether this yeast could utilize the corresponding tartaric acid esters (caftaric, p–coutaric, and fertaric acids, respectively). Red wines fr...

Glucocorticoids shift arachidonic acid metabolism toward endocannabinoid synthesis: a non-genomic anti-inflammatory switch

PubMed Central

Malcher-Lopes, Renato; Franco, Alier; Tasker, Jeffrey G.

2008-01-01

Glucocorticoids are capable of exerting both genomic and non-genomic actions in target cells of multiple tissues, including the brain, which trigger an array of electrophysiological, metabolic, secretory and inflammatory regulatory responses. Here, we have attempted to show how glucocorticoids may generate a rapid anti-inflammatory response by promoting arachidonic acid-derived endocannabinoid biosynthesis. According to our hypothesized model, non-genomic action of glucocorticoids results in the global shift of membrane lipid metabolism, subverting metabolic pathways toward the synthesis of the anti-inflammatory endocannabinoids, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), and away from arachidonic acid production. Post-transcriptional inhibition of cyclooxygenase-2 (COX2) synthesis by glucocorticoids assists this mechanism by suppressing the synthesis of pro-inflammatory prostaglandins as well as endocannabinoid-derived prostanoids. In the central nervous system (CNS) this may represent a major neuroprotective system, which may cross-talk with leptin signaling in the hypothalamus allowing for the coordination between energy homeostasis and the inflammatory response. PMID:18295199

Taurocholic acid metabolism by gut microbes and colon cancer

PubMed Central

Ridlon, Jason M.; Wolf, Patricia G.; Gaskins, H. Rex

2016-01-01

ABSTRACT Colorectal cancer (CRC) is one of the most frequent causes of cancer death worldwide and is associated with adoption of a diet high in animal protein and saturated fat. Saturated fat induces increased bile secretion into the intestine. Increased bile secretion selects for populations of gut microbes capable of altering the bile acid pool, generating tumor-promoting secondary bile acids such as deoxycholic acid and lithocholic acid. Epidemiological evidence suggests CRC is associated with increased levels of DCA in serum, bile, and stool. Mechanisms by which secondary bile acids promote CRC are explored. Furthermore, in humans bile acid conjugation can vary by diet. Vegetarian diets favor glycine conjugation while diets high in animal protein favor taurine conjugation. Metabolism of taurine conjugated bile acids by gut microbes generates hydrogen sulfide, a genotoxic compound. Thus, taurocholic acid has the potential to stimulate intestinal bacteria capable of converting taurine and cholic acid to hydrogen sulfide and deoxycholic acid, a genotoxin and tumor-promoter, respectively. PMID:27003186

Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers.

PubMed

Pencek, R; Marmon, T; Roth, J D; Liberman, A; Hooshmand-Rad, R; Young, M A

2016-09-01

The bile acid analogue obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist in development for treatment of several chronic liver diseases. FXR activation regulates lipoprotein homeostasis. The effects of OCA on cholesterol and lipoprotein metabolism in healthy individuals were assessed. Two phase I studies were conducted to evaluate the effects of repeated oral doses of 5, 10 or 25 mg OCA on lipid variables after 14 or 20 days of consecutive administration in 68 healthy adults. Changes in HDL and LDL cholesterol levels were examined, in addition to nuclear magnetic resonance analysis of particle sizes and sub-fraction concentrations. OCA elicited changes in circulating cholesterol and particle size of LDL and HDL. OCA decreased HDL cholesterol and increased LDL cholesterol, independently of dose. HDL particle concentrations declined as a result of a reduction in medium and small HDL. Total LDL particle concentrations increased because of an increase in large LDL particles. Changes in lipoprotein metabolism attributable to OCA in healthy individuals were found to be consistent with previously reported changes in patients receiving OCA with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. © 2016 John Wiley & Sons Ltd.

Mechanisms of triglyceride metabolism in patients with bile acid diarrhea

PubMed Central

Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

2016-01-01

Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment. PMID:27570415

The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism.

PubMed

Yoon, Mee-Sup

2016-07-01

Insulin is required for maintenance of glucose homeostasis. Despite the importance of insulin sensitivity to metabolic health, the mechanisms that induce insulin resistance remain unclear. Branched-chain amino acids (BCAAs) belong to the essential amino acids, which are both direct and indirect nutrient signals. Even though BCAAs have been reported to improve metabolic health, an increased BCAA plasma level is associated with a high risk of metabolic disorder and future insulin resistance, or type 2 diabetes mellitus (T2DM). The activation of mammalian target of rapamycin complex 1 (mTORC1) by BCAAs has been suggested to cause insulin resistance. In addition, defective BCAA oxidative metabolism might occur in obesity, leading to a further accumulation of BCAAs and toxic intermediates. This review provides the current understanding of the mechanism of BCAA-induced mTORC1 activation, as well as the effect of mTOR activation on metabolic health in terms of insulin sensitivity. Furthermore, the effects of impaired BCAA metabolism will be discussed in detail.

Short- and medium-chain fatty acids in energy metabolism: the cellular perspective.

PubMed

Schönfeld, Peter; Wojtczak, Lech

2016-06-01

Short- and medium-chain fatty acids (SCFAs and MCFAs), independently of their cellular signaling functions, are important substrates of the energy metabolism and anabolic processes in mammals. SCFAs are mostly generated by colonic bacteria and are predominantly metabolized by enterocytes and liver, whereas MCFAs arise mostly from dietary triglycerides, among them milk and dairy products. A common feature of SCFAs and MCFAs is their carnitine-independent uptake and intramitochondrial activation to acyl-CoA thioesters. Contrary to long-chain fatty acids, the cellular metabolism of SCFAs and MCFAs depends to a lesser extent on fatty acid-binding proteins. SCFAs and MCFAs modulate tissue metabolism of carbohydrates and lipids, as manifested by a mostly inhibitory effect on glycolysis and stimulation of lipogenesis or gluconeogenesis. SCFAs and MCFAs exert no or only weak protonophoric and lytic activities in mitochondria and do not significantly impair the electron transport in the respiratory chain. SCFAs and MCFAs modulate mitochondrial energy production by two mechanisms: they provide reducing equivalents to the respiratory chain and partly decrease efficacy of oxidative ATP synthesis. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

[Roles of organic acid metabolism in plant adaptation to nutrient deficiency and aluminum toxicity stress].

PubMed

Wang, Jianfei; Shen, Qirong

2006-11-01

Organic acids not only act as the intermediates in carbon metabolism, but also exert key roles in the plant adaptation to nutrient deficiency and metal stress and in the plant-microbe interactions at root-soil interface. From the viewpoint of plant nutrition, this paper reviewed the research progress on the formation and physiology of organic acids in plant, and their functions in nitrogen metabolism, phosphorus and iron uptake, aluminum tolerance, and soil ecology. New findings in the membrane transport of organic acids and the biotechnological manipulation of organic acids in transgenic model were also discussed. This novel perspectives of organic acid metabolism and its potential manipulation might present a possibility to understand the fundamental aspects of plant physiology, and lead to the new strategies to obtain crop varieties better adapted to environmental and metal stress.

Active role of fatty acid amino acid conjugates in nitrogen metabolism in Spodoptera litura larvae

PubMed Central

Yoshinaga, Naoko; Aboshi, Takako; Abe, Hiroaki; Nishida, Ritsuo; Alborn, Hans T.; Tumlinson, James H.; Mori, Naoki

2008-01-01

Since the first fatty acid amino acid conjugate (FAC) was isolated from regurgitant of Spodoptera exigua larvae in 1997 [volicitin: N-(17-hydroxylinolenoyl)-l-glutamine], their role as elicitors of induced responses in plants has been well documented. However, studies of the biosyntheses and the physiological role of FACs in the insect have been minimal. By using 14C-labeled glutamine, glutamic acid, and linolenic acid in feeding studies of Spodoptera litura larvae, combined with tissue analyses, we found glutamine in the midgut cells to be a major source for biosynthesis of FACs. Furthermore, 20% of the glutamine moiety of FACs was derived from glutamic acid and ammonia through enzymatic reaction of glutamine synthetase (GS). To determine whether FACs improve GS productivity, we studied nitrogen assimilation efficiency of S. litura larvae fed on artificial diets containing 15NH4Cl and glutamic acid. When the diet was enriched with linolenic acid, the nitrogen assimilation efficiency improved from 40% to >60%. In the lumen, the biosynthesized FACs are hydrolyzed to fatty acids and glutamine, which are reabsorbed into tissues and hemolymph. These results strongly suggested that FACs play an active role in nitrogen assimilation in Lepidoptera larva and that glutamine containing FACs in the gut lumen may function as a form of storage of glutamine, a key compound of nitrogen metabolism. PMID:18997016

Ca2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism.

PubMed

Antkiewicz-Michaluk, L; Románska, I; Vetulani, J

1997-07-30

To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus accumbens, striatum and frontal cortex. Some rats received nifedipine, 5 mg/kg i.p., before each injection of LSD to assess the effect of a Ca2+ channel blockade. High-dose LSD treatment (8 x 2 mg/kg per day) caused a strong stimulation of dopamine metabolism in the nucleus accumbens and striatum, and serotonin metabolism in the nucleus accumbens: the changes were observed 24 (but not 1 h) after the last dose. The changes induced by the low-dose treatment (8 x 0.1 mg/kg per day) had a different pattern, suggesting the release of dopamine from vesicles to cytoplasm. Co-administration of nifedipine completely prevented the LSD-induced biochemical changes. The results suggest that Ca2+ channel blocking agents may prevent development of some behavioral consequences of chronically used LSD.

Nontargeted LC-MS Metabolomics Approach for Metabolic Profiling of Plasma and Urine from Pigs Fed Branched Chain Amino Acids for Maximum Growth Performance.

PubMed

Soumeh, Elham A; Hedemann, Mette S; Poulsen, Hanne D; Corrent, Etienne; van Milgen, Jacob; Nørgaard, Jan V

2016-12-02

The metabolic response in plasma and urine of pigs when feeding an optimum level of branched chain amino acids (BCAAs) for best growth performance is unknown. The objective of the current study was to identify the metabolic phenotype associated with the BCAAs intake level that could be linked to the animal growth performance. Three dose-response studies were carried out to collect blood and urine samples from pigs fed increasing levels of Ile, Val, or Leu followed by a nontargeted LC-MS approach to characterize the metabolic profile of biofluids when dietary BCAAs are optimum for animal growth. Results showed that concentrations of plasma hypoxanthine and tyrosine (Tyr) were higher while concentrations of glycocholic acid, tauroursodeoxycholic acid, and taurocholic acid were lower when the dietary Ile was optimum. Plasma 3-methyl-2-oxovaleric acid and creatine were lower when dietary Leu was optimum. The optimum dietary Leu resulted in increased urinary excretion of ascorbic acid and choline and relatively decreased excretion of 2-aminoadipic acid, acetyl-dl-valine, Ile, 2-methylbutyrylglycine, and Tyr. In conclusion, plasma glycocholic acid and taurocholic acid were discriminating metabolites to the optimum dietary Ile. The optimum dietary Leu was associated with reduced plasma creatine and urinary 2-aminoadipic acid and elevated urinary excretion of ascorbic acid and choline. The optimum dietary Val had a less pronounced metabolic response reflected in plasma or urine than other BCAA.

Combined treatment with caffeic and ferulic acid from Baccharis uncinella C. DC. (Asteraceae) protects against metabolic syndrome in mice.

PubMed

Bocco, B M; Fernandes, G W; Lorena, F B; Cysneiros, R M; Christoffolete, M A; Grecco, S S; Lancellotti, C L; Romoff, P; Lago, J H G; Bianco, A C; Ribeiro, M O

2016-03-01

Fractionation of the EtOH extract from aerial parts of Baccharis uncinella C. DC. (Asteraceae) led to isolation of caffeic and ferulic acids, which were identified from spectroscopic and spectrometric evidence. These compounds exhibit antioxidant and anti-inflammatory properties and have been shown to be effective in the prevention/treatment of metabolic syndrome. This study investigated whether the combined treatment of caffeic and ferulic acids exhibits a more significant beneficial effect in a mouse model with metabolic syndrome. The combination treatment with caffeic and ferulic acids was tested for 60 days in C57 mice kept on a high-fat (40%) diet. The data obtained indicated that treatment with caffeic and ferulic acids prevented gain in body weight induced by the high-fat diet and improved hyperglycemia, hypercholesterolemia and hypertriglyceridemia. The expression of a number of metabolically relevant genes was affected in the liver of these animals, showing that caffeic and ferulic acid treatment results in increased cholesterol uptake and reduced hepatic triglyceride synthesis in the liver, which is a likely explanation for the prevention of hepatic steatosis. In conclusion, the combined treatment of caffeic and ferulic acids displayed major positive effects towards prevention of multiple aspects of the metabolic syndrome and liver steatosis in an obese mouse model.

Triptolide-induced mitochondrial damage dysregulates fatty acid metabolism in mouse sertoli cells.

PubMed

Cheng, Yisen; Chen, Gaojian; Wang, Li; Kong, Jiamin; Pan, Ji; Xi, Yue; Shen, Feihai; Huang, Zhiying

2018-08-01

Triptolide is a major active ingredient of tripterygium glycosides, used for the therapy of immune and inflammatory diseases. However, its clinical applications are limited by severe male fertility toxicity associated with decreased sperm count, mobility and testicular injures. In this study, we determined that triptoide-induced mitochondrial dysfunction triggered reduction of lactate and dysregulation of fatty acid metabolism in mouse Sertoli cells. First, triptolide induced mitochondrial damage through the suppressing of proliferator-activated receptor coactivator-1 alpha (PGC-1α) activity and protein. Second, mitochondrial damage decreased lactate production and dysregulated fatty acid metabolism. Finally, mitochondrial dysfunction was initiated by the inhibition of sirtuin 1 (SIRT1) with the regulation of AMP-activated protein kinase (AMPK) in Sertoli cells after triptolide treatment. Meanwhile, triptolide induced mitochondrial fatty acid oxidation dysregulation by increasing AMPK phosphorylation. Taken together, we provide evidence that the mechanism of triptolide-induced testicular toxicity under mitochondrial injury may involve a metabolic change. Copyright © 2018 Elsevier B.V. All rights reserved.

PGC-1α-mediated branched-chain amino acid metabolism in the skeletal muscle.

PubMed

Hatazawa, Yukino; Tadaishi, Miki; Nagaike, Yuta; Morita, Akihito; Ogawa, Yoshihiro; Ezaki, Osamu; Takai-Igarashi, Takako; Kitaura, Yasuyuki; Shimomura, Yoshiharu; Kamei, Yasutomi; Miura, Shinji

2014-01-01

Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1α in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Branched-chain amino acid (BCAA) metabolism mainly occurs in skeletal muscle mitochondria, and enzymes related to BCAA metabolism are increased by exercise. Using murine skeletal muscle overexpressing PGC-1α and cultured cells, we investigated whether PGC-1α stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1α specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT) 2, branched-chain α-keto acid dehydrogenase (BCKDH), which catabolize BCAA. The expression of BCKDH kinase (BCKDK), which phosphorylates BCKDH and suppresses its enzymatic activity, was unchanged. The amount of BCAA in the skeletal muscle was significantly decreased in the transgenic mice compared with that in the wild-type mice. The amount of glutamic acid, a metabolite of BCAA catabolism, was increased in the transgenic mice, suggesting the activation of muscle BCAA metabolism by PGC-1α. In C2C12 cells, the overexpression of PGC-1α significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1α in the skeletal muscle is considered to significantly contribute to BCAA metabolism.

PGC-1α-Mediated Branched-Chain Amino Acid Metabolism in the Skeletal Muscle

PubMed Central

Nagaike, Yuta; Morita, Akihito; Ogawa, Yoshihiro; Ezaki, Osamu; Takai-Igarashi, Takako; Kitaura, Yasuyuki; Shimomura, Yoshiharu; Kamei, Yasutomi; Miura, Shinji

2014-01-01

Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1α in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Branched-chain amino acid (BCAA) metabolism mainly occurs in skeletal muscle mitochondria, and enzymes related to BCAA metabolism are increased by exercise. Using murine skeletal muscle overexpressing PGC-1α and cultured cells, we investigated whether PGC-1α stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1α specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT) 2, branched-chain α-keto acid dehydrogenase (BCKDH), which catabolize BCAA. The expression of BCKDH kinase (BCKDK), which phosphorylates BCKDH and suppresses its enzymatic activity, was unchanged. The amount of BCAA in the skeletal muscle was significantly decreased in the transgenic mice compared with that in the wild-type mice. The amount of glutamic acid, a metabolite of BCAA catabolism, was increased in the transgenic mice, suggesting the activation of muscle BCAA metabolism by PGC-1α. In C2C12 cells, the overexpression of PGC-1α significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1α in the skeletal muscle is considered to significantly contribute to BCAA metabolism. PMID:24638054

Metabolic changes in rat serum after administration of suberoylanilide hydroxamic acid and discriminated by SVM.

PubMed

Yu, J; Wu, H; Lin, Z; Su, K; Zhang, J; Sun, F; Wang, X; Wen, C; Cao, H; Hu, L

2017-12-01

Suberoylanilide hydroxamic acid (SAHA) exerts marked anticancer effects via promotion of apoptosis, cell cycle arrest, and prevention of oncogene expression. In this study, serum metabolomics and artificial intelligence recognition were used to investigate SAHA toxicity. Forty rats (220 ± 20 g) were randomly divided into control and three SAHA groups (low, medium, and high); the experimental groups were treated with 12.3, 24.5, or 49.0 mg kg -1 SAHA once a day via intragastric administration. After 7 days, blood samples from the four groups were collected and analyzed by gas chromatography-mass spectrometry, and pathological changes in the liver were examined using microscopy. The results showed that increased levels of urea, oleic acid, and glutaconic acid were the most significant indicators of toxicity. Octadecanoic acid, pentadecanoic acid, glycerol, propanoic acid, and uric acid levels were lower in the high SAHA group. Microscopic observation revealed no obvious damage to the liver. Based on these data, a support vector machine (SVM) discrimination model was established that recognized the metabolic changes in the three SAHA groups and the control group with 100% accuracy. In conclusion, the main toxicity caused by SAHA was due to excessive metabolism of saturated fatty acids, which could be recognized by an SVM model.

A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia

PubMed Central

Kaliannan, Kanakaraju; Wang, Bin; Li, Xiang-Yong; Kim, Kui-Jin; Kang, Jing X.

2015-01-01

Metabolic endotoxemia, commonly derived from gut dysbiosis, is a primary cause of chronic low grade inflammation that underlies many chronic diseases. Here we show that mice fed a diet high in omega-6 fatty acids exhibit higher levels of metabolic endotoxemia and systemic low-grade inflammation, while transgenic conversion of tissue omega-6 to omega-3 fatty acids dramatically reduces endotoxemic and inflammatory status. These opposing effects of tissue omega-6 and omega-3 fatty acids can be eliminated by antibiotic treatment and animal co-housing, suggesting the involvement of the gut microbiota. Analysis of gut microbiota and fecal transfer revealed that elevated tissue omega-3 fatty acids enhance intestinal production and secretion of intestinal alkaline phosphatase (IAP), which induces changes in the gut bacteria composition resulting in decreased lipopolysaccharide production and gut permeability, and ultimately, reduced metabolic endotoxemia and inflammation. Our findings uncover an interaction between host tissue fatty acid composition and gut microbiota as a novel mechanism for the anti-inflammatory effect of omega-3 fatty acids. Given the excess of omega-6 and deficiency of omega-3 in the modern Western diet, the differential effects of tissue omega-6 and omega-3 fatty acids on gut microbiota and metabolic endotoxemia provide insight into the etiology and management of today’s health epidemics. PMID:26062993

Metabolism of vertebrate amino sugars with N-glycolyl groups: mechanisms underlying gastrointestinal incorporation of the non-human sialic acid xeno-autoantigen N-glycolylneuraminic acid.

PubMed

Banda, Kalyan; Gregg, Christopher J; Chow, Renee; Varki, Nissi M; Varki, Ajit

2012-08-17

Although N-acetyl groups are common in nature, N-glycolyl groups are rare. Mammals express two major sialic acids, N-acetylneuraminic acid and N-glycolylneuraminic acid (Neu5Gc). Although humans cannot produce Neu5Gc, it is detected in the epithelial lining of hollow organs, endothelial lining of the vasculature, fetal tissues, and carcinomas. This unexpected expression is hypothesized to result via metabolic incorporation of Neu5Gc from mammalian foods. This accumulation has relevance for diseases associated with such nutrients, via interaction with Neu5Gc-specific antibodies. Little is known about how ingested sialic acids in general and Neu5Gc in particular are metabolized in the gastrointestinal tract. We studied the gastrointestinal and systemic fate of Neu5Gc-containing glycoproteins (Neu5Gc-glycoproteins) or free Neu5Gc in the Neu5Gc-free Cmah(-/-) mouse model. Ingested free Neu5Gc showed rapid absorption into the circulation and urinary excretion. In contrast, ingestion of Neu5Gc-glycoproteins led to Neu5Gc incorporation into the small intestinal wall, appearance in circulation at a steady-state level for several hours, and metabolic incorporation into multiple peripheral tissue glycoproteins and glycolipids, thus conclusively proving that Neu5Gc can be metabolically incorporated from food. Feeding Neu5Gc-glycoproteins but not free Neu5Gc mimics the human condition, causing tissue incorporation into human-like sites in Cmah(-/-) fetal and adult tissues, as well as developing tumors. Thus, glycoproteins containing glycosidically linked Neu5Gc are the likely dietary source for human tissue accumulation, and not the free monosaccharide. This human-like model can be used to elucidate specific mechanisms of Neu5Gc delivery from the gut to tissues, as well as general mechanisms of metabolism of ingested sialic acids.

Insulin resistance and the metabolism of branched-chain amino acids in humans.

PubMed

Adeva, María M; Calviño, Jesús; Souto, Gema; Donapetry, Cristóbal

2012-07-01

Peripheral resistance to insulin action is the major mechanism causing the metabolic syndrome and eventually type 2 diabetes mellitus. The metabolic derangement associated with insulin resistance is extensive and not restricted to carbohydrates. The branched-chain amino acids (BCAAs) are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in conditions featuring insulin resistance, insulin deficiency, or both. Obesity, the metabolic syndrome and diabetes mellitus display a gradual increase in the plasma concentration of BCAAs, from the obesity-related low-grade insulin-resistant state to the severe deficiency of insulin action in diabetes ketoacidosis. Obesity-associated hyperinsulinemia succeeds in maintaining near-normal or slightly elevated plasma concentration of BCAAs, despite the insulin-resistant state. The low circulating levels of insulin and/or the deeper insulin resistance occurring in diabetes mellitus are associated with more marked elevation in the plasma concentration of BCAAs. In diabetes ketoacidosis, the increase in plasma BCAAs is striking, returning to normal when adequate metabolic control is achieved. The metabolism of BCAAs is also disturbed in other situations typically featuring insulin resistance, including kidney and liver dysfunction. However, notwithstanding the insulin-resistant state, the plasma level of BCAAs in these conditions is lower than in healthy subjects, suggesting that these organs are involved in maintaining BCAAs blood concentration. The pathogenesis of the decreased BCAAs plasma level in kidney and liver dysfunction is unclear, but a decreased afflux of these amino acids into the blood stream has been observed.

Effect of Bioprocessing on the In Vitro Colonic Microbial Metabolism of Phenolic Acids from Rye Bran Fortified Breads.

PubMed

Koistinen, Ville M; Nordlund, Emilia; Katina, Kati; Mattila, Ismo; Poutanen, Kaisa; Hanhineva, Kati; Aura, Anna-Marja

2017-03-08

Cereal bran is an important source of dietary fiber and bioactive compounds, such as phenolic acids. We aimed to study the phenolic acid metabolism of native and bioprocessed rye bran fortified refined wheat bread and to elucidate the microbial metabolic route of phenolic acids. After incubation in an in vitro colon model, the metabolites were analyzed using two different methods applying mass spectrometry. While phenolic acids were released more extensively from the bioprocessed bran bread and ferulic acid had consistently higher concentrations in the bread type during fermentation, there were only minor differences in the appearance of microbial metabolites, including the diminished levels of certain phenylacetic acids in the bioprocessed bran. This may be due to rye matrix properties, saturation of ferulic acid metabolism, or a rapid formation of intermediary metabolites left undetected. In addition, we provide expansion to the known metabolic pathways of phenolic acids.

Regulation of intestinal protein metabolism by amino acids.

PubMed

Bertrand, Julien; Goichon, Alexis; Déchelotte, Pierre; Coëffier, Moïse

2013-09-01

Gut homeostasis plays a major role in health and may be regulated by quantitative and qualitative food intake. In the intestinal mucosa, an intense renewal of proteins occurs, at approximately 50% per day in humans. In some pathophysiological conditions, protein turnover is altered and may contribute to intestinal or systemic diseases. Amino acids are key effectors of gut protein turnover, both as constituents of proteins and as regulatory molecules limiting intestinal injury and maintaining intestinal functions. Many studies have focused on two amino acids: glutamine, known as the preferential substrate of rapidly dividing cells, and arginine, another conditionally essential amino acid. The effects of glutamine and arginine on protein synthesis appear to be model and condition dependent, as are the involved signaling pathways. The regulation of gut protein degradation by amino acids has been minimally documented until now. This review will examine recent data, helping to better understand how amino acids regulate intestinal protein metabolism, and will explore perspectives for future studies.

Probing fatty acid metabolism in bacteria, cyanobacteria, green microalgae and diatoms with natural and unnatural fatty acids.

PubMed

Beld, Joris; Abbriano, Raffaela; Finzel, Kara; Hildebrand, Mark; Burkart, Michael D

2016-04-01

In both eukaryotes and prokaryotes, fatty acid synthases are responsible for the biosynthesis of fatty acids in an iterative process, extending the fatty acid by two carbon units every cycle. Thus, odd numbered fatty acids are rarely found in nature. We tested whether representatives of diverse microbial phyla have the ability to incorporate odd-chain fatty acids as substrates for their fatty acid synthases and their downstream enzymes. We fed various odd and short chain fatty acids to the bacterium Escherichia coli, cyanobacterium Synechocystis sp. PCC 6803, green microalga Chlamydomonas reinhardtii and diatom Thalassiosira pseudonana. Major differences were observed, specifically in the ability among species to incorporate and elongate short chain fatty acids. We demonstrate that E. coli, C. reinhardtii, and T. pseudonana can produce longer fatty acid products from short chain precursors (C3 and C5), while Synechocystis sp. PCC 6803 lacks this ability. However, Synechocystis can incorporate and elongate longer chain fatty acids due to acyl-acyl carrier protein synthetase (AasS) activity, and knockout of this protein eliminates the ability to incorporate these fatty acids. In addition, expression of a characterized AasS from Vibrio harveyii confers a similar capability to E. coli. The ability to desaturate exogenously added fatty acids was only observed in Synechocystis and C. reinhardtii. We further probed fatty acid metabolism of these organisms by feeding desaturase inhibitors to test the specificity of long-chain fatty acid desaturases. In particular, supplementation with thia fatty acids can alter fatty acid profiles based on the location of the sulfur in the chain. We show that coupling sensitive gas chromatography mass spectrometry to supplementation of unnatural fatty acids can reveal major differences between fatty acid metabolism in various organisms. Often unnatural fatty acids have antibacterial or even therapeutic properties. Feeding of short

Improving Fatty Acid Availability for Bio-Hydrocarbon Production in Escherichia coli by Metabolic Engineering

PubMed Central

Lin, Fengming; Chen, Yu; Levine, Robert; Lee, Kilho; Yuan, Yingjin; Lin, Xiaoxia Nina

2013-01-01

Previous studies have demonstrated the feasibility of producing fatty-acid-derived hydrocarbons in Escherichia coli. However, product titers and yields remain low. In this work, we demonstrate new methods for improving fatty acid production by modifying central carbon metabolism and storing fatty acids in triacylglycerol. Based on suggestions from a computational model, we deleted seven genes involved in aerobic respiration, mixed-acid fermentation, and glyoxylate bypass (in the order of cyoA, nuoA, ndh, adhE, dld, pta, and iclR) to modify the central carbon metabolic/regulatory networks. These gene deletions led to increased total fatty acids, which were the highest in the mutants containing five or six gene knockouts. Additionally, when two key enzymes in the fatty acid biosynthesis pathway were over-expressed, we observed further increase in strain △cyoA△adhE△nuoA△ndh△pta△dld, leading to 202 mg/g dry cell weight of total fatty acids, ~250% of that in the wild-type strain. Meanwhile, we successfully introduced a triacylglycerol biosynthesis pathway into E. coli through heterologous expression of wax ester synthase/acyl-coenzyme:diacylglycerol acyltransferase (WS/DGAT) enzymes. The added pathway improved both the amount and fuel quality of the fatty acids. These new metabolic engineering strategies are providing promising directions for future investigation. PMID:24147139

[Influence of exogenous gamma-aminobutyric acid (GABA) on GABA metabolism and amino acid contents in roots of melon seedling under hypoxia stress].

PubMed

Wang, Chun-Yan; Li, Jing-Rui; Xia, Qing-Ping; Wu, Xiao-Lei; Gao, Hong-Bo

2014-07-01

This paper investigated the influence of gamma-aminobutyric acid (GABA) on GABA metabolism and amino acid content under hypoxia stress by accurately controlling the level of dissolved oxygen in hydroponics, using the roots of melon 'Xiyu 1' seedlings as the test material. The results showed that compared with the control, the growth of roots was inhibited seriously under hypoxia stress. Meanwhile, the hypoxia-treated roots had significantly higher activities of glutamate decarboxylase (GAD), glutamate dehydrogenase (GDH), glutamate synthase (GOGAT), glutamine synthetase (GS), alanine aminotransferase (ALT), aspartate aminotransferase (AST) as well as the contents of GABA, pyruvic acid, alanine (Ala) and aspartic acid (Asp). But the contents of glutamic acid (Glu) and alpha-keto glutaric acid in roots under hypoxia stress was obviously lower than those of the control. Exogenous treatment with GABA alleviated the inhibition effect of hypoxia stress on root growth, which was accompanied by an increase in the contents of endogenous GABA, Glu, alpha-keto glutaric acid and Asp. Furthermore, under hypoxia stress, the activities of GAD, GDH, GOGAT, GS, ALT, AST as well as the contents of pyruvic acid and Ala significantly decreased in roots treated with GABA. However, adding GABA and viny-gamma-aminobutyric acid (VGB) reduced the alleviation effect of GABA on melon seedlings under hypoxia stress. The results suggested that absorption of GABA by roots could alleviate the injury of hypoxia stress to melon seedlings. This meant that GABA treatment allows the normal physiological metabolism under hypoxia by inhibiting the GAD activity through feedback and maintaining higher Glu content as well as the bal- ance of carbon and nitrogen.

Analysis of the Metabolic Pathways Affected by Poly(γ-glutamic Acid) in Arabidopsis thaliana Based on GeneChip Microarray.

PubMed

Xu, Zongqi; Lei, Peng; Feng, Xiaohai; Li, Sha; Xu, Hong

2016-08-17

Plant growth is promoted by poly(γ-glutamic acid) (γ-PGA). However, the molecular mechanism underlying such promotion is not yet well understood. Therefore, we used GeneChip microarrays to explore the effects of γ-PGA on gene transcription in Arabidopsis thaliana. Our results revealed 299 genes significantly regulated by γ-PGA. These differently expressed genes participate mainly in metabolic and cellular processes and in stimuli responses. The metabolic pathways linked to these differently expressed genes were also investigated. A total of 64 of the 299 differently expressed genes were shown to be directly involved in 24 pathways such as brassinosteroid biosynthesis, α-linolenic acid metabolism, phenylpropanoid biosynthesis, and nitrogen metabolism, all of which were influenced by γ-PGA. The analysis demonstrated that γ-PGA promoted nitrogen assimilation and biosynthesis of brassinosteroids, jasmonic acid, and lignins, providing a better explanation for why γ-PGA promotes growth and enhances stress tolerance in plants.

The role of free fatty acids in the inflammatory and cardiometabolic profile in adolescents with metabolic syndrome engaged in interdisciplinary therapy.

PubMed

Masquio, Deborah Cristina Landi; de Piano-Ganen, Aline; Oyama, Lila Missae; Campos, Raquel Munhoz da Silveira; Santamarina, Aline Boveto; de Souza, Gabriel Inácio de Morais Honorato; Gomes, Aline Dal'Olio; Moreira, Renata Guimarães; Corgosinho, Flávia Campos; do Nascimento, Claudia Maria Oller; Tock, Lian; Tufik, Sergio; de Mello, Marco Túlio; Dâmaso, Ana R

2016-07-01

The purpose of the present study was to evaluate if interdisciplinary therapy can influence the cardiometabolic and serum free fatty acid profile. The second aim was to evaluate if there is an association between serum free fatty acids, inflammation and cardiometabolic biomarkers in obese adolescents with and without metabolic syndrome submitted to a long-term interdisciplinary therapy. The study involved 108 postpuberty obese adolescents, who were divided according to metabolic syndrome (MetS) diagnosis: MetS (n=32) and Non-MetS (n=76). The interdisciplinary therapy consisted of a 1-year period of nutrition, psychology, physical exercise and clinical support. After therapy, both groups improved metabolic, inflammatory (leptin, adiponectin, leptin/adiponectin ratio, adiponectin/leptin ratio and C-reactive protein) and cardiometabolic profile (PAI-1 and ICAM). Metabolic syndrome prevalence reduced from 28.70% to 12.96%. Both groups reduced myristic acid (C14:0) and increased docosahexaenoic acid (DHA, C22:6n3), heneicosapentaenoic acid (HPA, C21:5n3) and arachidonic acid (C20:4n6). After adjustment for metabolic syndrome and the number of metabolic syndrome parameters, multiple regression analysis showed that changes in VCAM and PAI-1 were negatively associated with changes in cis-linoleic acid (C18:2n6c). Additionally, changes in trans-linoleic acid (C18:2n6t) were also positively associated with these biomarkers. Moreover, leptin and leptin/adiponectin ratio were negatively associated with changes in docosapentaenoic acid (DPA, C22:5n3) and stearidonic acid (SDA, C18:4n3). Adiponectin/leptin ratio was positively associated with docosapentaenoic acid (DPA, C22:5n3). Changes in adiponectin were positively correlated with changes in omega 3, such as heneicosapentaenoic acid (HPA, C21:5n3) and docosapentaenoic acid (DPA, C22:5n3). Results support that interdisciplinary therapy can control inflammatory and cardiometabolic profile in obese adolescents. Moreover, serum

The Effect of Marine Derived n-3 Fatty Acids on Adipose Tissue Metabolism and Function

PubMed Central

Todorčević, Marijana; Hodson, Leanne

2015-01-01

Adipose tissue function is key determinant of metabolic health, with specific nutrients being suggested to play a role in tissue metabolism. One such group of nutrients are the n-3 fatty acids, specifically eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). Results from studies where human, animal and cellular models have been utilised to investigate the effects of EPA and/or DHA on white adipose tissue/adipocytes suggest anti-obesity and anti-inflammatory effects. We review here evidence for these effects, specifically focusing on studies that provide some insight into metabolic pathways or processes. Of note, limited work has been undertaken investigating the effects of EPA and DHA on white adipose tissue in humans whilst more work has been undertaken using animal and cellular models. Taken together it would appear that EPA and DHA have a positive effect on lowering lipogenesis, increasing lipolysis and decreasing inflammation, all of which would be beneficial for adipose tissue biology. What remains to be elucidated is the duration and dose required to see a favourable effect of EPA and DHA in vivo in humans, across a range of adiposity. PMID:26729182

Abscisic Acid Metabolism in Salt-Stressed Cells of Dunaliella salina

PubMed Central

Cowan, A. Keith; Rose, Peter D.

1991-01-01

The interrelationship between abscisic acid (ABA) production and β-carotene accumulation was investigated in salt-stressed cells of the halotolerant green alga Dunaliella salina var bardawil. Cells were supplied with either R-[2-14C]mevalonolactone or [14C] sodium bicarbonate for 20 hours and then exposed to increased salinity (1.5 to 3.0 molar NaCl) for various lengths of time. Incorporation of label into abscisic acid and phaseic acid and the distribution of [14C]ABA between the cells and incubation media were monitored. [14C]ABA and [14C]phaseic acid were identified as products of both R-[2-14C]mevalonolactone and [14C]sodium bicarbonate metabolism. ABA metabolism was enhanced by hypersalinity stress. Actinomycin D, chloramphenicol, and cycloheximide abolished the stress-induced production of ABA, suggesting a role for gene activation in the process. Kinetic analysis of both ABA and β-carotene production demonstrated two stages of accelerated β-carotene production. In addition, ABA levels increased rapidly, and this increase occurred coincident with the early period of accelerated β-carotene production. A possible role for ABA as a regulator of carotenogenesis in cells of D. salina is therefore discussed. PMID:16668469

Uric acid, an important screening tool to detect inborn errors of metabolism: a case series.

PubMed

Jasinge, Eresha; Kularatnam, Grace Angeline Malarnangai; Dilanthi, Hewa Warawitage; Vidanapathirana, Dinesha Maduri; Jayasena, Kandana Liyanage Subhashinie Priyadarshika Kapilani Menike; Chandrasiri, Nambage Dona Priyani Dhammika; Indika, Neluwa Liyanage Ruwan; Ratnayake, Pyara Dilani; Gunasekara, Vindya Nandani; Fairbanks, Lynette Dianne; Stiburkova, Blanka

2017-09-06

Uric acid is the metabolic end product of purine metabolism in humans. Altered serum and urine uric acid level (both above and below the reference ranges) is an indispensable marker in detecting rare inborn errors of metabolism. We describe different case scenarios of 4 Sri Lankan patients related to abnormal uric acid levels in blood and urine. CASE 1: A one-and-half-year-old boy was investigated for haematuria and a calculus in the bladder. Xanthine crystals were seen in microscopic examination of urine sediment. Low uric acid concentrations in serum and low urinary fractional excretion of uric acid associated with high urinary excretion of xanthine and hypoxanthine were compatible with xanthine oxidase deficiency. CASE 2: An 8-month-old boy presented with intractable seizures, feeding difficulties, screaming episodes, microcephaly, facial dysmorphism and severe neuro developmental delay. Low uric acid level in serum, low fractional excretion of uric acid and radiological findings were consistent with possible molybdenum cofactor deficiency. Diagnosis was confirmed by elevated levels of xanthine, hypoxanthine and sulfocysteine levels in urine. CASE 3: A 3-year-10-month-old boy presented with global developmental delay, failure to thrive, dystonia and self-destructive behaviour. High uric acid levels in serum, increased fractional excretion of uric acid and absent hypoxanthine-guanine phosphoribosyltransferase enzyme level confirmed the diagnosis of Lesch-Nyhan syndrome. CASE 4: A 9-year-old boy was investigated for lower abdominal pain, gross haematuria and right renal calculus. Low uric acid level in serum and increased fractional excretion of uric acid pointed towards hereditary renal hypouricaemia which was confirmed by genetic studies. Abnormal uric acid level in blood and urine is a valuable tool in screening for clinical conditions related to derangement of the nucleic acid metabolic pathway.

Amino acid metabolism of Malassezia furfur.

PubMed

El-Gothamy, Z

1981-01-01

The mechanism responsible for the hypopigmentation which follows pityriasis versicolor (P.V.) infection has not yet been satisfactorily explained. This work was done in order to study the effect of Malassezia furfur on the decomposition or the utilization of the amino acid tyrosine in vitro. No effect could be noted, which points to the assumption that the effect of the causative fungus of P.V. on melanogenesis is most probably due to the blocking of melanine synthesis by one of the product of M. furfur metabolism without using tyrosine.

Metabonomics Indicates Inhibition of Fatty Acid Synthesis, β-Oxidation, and Tricarboxylic Acid Cycle in Triclocarban-Induced Cardiac Metabolic Alterations in Male Mice.

PubMed

Xie, Wenping; Zhang, Wenpeng; Ren, Juan; Li, Wentao; Zhou, Lili; Cui, Yuan; Chen, Huiming; Yu, Wenlian; Zhuang, Xiaomei; Zhang, Zhenqing; Shen, Guolin; Li, Haishan

2018-02-14

Triclocarban (TCC) has been identified as a new environmental pollutant that is potentially hazardous to human health; however, the effects of short-term TCC exposure on cardiac function are not known. The aim of this study was to use metabonomics and molecular biology techniques to systematically elucidate the molecular mechanisms of TCC-induced effects on cardiac function in mice. Our results show that TCC inhibited the uptake, synthesis, and oxidation of fatty acids, suppressed the tricarboxylic acid (TCA) cycle, and increased aerobic glycolysis levels in heart tissue after short-term TCC exposure. TCC also inhibited the nuclear peroxisome proliferator-activated receptor α (PPARα), confirming its inhibitory effects on fatty acid uptake and oxidation. Histopathology and other analyses further confirm that TCC altered mouse cardiac physiology and pathology, ultimately affecting normal cardiac metabolic function. We elucidate the molecular mechanisms of TCC-induced harmful effects on mouse cardiac metabolism and function from a new perspective, using metabonomics and bioinformatics analysis data.

Metabolic Control in Mammalian Fed-Batch Cell Cultures for Reduced Lactic Acid Accumulation and Improved Process Robustness

PubMed Central

Konakovsky, Viktor; Clemens, Christoph; Müller, Markus Michael; Bechmann, Jan; Berger, Martina; Schlatter, Stefan; Herwig, Christoph

2016-01-01

Biomass and cell-specific metabolic rates usually change dynamically over time, making the “feed according to need” strategy difficult to realize in a commercial fed-batch process. We here demonstrate a novel feeding strategy which is designed to hold a particular metabolic state in a fed-batch process by adaptive feeding in real time. The feed rate is calculated with a transferable biomass model based on capacitance, which changes the nutrient flow stoichiometrically in real time. A limited glucose environment was used to confine the cell in a particular metabolic state. In order to cope with uncertainty, two strategies were tested to change the adaptive feed rate and prevent starvation while in limitation: (i) inline pH and online glucose concentration measurement or (ii) inline pH alone, which was shown to be sufficient for the problem statement. In this contribution, we achieved metabolic control within a defined target range. The direct benefit was two-fold: the lactic acid profile was improved and pH could be kept stable. Multivariate Data Analysis (MVDA) has shown that pH influenced lactic acid production or consumption in historical data sets. We demonstrate that a low pH (around 6.8) is not required for our strategy, as glucose availability is already limiting the flux. On the contrary, we boosted glycolytic flux in glucose limitation by setting the pH to 7.4. This new approach led to a yield of lactic acid/glucose (Y L/G) around zero for the whole process time and high titers in our labs. We hypothesize that a higher carbon flux, resulting from a higher pH, may lead to more cells which produce more product. The relevance of this work aims at feeding mammalian cell cultures safely in limitation with a desired metabolic flux range. This resulted in extremely stable, low glucose levels, very robust pH profiles without acid/base interventions and a metabolic state in which lactic acid was consumed instead of being produced from day 1. With this

Dietary fatty acids linking postprandial metabolic response and chronic diseases.

PubMed

Ortega, Almudena; Varela, Lourdes M; Bermudez, Beatriz; Lopez, Sergio; Abia, Rocio; Muriana, Francisco J G

2012-01-01

Chronic diseases are by far one of the main causes of mortality in the world. One of the current global recommendations to counteract disability and premature death resulting from chronic diseases is to decrease the consumption of energy-dense high-fat diets, particularly those rich in saturated fatty acids (SFA). The most effective replacement for SFA in terms of risk factor outcomes for chronic disease are polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). The biochemical basis for healthy benefits of such a dietary pattern has been widely evaluated under fasting conditions. However, the increasing amount of data available from multiple studies suggest that the postprandial state, i.e., "the period that comprises and follows a meal", plays an important, yet underappreciated, role in the genesis of numerous pathological conditions. In this review, the potential of MUFA, PUFA, and SFA to postprandially affect selected metabolic abnormalities related to chronic diseases is discussed.

Effects of cadmium stress on growth and amino acid metabolism in two Compositae plants.

PubMed

Zhu, Guangxu; Xiao, Huayun; Guo, Qingjun; Zhang, Zhongyi; Zhao, Jingjing; Yang, Dan

2018-08-30

Cadmium, a high toxic heavy metal, is one of the most serious contaminants in soil and a potential threat to plant growth and human health. Amino acid metabolism has the central role in heavy metal stress resistance of plants. In this paper, a pot experiment was carried out to study the effects of different concentrations of cadmium (0, 3, 6, 12, 30 mg kg -1 ) on the growth, Cd accumulation and amino acid metabolism in two Compositae plants (Ageratum conyzoides L. and Crassocephalum crepidioides). The results showed that under cadmium stress, C. crepidioides accumulated more Cd in its shoot and was tolerant to Cd, whereas its low Cd-accumulating relative, A. conyzoides, suffered reduced growth. The Cd content in the aerial part of C. crepidioides exceeded the threshold of Cd-hyperaccumulator. Furthermore, the bioaccumulation factor (BCF) and biological transfer factor (BTF) values for Cd in C. crepidioides were > 1. Thus, C. crepidioides can be regarded as Cd-hyperaccumulator. The comparison between both studied plants indicated that Cd stress resulted in a differential but coordinated response of amino acid levels, which are playing a significant role in plant adaptation to Cd stress. Glu, Gln, Asp, Asn, Gaba, Val and Ala dominated the major amino acids. Higher Cd tolerance and Cd accumulation in C. crepidioides was associated with greater accumulation of free amino acids, especially for Gln and Asn, in C. crepidioides than in A. conyzoides. Copyright © 2018 Elsevier Inc. All rights reserved.

Bifidobacterium breve with α-linolenic acid and linoleic acid alters fatty acid metabolism in the maternal separation model of irritable bowel syndrome.

PubMed

Barrett, Eoin; Fitzgerald, Patrick; Dinan, Timothy G; Cryan, John F; Ross, R Paul; Quigley, Eamonn M; Shanahan, Fergus; Kiely, Barry; Fitzgerald, Gerald F; O'Toole, Paul W; Stanton, Catherine

2012-01-01

The aim of this study was to compare the impact of dietary supplementation with a Bifidobacterium breve strain together with linoleic acid & α-linolenic acid, for 7 weeks, on colonic sensitivity and fatty acid metabolism in rats. Maternally separated and non-maternally separated Sprague Dawley rats (n = 15) were orally gavaged with either B. breve DPC6330 (10(9) microorganisms/day) alone or in combination with 0.5% (w/w) linoleic acid & 0.5% (w/w) α-linolenic acid, daily for 7 weeks and compared with trehalose and bovine serum albumin. Tissue fatty acid composition was assessed by gas-liquid chromatography and visceral hypersensitivity was assessed by colorectal distension. Significant differences in the fatty acid profiles of the non-separated controls and maternally separated controls were observed for α-linolenic acid and arachidonic acid in the liver, oleic acid and eicosenoic acid (c11) in adipose tissue, and for palmitoleic acid and docosahexaenoic acid in serum (p<0.05). Administration of B. breve DPC6330 to MS rats significantly increased palmitoleic acid, arachidonic acid and docosahexaenoic acid in the liver, eicosenoic acid (c11) in adipose tissue and palmitoleic acid in the prefrontal cortex (p<0.05), whereas feeding B. breve DPC6330 to non separated rats significantly increased eicosapentaenoic acid and docosapentaenoic acid in serum (p<0.05) compared with the NS un-supplemented controls. Administration of B. breve DPC6330 in combination with linoleic acid and α-linolenic acid to maternally separated rats significantly increased docosapentaenoic acid in the serum (p<0.01) and α-linolenic acid in adipose tissue (p<0.001), whereas feeding B. breve DPC6330 with fatty acid supplementation to non-separated rats significantly increased liver and serum docosapentaenoic acid (p<0.05), and α-linolenic acid in adipose tissue (p<0.001). B. breve DPC6330 influenced host fatty acid metabolism. Administration of B. breve DPC6330 to maternally separated rats

Bifidobacterium breve with α-Linolenic Acid and Linoleic Acid Alters Fatty Acid Metabolism in the Maternal Separation Model of Irritable Bowel Syndrome

PubMed Central

Barrett, Eoin; Fitzgerald, Patrick; Dinan, Timothy G.; Cryan, John F.; Ross, R. Paul; Quigley, Eamonn M.; Shanahan, Fergus; Kiely, Barry; Fitzgerald, Gerald F.; O'Toole, Paul W.; Stanton, Catherine

2012-01-01

The aim of this study was to compare the impact of dietary supplementation with a Bifidobacterium breve strain together with linoleic acid & α-linolenic acid, for 7 weeks, on colonic sensitivity and fatty acid metabolism in rats. Maternally separated and non-maternally separated Sprague Dawley rats (n = 15) were orally gavaged with either B. breve DPC6330 (109 microorganisms/day) alone or in combination with 0.5% (w/w) linoleic acid & 0.5% (w/w) α-linolenic acid, daily for 7 weeks and compared with trehalose and bovine serum albumin. Tissue fatty acid composition was assessed by gas-liquid chromatography and visceral hypersensitivity was assessed by colorectal distension. Significant differences in the fatty acid profiles of the non-separated controls and maternally separated controls were observed for α-linolenic acid and arachidonic acid in the liver, oleic acid and eicosenoic acid (c11) in adipose tissue, and for palmitoleic acid and docosahexaenoic acid in serum (p<0.05). Administration of B. breve DPC6330 to MS rats significantly increased palmitoleic acid, arachidonic acid and docosahexaenoic acid in the liver, eicosenoic acid (c11) in adipose tissue and palmitoleic acid in the prefrontal cortex (p<0.05), whereas feeding B. breve DPC6330 to non separated rats significantly increased eicosapentaenoic acid and docosapentaenoic acid in serum (p<0.05) compared with the NS un-supplemented controls. Administration of B. breve DPC6330 in combination with linoleic acid and α-linolenic acid to maternally separated rats significantly increased docosapentaenoic acid in the serum (p<0.01) and α-linolenic acid in adipose tissue (p<0.001), whereas feeding B. breve DPC6330 with fatty acid supplementation to non-separated rats significantly increased liver and serum docosapentaenoic acid (p<0.05), and α-linolenic acid in adipose tissue (p<0.001). B. breve DPC6330 influenced host fatty acid metabolism. Administration of B. breve DPC6330 to maternally separated rats

Amino Acid Metabolism in Acute Renal Failure: Influence of Intravenous Essential L-Amino Acid Hyperalimentation Therapy

PubMed Central

Abel, Ronald M.; Shih, Vivian E.; Abbott, William M.; Beck, Clyde H.; Fischer, Josef E.

1974-01-01

A solution of 8 essential I-amino acids and hypertonic dextrose was administered to 5 patients in acute postoperative renal failure in a program of hyperalimentation designed to decrease the patient's catabolic state and to accrue certain metabolic benefits. A sixth patient receiving intravenous glucose alone served as a control. The pretreatment plasma concentrations of amino acids in all 6 patients did not differ significantly from normal; following intravenous essential amino acids at a dose of approximately 12.6 gm/24 hours, no significant elevations out of the normal range of these substances occurred. Since urinary excretion rates did not dramatically increase, urinary loss was excluded as a possible cause for the failure of increase of plasma concentrations. The results suggest that the administration of an intravenous solution of 1-amino acids and hypertonic dextrose is associated with rapid clearance from the blood of these substances and, with a failure of increased urinary excretion, indirect evidence of amino acid utilization for protein synthesis has been obtained. Histidine supplementation in patients with acute renal failure is probably unnecessary based on the lack of significant decreases in histidine concentrations in these patients. PMID:4850497

Aging rather than stress strongly influences amino acid metabolisms in the brain and genital organs of female mice.

PubMed

Kodaira, Momoko; Nagasawa, Mao; Yamaguchi, Takeshi; Ikeda, Hiromi; Minaminaka, Kimie; Chowdhury, Vishwajit S; Yasuo, Shinobu; Furuse, Mitsuhiro

2017-03-01

Aging and stress affect quality of life, and proper nourishment is one of means of preventing this effect. Today, there is a focus on the amount of protein consumed by elderly people; however, changes in the amino acid metabolism of individuals have not been fully considered. In addition, the difference between average life span and healthy life years is larger in females than it is in males. To prolong the healthy life years of females, in the present study we evaluated the influence of stress and aging on metabolism and emotional behavior by comparing young and middle-aged female mice. After 28 consecutive days of immobilization stress, behavioral tests were conducted and tissue sampling was performed. The results showed that the body weight of middle-aged mice was severely lowered by stress, but emotional behaviors were hardly influenced by either aging or stress. Aging influenced changes in amino acid metabolism in the brain and increased various amino acid levels in the uterus and ovary. In conclusion, we found that aged mice were more susceptible to stress in terms of body-weight reduction, and that amino acid metabolisms in the brain and genital organs were largely influenced by aging rather than by stress. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Ammonium Metabolism Enzymes Aid Helicobacter pylori Acid Resistance

PubMed Central

Miller, Erica F.

2014-01-01

The gastric pathogen Helicobacter pylori possesses a highly active urease to support acid tolerance. Urea hydrolysis occurs inside the cytoplasm, resulting in the production of NH3 that is immediately protonated to form NH4+. This ammonium must be metabolized or effluxed because its presence within the cell is counterproductive to the goal of raising pH while maintaining a viable proton motive force (PMF). Two compatible hypotheses for mitigating intracellular ammonium toxicity include (i) the exit of protonated ammonium outward via the UreI permease, which was shown to facilitate diffusion of both urea and ammonium, and/or (ii) the assimilation of this ammonium, which is supported by evidence that H. pylori assimilates urea nitrogen into its amino acid pools. We investigated the second hypothesis by constructing strains with altered expression of the ammonium-assimilating enzymes glutamine synthetase (GS) and glutamate dehydrogenase (GDH) and the ammonium-evolving periplasmic enzymes glutaminase (Ggt) and asparaginase (AsnB). H. pylori strains expressing elevated levels of either GS or GDH are more acid tolerant than the wild type, exhibit enhanced ammonium production, and are able to alkalize the medium faster than the wild type. Strains lacking the genes for either Ggt or AsnB are acid sensitive, have 8-fold-lower urea-dependent ammonium production, and are more acid sensitive than the parent. Additionally, we found that purified H. pylori GS produces glutamine in the presence of Mg2+ at a rate similar to that of unadenylated Escherichia coli GS. These data reveal that all four enzymes contribute to whole-cell acid resistance in H. pylori and are likely important for assimilation and/or efflux of urea-derived ammonium. PMID:24936052

Metabolism of lithocholic and chenodeoxycholic acids in the squirrel monkey

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suzuki, H.; Hamada, M.; Kato, F.

1985-09-01

Metabolism of lithocholic acid (LCA) and chenodeoxycholic acid (CDCA) was studied in the squirrel monkey to clarify the mechanism of the lack of toxicity of CDCA in this animal. Radioactive LCA was administered to squirrel monkeys with biliary fistula. Most radioactivity was excreted in the bile in the form of unsulfated lithocholyltaurine. The squirrel monkey thus differs from humans and chimpanzees, which efficiently sulfate LCA, and is similar to the rhesus monkey and baboon in that LCA is poorly sulfated. When labeled CDCA was orally administered to squirrel monkeys, less than 20% of the dosed radioactivity was recovered as LCAmore » and its further metabolites in feces over 3 days, indicating that bacterial metabolism of CDCA into LCA is strikingly less than in other animals and in humans. It therefore appears that LCA, known as a hepatotoxic secondary bile acid, is not accumulated in the squirrel monkey, not because of its rapid turnover through sulfation, but because of the low order of its production.« less

METABOLISM OF ω-AMINO ACIDS V.

PubMed Central

Hardman, John K.; Stadtman, Thressa C.

1963-01-01

Hardman, John K. (National Heart Institute, National Institutes of Health, Bethesda, Md.) and Thressa C. Stadtman. Metabolism of ω-amino acids. V. Energetics of the γ-aminobutyrate fermentation by Clostridium aminobutyricum. J. Bacteriol. 85:1326–1333. 1963.—Clostridium aminobutyricum utilizes γ-aminobutyrate as its sole carbon, nitrogen, and energy source, producing ammonia, acetate, and butyrate as a result of this fermentation. Coenzyme A (CoA)-transferase, phosphotransacetylase, and acetokinase activities have been demonstrated in crude extracts of the organism; the coupling of the reactions catalyzed by these enzymes to the fermentation reactions provides a mechanism whereby C. aminobutyricum can obtain energy, in the form of adenosine triphosphate, from the decomposition of γ-aminobutyrate. Indirect evidence of additional phosphorylation, at the electron-transport level, has been obtained from molar growth yield studies and from the inhibition by 2,4-dinitrophenol of butyrate synthesis from γ-aminobutyrate and from crotonyl-CoA. PMID:14047225

Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells

PubMed Central

Angela, Mulki; Endo, Yusuke; Asou, Hikari K.; Yamamoto, Takeshi; Tumes, Damon J.; Tokuyama, Hirotake; Yokote, Koutaro; Nakayama, Toshinori

2016-01-01

To fulfil the bioenergetic requirements for increased cell size and clonal expansion, activated T cells reprogramme their metabolic signatures from energetically quiescent to activated. However, the molecular mechanisms and essential components controlling metabolic reprogramming in T cells are not well understood. Here, we show that the mTORC1–PPARγ pathway is crucial for the fatty acid uptake programme in activated CD4+ T cells. This pathway is required for full activation and rapid proliferation of naive and memory CD4+ T cells. PPARγ directly binds and induces genes associated with fatty acid uptake in CD4+ T cells in both mice and humans. The PPARγ-dependent fatty acid uptake programme is critical for metabolic reprogramming. Thus, we provide important mechanistic insights into the metabolic reprogramming mechanisms that govern the expression of key enzymes, fatty acid metabolism and the acquisition of an activated phenotype during CD4+ T cell activation. PMID:27901044

Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders

PubMed Central

Burrage, Lindsay C.; Nagamani, Sandesh C.S.; Campeau, Philippe M.; Lee, Brendan H.

2014-01-01

Branched-chain amino acid (BCAA) metabolism plays a central role in the pathophysiology of both rare inborn errors of metabolism and the more common multifactorial diseases. Although deficiency of the branched-chain ketoacid dehydrogenase (BCKDC) and associated elevations in the BCAAs and their ketoacids have been recognized as the cause of maple syrup urine disease (MSUD) for decades, treatment options for this disorder have been limited to dietary interventions. In recent years, the discovery of improved leucine tolerance after liver transplantation has resulted in a new therapeutic strategy for this disorder. Likewise, targeting the regulation of the BCKDC activity may be an alternative potential treatment strategy for MSUD. The regulation of the BCKDC by the branched-chain ketoacid dehydrogenase kinase has also been implicated in a new inborn error of metabolism characterized by autism, intellectual disability and seizures. Finally, there is a growing body of literature implicating BCAA metabolism in more common disorders such as the metabolic syndrome, cancer and hepatic disease. This review surveys the knowledge acquired on the topic over the past 50 years and focuses on recent developments in the field of BCAA metabolism. PMID:24651065

Pyroglutamic acid-induced metabolic acidosis: a case report.

PubMed

Luyasu, S; Wamelink, M M C; Galanti, L; Dive, A

2014-06-01

High anion gap metabolic acidosis due to pyroglutamic acid (5-oxoproline) is a rare complication of acetaminophen treatment (which depletes glutathione stores) and is often associated with clinically moderate to severe encephalopathy. Acquired 5-oxoprolinase deficiency (penicillins) or the presence of other risk factors of glutathione depletion such as malnutrition or sepsis seems to be necessary for symptoms development. We report the case of a 55-year-old women who developed a symptomatic overproduction of 5-oxoproline during flucloxacillin treatment for severe sepsis while receiving acetaminophen for fever control. Hemodialysis accelerated the clearance of the accumulated organic acid, and was followed by a sustained clinical improvement.

Modulation of fatty acid metabolism is involved in the alleviation of isoproterenol-induced rat heart failure by fenofibrate

PubMed Central

LI, PING; LUO, SHIKE; PAN, CHUNJI; CHENG, XIAOSHU

2015-01-01

Heart failure is a disease predominantly caused by an energy metabolic disorder in cardiomyocytes. The present study investigated the inhibitory effects of fenofibrate (FF) on isoproterenol (ISO)-induced hear failure in rats, and examined the underlying mechanisms. The rats were divided into CON, ISO (HF model), FF and FF+ISO (HF animals pretreated with FF) groups. The cardiac structure and function of the rats were assessed, and contents of free fatty acids and glucose metabolic products were determined. In addition, myocardial cells were isolated from neonatal rats and used in vitro to investigate the mechanisms by which FF relieves heart failure. Western blot analysis was performed to quantify the expression levels of peroxisome proliferator-activated receptor (PPAR)α and uncoupling protein 2 (UCP2). FF effectively alleviated the ISO-induced cardiac structural damage, functional decline, and fatty acid and carbohydrate metabolic abnormalities. Compared with the ISO group, the serum levels of brain natriuretic peptide (BNP), free fatty acids, lactic acid and pyruvic acid were decreased in the FF animals. In the cultured myocardial cells, lactic acid and pyruvic acid contents were lower in the supernatants obtained from the FF animals, with lower levels of mitochondrial ROS production and cell necrosis, compared with the ISO group, whereas PPARα upregulation and UCP2 downregulation occurred in the FF+ISO group. The results demonstrated that FF efficiently alleviated heart failure in the ISO-induced rat model, possibly via promoting fatty acid oxidation. PMID:26497978

Circulating linoleic acid and alpha-linolenic acid and glucose metabolism: the Hoorn Study.

PubMed

Cabout, Mieke; Alssema, Marjan; Nijpels, Giel; Stehouwer, Coen D A; Zock, Peter L; Brouwer, Ingeborg A; Elshorbagy, Amany K; Refsum, Helga; Dekker, Jacqueline M

2017-09-01

Data on the relation between linoleic acid (LA) and alpha-linolenic acid (ALA) and type 2 diabetes mellitus (T2DM) risk are scarce and inconsistent. The aim of this study was to investigate the association of serum LA and ALA with fasting and 2 h post-load plasma glucose and glycated hemoglobin (HbA1c). This study included 667 participants from third examination (2000) of the population-based Hoorn study in which individuals with glucose intolerance were overrepresented. Fatty acid profiles in serum total lipids were measured at baseline, in 2000. Diabetes risk markers were measured at baseline and follow-up in 2008. Linear regression models were used in cross-sectional and prospective analyses. In cross-sectional analyses (n = 667), serum LA was inversely associated with plasma glucose, both in fasting conditions (B = -0.024 [-0.045, -0.002]) and 2 h after glucose tolerance test (B = -0.099 [-0.158, -0.039]), but not with HbA1c (B = 0.000 [-0.014, 0.013]), after adjustment for relevant factors. In prospective analyses (n = 257), serum LA was not associated with fasting (B = 0.003 [-0.019, 0.025]) or post-load glucose (B = -0.026 [-0.100, 0.049]). Furthermore, no significant associations were found between serum ALA and glucose metabolism in cross-sectional or prospective analyses. In this study, serum LA was inversely associated with fasting and post-load glucose in cross-sectional, but not in prospective analyses. Further studies are needed to elucidate the exact role of serum LA and ALA levels and dietary polyunsaturated fatty acids in glucose metabolism.

Dysregulation of hepatic fatty acid metabolism in chronic kidney disease.

PubMed

Jin, Kyubok; Norris, Keith; Vaziri, Nosratola D

2013-02-01

Chronic kidney disease (CKD) results in hypertriglyceridemia which is largely due to impaired clearance of triglyceride-rich lipoproteins occasioned by downregulation of lipoprotein lipase and very low-density lipoprotein (LDL) receptor in the skeletal muscle and adipose tissue and of hepatic lipase and LDL receptor-related protein in the liver. However, data on the effect of CKD on fatty acid metabolism in the liver is limited and was investigated here. Male Sprague-Dawley rats were randomized to undergo 5/6 nephrectomy (CRF) or sham operation (control) and observed for 12 weeks. The animals were then euthanized and their liver tissue tested for nuclear translocation (activation) of carbohydrate-responsive element binding protein (ChREBP) and sterol-responsive element binding protein-1 (SREBP-1) which independently regulate the expression of key enzyme in fatty acid synthesis, i.e. fatty acid synthase (FAS) and acyl-CoA carboxylase (ACC) as well as nuclear Peroxisome proliferator-activated receptor alpha (PPARα) which regulates the expression of enzymes involved in fatty acid oxidation and transport, i.e. L-FABP and CPT1A. In addition, the expression of ATP synthase α, ATP synthase β, glycogen synthase and diglyceride acyltransferase 1 (DGAT1) and DGAT2 were determined. Compared with controls, the CKD rats exhibited hypertriglyceridemia, elevated plasma and liver tissue free fatty acids, increased nuclear ChREBP and reduced nuclear SREBP-1 and PPARα, upregulation of ACC and FAS and downregulation of L-FABP, CPT1A, ATP synthase α, glycogen synthase and DGAT in the liver tissue. Liver in animals with advanced CKD exhibits ChREBP-mediated upregulation of enzymes involved in fatty acid synthesis, downregulation of PPARα-regulated fatty acid oxidation system and reduction of DGAT resulting in reduced fatty acid incorporation in triglyceride.

beta-Methyl-15-p-iodophenylpentadecanoic acid metabolism and kinetics in the isolated rat heart.

PubMed

DeGrado, T R; Holden, J E; Ng, C K; Raffel, D M; Gatley, S J

1989-01-01

The use of 15-p-iodophenyl-beta-methyl-pentadecanoic acid (beta Me-IPPA) as an indicator of long chain fatty acid (LCFA) utilization in nuclear medicine studies was evaluated in the isolated, perfused, working rat heart. Time courses of radioactivity (residue curves) were obtained following bolus injections of both beta Me-IPPA and its straight chain counterpart 15-p-iodophenyl-pentadecanoic acid (IPPA). IPPA kinetics clearly indicated flow independent impairment of fatty acid oxidation caused by the carnitine palmitoyltransferase I inhibitor 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). In contrast, beta Me-IPPA kinetics were insensitive to changes in fatty acid oxidation rate and net utilization of long chain fatty acid. Analysis of radiolabeled species in coronary effluent and heart homogenates showed the methylated fatty acid to be readily incorporated into complex lipids but a poor substrate for oxidation. POCA did not significantly alter metabolism of the tracer, suggesting that the tracer is poorly metabolized beyond beta Me-IPPA-CoA in the oxidative pathway.

Nocturnal Accumulation of Malic Acid Occurs in Mesophyll Tissue without Proton Transport to Epidermal Tissue in the Inducible Crassulacean Acid Metabolism Plant Mesembryanthemum crystallinum1

PubMed Central

Winter, Klaus; Edwards, Gerald E.; Holtum, Joseph A. M.

1981-01-01

The inducible Crassulacean acid metabolism plant, Mesembryanthemum crystallinum, accumulates malic acid, i.e. equivalent amounts of malate anions and protons in the mesophyll cells at night. Levels of malate and titratable acidity are low in the epidermal tissue and do not change significantly during the day/night cycle. This result is in contrast to a recent report (Bloom 1979 Plant Physiol 64: 919-923) that the synthesis of malic acid during dark CO2 fixation is associated with an equivalent exchange of inorganic cations from epidermal tissue with protons in the mesophyll cells. PMID:16661916

Alternative carbohydrate reserves used in the daily cycle of crassulacean acid metabolism

Treesearch

C.C. Black; J.-Q. Chen; R.L. Doong; M.N. Angelov; Shi-Jean S. Sung

1996-01-01

Each day a massive interlocked biochemical cycle occurs in the green tissues of crassulacean acid metabolism plants.The function of this interlocked cycle, in its simplest context, is to furnish most of the CO2 for CAM plant photosynthesis.In this unified presentation our aims are (1) to divide CAM plants into two metabolic groups, (2) to...

Physiological and Metabolic Effects of 5-Aminolevulinic Acid for Mitigating Salinity Stress in Creeping Bentgrass

PubMed Central

Yang, Zhimin; Chang, Zuoliang; Sun, Lihong; Yu, Jingjin; Huang, Bingru

2014-01-01

The objectives of this study were to determine whether foliar application of a chlorophyll precursor, 5-aminolevulinic acid (ALA), could mitigate salinity stress damages in perennial grass species by regulating photosynthetic activities, ion content, antioxidant metabolism, or metabolite accumulation. A salinity-sensitive perennial grass species, creeping bentgrass (Agrostis stolonifera), was irrigated daily with 200 mM NaCl for 28 d, which were foliar sprayed with water or ALA (0.5 mg L−1) weekly during the experiment in growth chamber. Foliar application of ALA was effective in mitigating physiological damage resulting from salinity stress, as manifested by increased turf quality, shoot growth rate, leaf relative water content, chlorophyll content, net photosynthetic rate, stomatal conductance and transpiration rate. Foliar application of ALA also alleviated membrane damages, as shown by lower membrane electrolyte leakage and lipid peroxidation, which was associated with increases in the activities of antioxidant enzymes. Leaf content of Na+ was reduced and the ratio of K+/Na+ was increased with ALA application under salinity stress. The positive effects of ALA for salinity tolerance were also associated with the accumulation of organic acids (α-ketoglutaric acid, succinic acid, and malic acid), amino acids (alanine, 5-oxoproline, aspartic acid, and γ -aminobutyric acid), and sugars (glucose, fructose, galactose, lyxose, allose, xylose, sucrose, and maltose). ALA-mitigation of physiological damages by salinity could be due to suppression of Na+ accumulation and enhanced physiological and metabolic activities related to photosynthesis, respiration, osmotic regulation, and antioxidant defense. PMID:25551443

The effect of trinitrobenzene sulfonic acid (TNB) on colonocyte arachidonic acid metabolism.

PubMed

Stratton, M D; Sexe, R; Peterson, B; Kaminski, D L; Li, A P; Longo, W E

1996-02-01

In previous studies we found that luminal perfusion of the isolated left colon of the rabbit with the hapten, trinitrobenzene, resulted in the production of an acute inflammatory process associated with alterations in eicosanoid metabolism. As the colitis was attenuated by cyclooxygenase inhibitors it is possible that the inflammation was mediated by arachidonic acid metabolites. In the present study it was intended to evaluate the effect of trinitrobenzene on eicosanoid metabolism in transformed human colonic cells by exposing Caco-2++ cells to various doses of trinitrobenzene. Cell injury was evaluated by measuring lactate dehydrogenase levels and cyclooxygenase and lipoxygenase activity was evaluated by measuring prostanoid and leukotriene production. In separate experiments resting and trinitrobenzene stimulated cells were treated with indomethacin and dexamethasone. Trinitrobenzene produced increased prostaglandin E2 and 6-keto prostaglandin F1alpha++ and increased lactate dehydrogenase levels. Leukotriene B4 was significantly increased compared to control values at the highest TNB concentration administered. Indomethacin inhibited the lactate dehydrogenase and prostanoid changes, suggesting that the inflammatory changes produced were mediated by the prostanoids. Dexamethasone administered for 1 hr prior to trinitrobenzene decreased the 6-keto prostaglandin F1alpha but did not alter trinitrobenzene produced changes in lactate dehydrogenase concentrations. Exposure of Caco-2 cells to dexamethasone for 24 hr decreased the trinitrobenzene produced lactate dehydrogenase and eicosanoid changes. The results suggest that trinitrobenzene produces an acute injury to Caco-2 cells that may be mediated by the cyclooxygenase enzymes.

Current advance in biological production of malic acid using wild type and metabolic engineered strains.

PubMed

Dai, Zhongxue; Zhou, Huiyuan; Zhang, Shangjie; Gu, Honglian; Yang, Qiao; Zhang, Wenming; Dong, Weiliang; Ma, Jiangfeng; Fang, Yan; Jiang, Min; Xin, Fengxue

2018-06-01

Malic acid (2-hydroxybutanedioic acid) is a four-carbon dicarboxylic acid, which has attracted great interest due to its wide usage as a precursor of many industrially important chemicals in the food, chemicals, and pharmaceutical industries. Several mature routes for malic acid production have been developed, such as chemical synthesis, enzymatic conversion and biological fermentation. With depletion of fossil fuels and concerns regarding environmental issues, biological production of malic acid has attracted more attention, which mainly consists of three pathways, namely non-oxidative pathway, oxidative pathway and glyoxylate cycle. In recent decades, metabolic engineering of model strains, and process optimization for malic acid production have been rapidly developed. Hence, this review comprehensively introduces an overview of malic acid producers and highlight some of the successful metabolic engineering approaches. Copyright © 2018 Elsevier Ltd. All rights reserved.

Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis

PubMed Central

Aldini, R; Camborata, C; Spinozzi, S; Franco, P; Cont, M; D'Errico, A; Vasuri, F; Degiovanni, A; Maroni, L; Adorini, L

2017-01-01

Obeticholic acid (OCA) is a semisynthetic bile acid (BA) analog and potent farnesoid X receptor agonist approved to treat cholestasis. We evaluated the biodistribution and metabolism of OCA administered to carbon tetrachloride‐induced cirrhotic rats. This was to ascertain if plasma and hepatic concentrations of OCA are potentially more harmful than those of endogenous BAs. After administration of OCA (30 mg/kg), we used liquid chromatography–mass spectrometry to measure OCA, its metabolites, and BAs at different timepoints in various organs and fluids. Plasma and hepatic concentrations of OCA and BAs were higher in cirrhotic rats than in controls. OCA and endogenous BAs had similar metabolic pathways in cirrhotic rats, although OCA hepatic and intestinal clearance were lower than in controls. BAs' qualitative and quantitative compositions were not modified by a single administration of OCA. In all the matrices studied, OCA concentrations were significantly lower than those of endogenous BAs, potentially much more cytotoxic. PMID:28411380

Cytochrome P450 2C8 and flavin-containing monooxygenases are involved in the metabolism of tazarotenic acid in humans.

PubMed

Attar, Mayssa; Dong, Dahai; Ling, Kah-Hiing John; Tang-Liu, Diane D-S

2003-04-01

Upon oral administration, tazarotene is rapidly converted to tazarotenic acid by esterases. The main circulating agent, tazarotenic acid is subsequently oxidized to the inactive sulfoxide metabolite. Therefore, alterations in the metabolic clearance of tazarotenic acid may have significant effects on its systemic exposure. The objective of this study was to identify the human liver microsomal enzymes responsible for the in vitro metabolism of tazarotenic acid. Tazarotenic acid was incubated with 1 mg/ml pooled human liver microsomes, in 100 mM potassium phosphate buffer (pH 7.4), at 37 degrees C, over a period of 30 min. The microsomal enzymes that may be involved in tazarotenic acid metabolism were identified through incubation with microsomes containing cDNA-expressed human microsomal isozymes. Chemical inhibition studies were then conducted to confirm the identity of the enzymes potentially involved in tazarotenic acid metabolism. Reversed-phase high performance liquid chromatography was used to quantify the sulfoxide metabolite, the major metabolite of tazarotenic acid. Upon incubation of tazarotenic acid with microsomes expressing CYP2C8, flavin-containing monooxygenase 1 (FMO1), or FMO3, marked formation of the sulfoxide metabolite was observed. The involvement of these isozymes in tazarotenic acid metabolism was further confirmed by inhibition of metabolite formation in pooled human liver microsomes by specific inhibitors of CYP2C8 or FMO. In conclusion, the in vitro metabolism of tazarotenic acid to its sulfoxide metabolite in human liver microsomes is mediated by CYP2C8 and FMO.

Evidence for differential activation of arachidonic acid metabolism in formylpeptide- and macrophage-activation-factor-stimulated guinea-pig macrophages.

PubMed Central

Homma, Y; Hashimoto, T; Nagai, Y; Takenawa, T

1985-01-01

Alterations of phospholipid and arachidonic acid metabolism were studied by treatment of guinea-pig peritoneal-exudate macrophages with chemotactic peptide, formylmethionyl-leucylphenylalanine (fMet-Leu-Phe) and macrophage activation factor (MAF). The chemotactic peptide caused a rapid rearrangement in inositol phospholipids, including a breakdown of polyphosphoinositides within 30s, followed by a resultant formation of phosphatidylinositol (PI), diacylglycerol, phosphatidic acid and non-esterified arachidonic acid within 5 min. In addition to these sequential alterations, arachidonic acid was released mainly from PI. On the other hand, MAF induced a slow liberation of arachidonic acid, mainly from phosphatidylethanolamine (PE) and phosphatidylcholine (PC) by phospholipase A2 after the incubation period of 30 min, but not any rapid changes in phospholipids. Treatment of macrophages for 15 min with fMet-Leu-Phe produced the leukotrienes (LTs) B4, C4 and D4, prostaglandins (PG) E2 and F2 alpha and thromboxane (TX) B2. In contrast, MAF could not stimulate the production of arachidonic acid metabolites during the incubation period of 15 min, but could enhance that of PGE2, PGF2 alpha, TXB2 and hydroxyeicosatetraenoic acids at 6 h. However, the stimulated formation of LTs was not detected at any time. These results indicate that the effects of fMet-Leu-Phe on both phospholipid and arachidonic acid metabolism are very different from those mediated by MAF. PMID:3931627

Ascorbic acid metabolism during sweet cherry (Prunus avium) fruit development

PubMed Central

Ni, Zhiyou; Lin, Lijin; Tang, Yi; Wang, Zhihui; Wang, Xun; Wang, Jin; Lv, Xiulan; Xia, Hui

2017-01-01

To elucidate metabolism of ascorbic acid (AsA) in sweet cherry fruit (Prunus avium ‘Hongdeng’), we quantified AsA concentration, cloned sequences involved in AsA metabolism and investigated their mRNA expression levels, and determined the activity levels of selected enzymes during fruit development and maturation. We found that AsA concentration was highest at the petal-fall period (0 days after anthesis) and decreased progressively during ripening, but with a slight increase at maturity. AsA did nevertheless continue to accumulate over time because of the increase in fruit fresh weight. Full-length cDNAs of 10 genes involved in the L-galactose pathway of AsA biosynthesis and 10 involved in recycling were obtained. Gene expression patterns of GDP-L-galactose phosphorylase (GGP2), L-galactono-1, 4-lactone dehydrogenase (GalLDH), ascorbate peroxidase (APX3), ascorbate oxidase (AO2), glutathione reductase (GR1), and dehydroascorbate reductase (DHAR1) were in accordance with the AsA concentration pattern during fruit development, indicating that genes involved in ascorbic acid biosynthesis, degradation, and recycling worked in concert to regulate ascorbic acid accumulation in sweet cherry fruit. PMID:28245268

Biodegradation of 5-chloro-2-picolinic acid by novel identified co-metabolizing degrader Achromobacter sp. f1.

PubMed

Wu, Zhi-Guo; Wang, Fang; Ning, Li-Qun; Stedtfeld, Robert D; Yang, Zong-Zheng; Cao, Jing-Guo; Sheng, Hong-Jie; Jiang, Xin

2017-06-01

Several bacteria have been isolated to degrade 4-chloronitrobenzene. Degradation of 4-chloronitrobenzene by Cupriavidus sp. D4 produces 5-chloro-2-picolinic acid as a dead-end by-product, a potential pollutant. To date, no bacterium that degrades 5-chloro-2-picolinic acid has been reported. Strain f1, isolated from a soil polluted by 4-chloronitrobenzene, was able to co-metabolize 5-chloro-2-picolinic acid in the presence of ethanol or other appropriate carbon sources. The strain was identified as Achromobacter sp. based on its physiological, biochemical characteristics, and 16S rRNA gene sequence analysis. The organism completely degraded 50, 100 and 200 mg L -1 of 5-chloro-2-picolinic acid within 48, 60, and 72 h, respectively. During the degradation of 5-chloro-2-picolinic acid, Cl - was released. The initial metabolic product of 5-chloro-2-picolinic acid was identified as 6-hydroxy-5-chloro-2-picolinic acid by LC-MS and NMR. Using a mixed culture of Achromobacter sp. f1 and Cupriavidus sp. D4 for degradation of 4-chloronitrobenzen, 5-chloro-2-picolinic acid did not accumulate. Results infer that Achromobacter sp. f1 can be used for complete biodegradation of 4-chloronitrobenzene in remedial applications.

Analysis of Growth Inhibition and Metabolism of Hydroxycinnamic Acids by Brewing and Spoilage Strains of Brettanomyces Yeast.

PubMed

Lentz, Michael; Harris, Chad

2015-10-15

Brettanomyces yeasts are well-known as spoilage organisms in both the wine and beer industries, but also contribute important desirable characters to certain beer styles. These properties are mediated in large part by Brettanomyces ' metabolism of hydroxycinnamic acids (HCAs) present in beverage raw materials. Here we compare growth inhibition by, and metabolism of, HCAs among commercial brewing strains and spoilage strains of B. bruxellensis and B. anomalus . These properties vary widely among the different strains tested and between the HCAs analyzed. Brewing strains showed more efficient metabolism of ferulic acid over p -coumaric acid, a trait not shared among the spoilage strains.

Increased Missense Mutation Burden of Fatty Acid Metabolism Related Genes in Nunavik Inuit Population

PubMed Central

Zhou, Sirui; Xiong, Lan; Xie, Pingxing; Ambalavanan, Amirthagowri; Bourassa, Cynthia V.; Dionne-Laporte, Alexandre; Spiegelman, Dan; Turcotte Gauthier, Maude; Henrion, Edouard; Diallo, Ousmane; Dion, Patrick A.; Rouleau, Guy A.

2015-01-01

Background Nunavik Inuit (northern Quebec, Canada) reside along the arctic coastline where for generations their daily energy intake has mainly been derived from animal fat. Given this particular diet it has been hypothesized that natural selection would lead to population specific allele frequency differences and unique variants in genes related to fatty acid metabolism. A group of genes, namely CPT1A, CPT1B, CPT1C, CPT2, CRAT and CROT, encode for three carnitine acyltransferases that are important for the oxidation of fatty acids, a critical step in their metabolism. Methods Exome sequencing and SNP array genotyping were used to examine the genetic variations in the six genes encoding for the carnitine acyltransferases in 113 Nunavik Inuit individuals. Results Altogether ten missense variants were found in genes CPT1A, CPT1B, CPT1C, CPT2 and CRAT, including three novel variants and one Inuit specific variant CPT1A p.P479L (rs80356779). The latter has the highest frequency (0.955) compared to other Inuit populations. We found that by comparison to Asians or Europeans, the Nunavik Inuit have an increased mutation burden in CPT1A, CPT2 and CRAT; there is also a high level of population differentiation based on carnitine acyltransferase gene variations between Nunavik Inuit and Asians. Conclusion The increased number and frequency of deleterious variants in these fatty acid metabolism genes in Nunavik Inuit may be the result of genetic adaptation to their diet and/or the extremely cold climate. In addition, the identification of these variants may help to understand some of the specific health risks of Nunavik Inuit. PMID:26010953

Enhanced pinocembrin production in Escherichia coli by regulating cinnamic acid metabolism

PubMed Central

Cao, Weijia; Ma, Weichao; Wang, Xin; Zhang, Bowen; Cao, Xun; Chen, Kequan; Li, Yan; Ouyang, Pingkai

2016-01-01

Microbial biosynthesis of pinocembrin is of great interest in the area of drug research and human healthcare. Here we found that the accumulation of the pathway intermediate cinnamic acid adversely affected pinocembrin production. Hence, a stepwise metabolic engineering strategy was carried out aimed at eliminating this pathway bottleneck and increasing pinocembrin production. The screening of gene source and the optimization of gene expression was first employed to regulate the synthetic pathway of cinnamic acid, which showed a 3.53-fold increase in pinocembrin production (7.76 mg/L) occurred with the alleviation of cinnamic acid accumulation in the engineered E. coli. Then, the downstream pathway that consuming cinnamic acid was optimized by the site-directed mutagenesis of chalcone synthase and cofactor engineering. S165M mutant of chalcone synthase could efficiently improve the pinocembrin production, and allowed the product titer of pinocembrin increased to 40.05 mg/L coupled with the malonyl-CoA engineering. With a two-phase pH fermentation strategy, the cultivation of the optimized strain resulted in a final pinocembrin titer of 67.81 mg/L. The results and engineering strategies demonstrated here would hold promise for the titer improvement of other flavonoids. PMID:27586788

Enhanced pinocembrin production in Escherichia coli by regulating cinnamic acid metabolism.

PubMed

Cao, Weijia; Ma, Weichao; Wang, Xin; Zhang, Bowen; Cao, Xun; Chen, Kequan; Li, Yan; Ouyang, Pingkai

2016-09-02

Microbial biosynthesis of pinocembrin is of great interest in the area of drug research and human healthcare. Here we found that the accumulation of the pathway intermediate cinnamic acid adversely affected pinocembrin production. Hence, a stepwise metabolic engineering strategy was carried out aimed at eliminating this pathway bottleneck and increasing pinocembrin production. The screening of gene source and the optimization of gene expression was first employed to regulate the synthetic pathway of cinnamic acid, which showed a 3.53-fold increase in pinocembrin production (7.76 mg/L) occurred with the alleviation of cinnamic acid accumulation in the engineered E. coli. Then, the downstream pathway that consuming cinnamic acid was optimized by the site-directed mutagenesis of chalcone synthase and cofactor engineering. S165M mutant of chalcone synthase could efficiently improve the pinocembrin production, and allowed the product titer of pinocembrin increased to 40.05 mg/L coupled with the malonyl-CoA engineering. With a two-phase pH fermentation strategy, the cultivation of the optimized strain resulted in a final pinocembrin titer of 67.81 mg/L. The results and engineering strategies demonstrated here would hold promise for the titer improvement of other flavonoids.

The role of bile acids in metabolic regulation.

PubMed

Vítek, Libor; Haluzík, Martin

2016-03-01

Bile acids (BA), long believed to only have lipid-digestive functions, have emerged as novel metabolic modulators. They have important endocrine effects through multiple cytoplasmic as well as nuclear receptors in various organs and tissues. BA affect multiple functions to control energy homeostasis, as well as glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor and the cytoplasmic G protein-coupled BA receptor TGR5 in a variety of tissues. However, BA also are aimed at many other cellular targets in a wide array of organs and cell compartments. Their role in the pathogenesis of diabetes, obesity and other 'diseases of civilization' becomes even more clear. They also interact with the gut microbiome, with important clinical implications, further extending the complexity of their biological functions. Therefore, it is not surprising that BA metabolism is substantially modulated by bariatric surgery, a phenomenon contributing favorably to the therapeutic effects of these surgical procedures. Based on these data, several therapeutic approaches to ameliorate obesity and diabetes have been proposed to affect the cellular targets of BA. © 2016 Society for Endocrinology.

High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice12345

PubMed Central

Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas DE

2015-01-01

Background: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Objective: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Design: Folic acid–supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr+/+ and Mthfr+/− mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Results: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr+/− mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr+/− livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr+/− mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. Conclusions: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2

Inflammation and ER Stress Regulate Branched-Chain Amino Acid Uptake and Metabolism in Adipocytes

PubMed Central

Burrill, Joel S.; Long, Eric K.; Reilly, Brian; Deng, Yingfeng; Armitage, Ian M.; Scherer, Philipp E.

2015-01-01

Inflammation plays a critical role in the pathology of obesity-linked insulin resistance and is mechanistically linked to the effects of macrophage-derived cytokines on adipocyte energy metabolism, particularly that of the mitochondrial branched-chain amino acid (BCAA) and tricarboxylic acid (TCA) pathways. To address the role of inflammation on energy metabolism in adipocytes, we used high fat-fed C57BL/6J mice and lean controls and measured the down-regulation of genes linked to BCAA and TCA cycle metabolism selectively in visceral but not in subcutaneous adipose tissue, brown fat, liver, or muscle. Using 3T3-L1 cells, TNFα, and other proinflammatory cytokine treatments reduced the expression of the genes linked to BCAA transport and oxidation. Consistent with this, [14C]-leucine uptake and conversion to triglycerides was markedly attenuated in TNFα-treated adipocytes, whereas the conversion to protein was relatively unaffected. Because inflammatory cytokines lead to the induction of endoplasmic reticulum stress, we evaluated the effects of tunicamycin or thapsigargin treatment of 3T3-L1 cells and measured a similar down-regulation in the BCAA/TCA cycle pathway. Moreover, transgenic mice overexpressing X-box binding protein 1 in adipocytes similarly down-regulated genes of BCAA and TCA metabolism in vivo. These results indicate that inflammation and endoplasmic reticulum stress attenuate lipogenesis in visceral adipose depots by down-regulating the BCAA/TCA metabolism pathway and are consistent with a model whereby the accumulation of serum BCAA in the obese insulin-resistant state is linked to adipose inflammation. PMID:25635940

Bacterial fatty acid metabolism in modern antibiotic discovery.

PubMed

Yao, Jiangwei; Rock, Charles O

2017-11-01

Bacterial fatty acid synthesis is essential for many pathogens and different from the mammalian counterpart. These features make bacterial fatty acid synthesis a desirable target for antibiotic discovery. The structural divergence of the conserved enzymes and the presence of different isozymes catalyzing the same reactions in the pathway make bacterial fatty acid synthesis a narrow spectrum target rather than the traditional broad spectrum target. Furthermore, bacterial fatty acid synthesis inhibitors are single-targeting, rather than multi-targeting like traditional monotherapeutic, broad-spectrum antibiotics. The single-targeting nature of bacterial fatty acid synthesis inhibitors makes overcoming fast-developing, target-based resistance a necessary consideration for antibiotic development. Target-based resistance can be overcome through multi-targeting inhibitors, a cocktail of single-targeting inhibitors, or by making the single targeting inhibitor sufficiently high affinity through a pathogen selective approach such that target-based mutants are still susceptible to therapeutic concentrations of drug. Many of the pathogens requiring new antibiotic treatment options encode for essential bacterial fatty acid synthesis enzymes. This review will evaluate the most promising targets in bacterial fatty acid metabolism for antibiotic therapeutics development and review the potential and challenges in advancing each of these targets to the clinic and circumventing target-based resistance. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. Copyright © 2016 Elsevier B.V. All rights reserved.

Association of branched and aromatic amino acids levels with metabolic syndrome and impaired fasting glucose in hypertensive patients.

PubMed

Weng, Liming; Quinlivan, Eoin; Gong, Yan; Beitelshees, Amber L; Shahin, Mohamed H; Turner, Stephen T; Chapman, Arlene B; Gums, John G; Johnson, Julie A; Frye, Reginald F; Garrett, Timothy J; Cooper-DeHoff, Rhonda M

2015-06-01

The three branched amino acids (valine, leucine, and isoleucine) and two aromatic amino acids (tyrosine and phenylalanine) have been associated with many adverse metabolic pathways, including diabetes. However, these associations have been identified primarily in otherwise healthy Caucasian populations. We aimed to investigate the association of this five-amino-acid signature with metabolic syndrome and impaired fasting glucose (IFG) in a hypertensive cohort of Caucasian and African Americans. We analyzed data from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) studies PEAR and PEAR2 conducted between 2005 and 2014. Subjects were enrolled at the University of Florida (Gainesville, FL), Emory University (Atlanta, GA), and Mayo Clinic (Rochester, MN). A total of 898 patients with essential hypertension were included in this study. Presence of metabolic syndrome and IFG at baseline were determined on the basis of measurements of demographic and biochemical data. Levels of the five amino acids were quantified by liquid chromatography-tandem mass spectroscopy (LC-MS/MS). With a multiple logistic regression model, we found that all five amino acids were significantly associated with metabolic syndrome in both Caucasian and African Americans. IFG and the five amino acids were associated in the Caucasian Americans. Only valine was significantly associated with IFG in African Americans. In both Caucasian and African Americans with uncomplicated hypertension, plasma levels of the five-amino-acid signature are associated with metabolic syndrome. Additionally, in Caucasians we have confirmed the five-amino-acid signature was associated with IFG.

SULPHUR-CONTAINING AMINO ACIDS METABOLISM IN EXPERIMENTAL HYPER- AND HYPOTHYROIDISM IN RATS.

PubMed

Nechiporuk, V; Zaichko, N; Korda, М; Melnyk, A; Koloshko, O

2017-10-01

Hyper- and hypothyroidism are some of the most common endocrinopathies that cause many metabolic disorders including amino acids metabolism. However, a specific molecular mechanism of thyroid hormones influence on sulphur-containing amino acids metabolism has not been established. The aim of our research was to investigate experimentally the influence of thyroid gland functional state on the main enzymatic systems of sulphur-containing amino acids metabolism in liver and kidneys, the content of homocysteine, cysteine and H2S in blood. The rats were administered with L-thyroxine and mercazolil to simulate the states of hyper- and hypothyroidism, which were confirmed by the content of fT3, fT4 and TSH in the blood. In liver and kidneys of the animals with hypothyroidism we observed the decrease in the activity of enzymes of remethylation cycle of S-adenosylmethioninsyntase, S-adenosylhomocysteinhyhdrolase, betaine-homocysteine methyltransferase. Suppression of transsulfuration transformation of homocysteine to cysteine in hypothyroidism was mainly due to the inhibition of cystathionine synthase activity of cystathionine-β-synthase, wherein cystathionase activity of cystathionine-γ-lyase was not changed. In animals with hypothyroidism we also noticed the inhibition of cysteine desulfunation reactions: the activity of enzymes of cystathionine-β-synthase, cystathionine-γ-lyase and cysteine aminotransferase significantly decreased in liver and kidneys. Experimental hyperthyroidism was accompanied by increase in activity of remethylation cycle enzymes, increase in cystationine synthase activity of cystathionine-β-synthase in liver and activity of these enzymes in kidneys. The simulation of hyperthyroidism led to the decrease of homocysteine concentration, and of hypothyroidism - to the increase of homocysteine and cysteine concentrations and reduced H2S content in blood of the animals. Thus, the significant risk factors for the development of atherosclerosis

Insulin response of the glucose and fatty acid metabolism in dry dairy cows across a range of body condition scores.

PubMed

De Koster, J; Hostens, M; Van Eetvelde, M; Hermans, K; Moerman, S; Bogaert, H; Depreester, E; Van den Broeck, W; Opsomer, G

2015-07-01

positively associated with these variables. These results reflect a decreased insulin sensitivity and a decreased insulin responsiveness of the glucose metabolism in overconditioned dry dairy cows. The minimal SSNEFA and the EC50 of the fatty acid metabolism were not associated with variables reflecting adiposity of the cows, meaning that the insulin response of the fatty acid metabolism was not associated with the level of fat accumulation in dry dairy cows. Additionally, within individual cows, the EC50 of the glucose metabolism was higher than the EC50 of the fatty acid metabolism, meaning that the response of the fatty acid metabolism occurs at lower insulin concentrations compared with the response of the glucose metabolism. It can be concluded that a negative association exists between the level of fat accumulation in pregnant dairy cows at the end of the dry period and the insulin response of the glucose metabolism. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Metabolic and microbial signatures in rat hepatocellular carcinoma treated with caffeic acid and chlorogenic acid.

PubMed

Zhang, Zhan; Wang, Di; Qiao, Shanlei; Wu, Xinyue; Cao, Shuyuan; Wang, Li; Su, Xiaojian; Li, Lei

2017-07-03

Hepatocellular carcinoma (HCC) treatment remains lack of effective chemopreventive agents, therefore it is very attractive and urgent to discover novel anti-HCC drugs. In the present study, the effects of chlorogenic acid (ChA) and caffeic acid (CaA) on HCC induced by diethylnitrosamine (DEN) were evaluated. ChA or CaA could reduce the histopathological changes and liver injury markers, such as alanine transarninase, aspartate aminotransferase, alkaline phosphatase, total bile acid, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol. The underlying mechanisms were investigated by a data integration strategy based on correlation analyses of metabonomics data and 16 S rRNA gene sequencing data. ChA or CaA could inhibit the increase of Rumincoccaceae UCG-004 and reduction of Lachnospiraceae incertae sedis, and Prevotella 9 in HCC rats. The principal component analysis and partial least squares discriminant analysis were applied to reveal the metabolic differences among these groups. 28 different metabolites showed a trend to return to normal in both CaA and ChA treatment. Among them, Bilirubin, L-Tyrosine, L-Methionine and Ethanolamine were correlated increased Rumincoccaceae UCG-004 and decreased of Lachnospiraceae incertae sedis and Prevotella 9. These correlations could be identified as metabolic and microbial signatures of HCC onset and potential therapeutic targets.

High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice.

PubMed

Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas D E; Rozen, Rima

2015-03-01

Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Folic acid-supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr(+/+) and Mthfr(+/-) mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr(+/-) mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr(+/-) livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr(+/-) mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot

Interactions between prebiotics, probiotics, polyunsaturated fatty acids and polyphenols: diet or supplementation for metabolic syndrome prevention?

PubMed

Peluso, Ilaria; Romanelli, Luca; Palmery, Maura

2014-05-01

The metabolic syndrome can be prevented by the Mediterranean diet, characterized by fiber, omega-3 polyunsaturated fatty acids and polyphenols. However, the composition of the Mediterranean diet, which can be viewed as a natural multiple supplement, is poorly controlled, and its beneficial effects poorly predictable. The metabolic syndrome is associated with intestinal dysbiosis and the gut microbioma seems to be the main target and player in the interactions occurring between probiotics, prebiotics, omega 3 polyunsaturated fatty acids, and polyphenols. From the reviewed evidence, it is reasonable to manage growth and metabolism of gut microflora with specific prebiotics and polyphenols. Even though the healthy properties of functional foods and nutraceuticals still need to be fully elucidated, available data suggest that well-designed supplements, containing the better ratio of omega-3 polyunsaturated fatty acids and antioxidants, specific probiotic strains, and selected polyphenols and prebiotics, could be useful in metabolic syndrome prevention and treatment.

In vitro and in vivo metabolism of all-trans- and 13-cis-retinoic acid in hamsters. Identification of 13-cis-4-oxoretinoic acid.

PubMed

Frolik, C A; Roller, P P; Roberts, A B; Sporn, M B

1980-09-10

Administration of either all-trans-[3H]- or 13-cis-[3H]retinoic acid to hamsters fed a normal diet results in the formation of a number of polar metabolites. At least one of these metabolites has been shown to be common to both isomers of retinoic acid and can be generated in a hamster liver 10,000 X g supernatant system using 13-cis-retinoic acid as substrate. It has been identified as 13-cis-4-oxoretinoic acid by mass spectral, ultraviolet absorption, and proton NMR characteristics, as well as by its co-migration with synthetic 13-cis-4-oxoretinoic acid in two different high pressure liquid chromatographic systems. In addition, its metabolic precursor, 13-cis-4-hydroxyretinoic acid, has been tentatively identified. These compounds are believed to be early metabolites in the elimination pathway of retinoic acid from the body.

Abscisic Acid Metabolism by a Cell-free Preparation from Echinocystis lobata Liquid Endoserum 1

PubMed Central

Gillard, Douglas F.; Walton, Daniel C.

1976-01-01

A cell-free enzyme system capable of metabolizing abscisic acid has been obtained from Eastern Wild Cucumber (Echinocystis lobata Michx.) liquid endosperm. The reaction products were determined to be phaseic acid (PA) and dihydrophaseic acid (DPA) by co-chromatography on thin layer chromatograms as the free acids, methyl esters, and their respective oxidation or reduction products. The crude enzyme preparation was separated by centrifugation into a particulate abscisic acid (ABA)-hydroxylating activity and a soluble PA-reducing activity. The particulate ABA-hydroxylating enzyme showed a requirement for O2 and NADPH, inhibition by CO, and high substrate specificity for (+)-ABA. Acetylation of short term incubation mixtures gave evidence for the presence of 6′-hydroxymethyl-ABA as an intermediate in PA formation. Determinations of endogenous ABA and DPA concentrations suggest that the ABA-hydroxylating and PA-reducing enzymes are extensively metabolizing ABA in the intact E. lobata seed. PMID:16659768

Primary fatty acid amide metabolism: conversion of fatty acids and an ethanolamine in N18TG2 and SCP cells.

PubMed

Farrell, Emma K; Chen, Yuden; Barazanji, Muna; Jeffries, Kristen A; Cameroamortegui, Felipe; Merkler, David J

2012-02-01

Primary fatty acid amides (PFAM) are important signaling molecules in the mammalian nervous system, binding to many drug receptors and demonstrating control over sleep, locomotion, angiogenesis, and many other processes. Oleamide is the best-studied of the primary fatty acid amides, whereas the other known PFAMs are significantly less studied. Herein, quantitative assays were used to examine the endogenous amounts of a panel of PFAMs, as well as the amounts produced after incubation of mouse neuroblastoma N(18)TG(2) and sheep choroid plexus (SCP) cells with the corresponding fatty acids or N-tridecanoylethanolamine. Although five endogenous primary amides were discovered in the N(18)TG(2) and SCP cells, a different pattern of relative amounts were found between the two cell lines. Higher amounts of primary amides were found in SCP cells, and the conversion of N-tridecanoylethanolamine to tridecanamide was observed in the two cell lines. The data reported here show that the N(18)TG(2) and SCP cells are excellent model systems for the study of PFAM metabolism. Furthermore, the data support a role for the N-acylethanolamines as precursors for the PFAMs and provide valuable new kinetic results useful in modeling the metabolic flux through the pathways for PFAM biosynthesis and degradation.

Branched-chain amino acids in metabolic signalling and insulin resistance

PubMed Central

Lynch, Christopher J.; Adams, Sean H.

2015-01-01

Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM. PMID:25287287

Branched-chain amino acids in metabolic signalling and insulin resistance.

PubMed

Lynch, Christopher J; Adams, Sean H

2014-12-01

Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.

CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders.

PubMed

Skotte, Line; Koch, Anders; Yakimov, Victor; Zhou, Sirui; Søborg, Bolette; Andersson, Mikael; Michelsen, Sascha W; Navne, Johan E; Mistry, Jacqueline M; Dion, Patrick A; Pedersen, Michael L; Børresen, Malene L; Rouleau, Guy A; Geller, Frank; Melbye, Mads; Feenstra, Bjarke

2017-06-01

Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders. Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A , was strongly associated with markers of n -3 fatty acid metabolism, including degree of unsaturation ( P =1.16×10 - 34 ), levels of polyunsaturated fatty acids, n -3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels ( P =2.35×10 - 15 , P =4.02×10 - 19 , and P =7.92×10 - 27 ). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm ( P =1.04×10 - 9 ). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779. Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations. © 2017 American Heart Association, Inc.

Dietary Omega-3 Fatty Acid Deficiency and High Fructose intake in the Development of Metabolic Syndrome Brain, Metabolic Abnormalities, and Non-Alcoholic Fatty Liver Disease

PubMed Central

Simopoulos, Artemis P.

2013-01-01

Western diets are characterized by both dietary omega-3 fatty acid deficiency and increased fructose intake. The latter found in high amounts in added sugars such as sucrose and high fructose corn syrup (HFCS). Both a low intake of omega-3 fatty acids or a high fructose intake contribute to metabolic syndrome, liver steatosis or non-alcoholic fatty liver disease (NAFLD), promote brain insulin resistance, and increase the vulnerability to cognitive dysfunction. Insulin resistance is the core perturbation of metabolic syndrome. Multiple cognitive domains are affected by metabolic syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function. Fish oil supplementation maintains proper insulin signaling in the brain, ameliorates NAFLD and decreases the risk to metabolic syndrome suggesting that adequate levels of omega-3 fatty acids in the diet can cope with the metabolic challenges imposed by high fructose intake in Western diets which is of major public health importance. This review presents the current status of the mechanisms involved in the development of the metabolic syndrome, brain insulin resistance, and NAFLD a most promising area of research in Nutrition for the prevention of these conditions, chronic diseases, and improvement of Public Health. PMID:23896654

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

PubMed Central

Catoire, Milène; Alex, Sheril; Paraskevopulos, Nicolas; Mattijssen, Frits; Evers-van Gogh, Inkie; Schaart, Gert; Jeppesen, Jacob; Kneppers, Anita; Mensink, Marco; Voshol, Peter J.; Olivecrona, Gunilla; Tan, Nguan Soon; Hesselink, Matthijs K. C.; Berbée, Jimmy F.; Rensen, Patrick C. N.; Kalkhoven, Eric; Schrauwen, Patrick; Kersten, Sander

2014-01-01

Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-δ, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise. PMID:24591600

Metabolism of clofibric acid in zebrafish embryos (Danio rerio) as determined by liquid chromatography-high resolution-mass spectrometry.

PubMed

Brox, Stephan; Seiwert, Bettina; Haase, Nora; Küster, Eberhard; Reemtsma, Thorsten

2016-01-01

The zebrafish embryo (ZFE) is increasingly used in ecotoxicology research but detailed knowledge of its metabolic potential is still limited. This study focuses on the xenobiotic metabolism of ZFE at different life-stages using the pharmaceutical compound clofibric acid as study compound. Liquid chromatography with quadrupole-time-of-flight mass spectrometry (LC-QToF-MS) is used to detect and to identify the transformation products (TPs). In screening experiments, a total of 18 TPs was detected and structure proposals were elaborated for 17 TPs, formed by phase I and phase II metabolism. Biotransformation of clofibric acid by the ZFE involves conjugation with sulfate or glucuronic acid, and, reported here for the first time, with carnitine, taurine, and aminomethanesulfonic acid. Further yet unknown cyclization products were identified using non-target screening that may represent a new detoxification pathway. Sulfate containing TPs occurred already after 3h of exposure (7hpf), and from 48h of exposure (52hpf) onwards, all TPs were detected. The detection of these TPs indicates the activity of phase I and phase II enzymes already at early life-stages. Additionally, the excretion of one TP into the exposure medium was observed. The results of this study outline the high metabolic potential of the ZFE with respect to the transformation of xenobiotics. Similarities but also differences to other test systems were observed. Biotransformation of test chemicals in toxicity testing with ZFE may therefore need further consideration. Copyright © 2016 Elsevier Inc. All rights reserved.

Designing medical foods for inherited metabolic disorders: why intact protein is superior to amino acids.

PubMed

Ney, Denise Marie; Etzel, Mark Raymond

2017-04-01

Phenylketonuria and tyrosinemia are inherited metabolic disorders characterized by high blood levels of phenylalanine (Phe) or tyrosine (Tyr), due to mutations in genes affecting Phe and Tyr metabolism, respectively. The primary management is a lifelong diet restricted in protein from natural foods in combination with medical foods comprised mixtures of synthetic amino acids. Compliance is often poor after childhood leading to neuropsychological sequela. Glycomacropeptide, an intact 64 amino acid glycophosphopeptide isolated from cheese whey, provides a new paradigm for the management of phenylketonuria and tyrosinemia because glycomacropeptide contains no Phe and Tyr in its pure form, and is also a prebiotic. Medical foods made from glycomacropeptide have been used successfully for the management of phenylketonuria and tyrosinemia. Preclinical and clinical studies demonstrate that intact protein from glycomacropeptide provides a more acceptable and physiologic source of defined protein compared to amino acids in medical foods. For example, harmful gut bacteria were reduced, beneficial short chain fatty acids increased, renal workload decreased, protein utilization increased, and bone fragility decreased using intact protein versus amino acids. Advances in biotechnology will propel the transition from synthetic amino acids to intact proteins for the management of inherited metabolic disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Cholesterol metabolism and lipid peroxidation processes in hypodynamia. Effect of using ascorbic acid and alpha-tocopherol].

PubMed

Elikov, A V; Tsapok, P I

2010-01-01

Study status of cholesterol metabolism, processes of lipid peroxidation and antioxidant protection in blood plasma, erythrocytes and homogenates of the, heart, liver, muscle femors of rats attached to movement active. Establishment effects application of ascorbic acid and alpha-tocopherol. Ascorbic acid and alpha-tocopherol were infused daily. The daily dosage was 2 and 1 mg respectively. Characteristic shift changes of cholesterol metabolism in conditions of limited muscular activity were revealed. It was shown that vitamin antioxidants play a role in correction of metabolic disorders in case of immobile distress syndrome.

Analysis of Growth Inhibition and Metabolism of Hydroxycinnamic Acids by Brewing and Spoilage Strains of Brettanomyces Yeast

PubMed Central

Lentz, Michael; Harris, Chad

2015-01-01

Brettanomyces yeasts are well-known as spoilage organisms in both the wine and beer industries, but also contribute important desirable characters to certain beer styles. These properties are mediated in large part by Brettanomyces’ metabolism of hydroxycinnamic acids (HCAs) present in beverage raw materials. Here we compare growth inhibition by, and metabolism of, HCAs among commercial brewing strains and spoilage strains of B. bruxellensis and B. anomalus. These properties vary widely among the different strains tested and between the HCAs analyzed. Brewing strains showed more efficient metabolism of ferulic acid over p-coumaric acid, a trait not shared among the spoilage strains. PMID:28231223

Metabolism of 2-chloro-1,1-difluoroethene to glyoxylic and glycolic acid in rat hepatic microsomes.

PubMed

Baker, M T; Vasquez, M T; Bates, J N; Chiang, C K

1990-01-01

The complete metabolic fate of the volatile anesthetic halothane is unclear since 2-chloro-1,1-diflurorethene (CDE), a reductive halothane metabolite, is known to readily release inorganic fluoride upon oxidation by cytochrome P-450. This study sought to clarify the metabolism of CDE by determining its metabolites and the roles of induce cytochrome P-450 forms in its metabolism. Upon incubation of [14C]CDE with rat hepatic microsomes, two major radioactive products were found which accounted for greater than 94% of the total metabolites. These compounds were determined to be the nonhalogenated compounds, glyoxylic and glycolic acids, which were formed in a ratio of approximately 1 to 2 of glyoxylic to glycolic acid. No other radioactive metabolites could be detected. Following incubation of CDE with hepatic microsomes isolated from rats treated with cytochrome P-450 inducers, measurement of fluoride release showed that phenobarbital induced CDE metabolism to the greatest degree at high CDE levels, isoniazid was the most effective inducer at low CDE concentrations, and beta-naphthoflavone was ineffective as an inducer. These results suggest that CDE biotransformation primarily involves the generation of an epoxide intermediate, which undergoes mechanisms of decay leading to total dehalogenation of the molecule, and that this metabolism is preferentially carried out by the phenobarbital- and ethanol-inducible forms of cytochrome P-450.

Analysis of l-glutamic acid fermentation by using a dynamic metabolic simulation model of Escherichia coli

PubMed Central

2013-01-01

Background Understanding the process of amino acid fermentation as a comprehensive system is a challenging task. Previously, we developed a literature-based dynamic simulation model, which included transcriptional regulation, transcription, translation, and enzymatic reactions related to glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and the anaplerotic pathway of Escherichia coli. During simulation, cell growth was defined such as to reproduce the experimental cell growth profile of fed-batch cultivation in jar fermenters. However, to confirm the biological appropriateness of our model, sensitivity analysis and experimental validation were required. Results We constructed an l-glutamic acid fermentation simulation model by removing sucAB, a gene encoding α-ketoglutarate dehydrogenase. We then performed systematic sensitivity analysis for l-glutamic acid production; the results of this process corresponded with previous experimental data regarding l-glutamic acid fermentation. Furthermore, it allowed us to predicted the possibility that accumulation of 3-phosphoglycerate in the cell would regulate the carbon flux into the TCA cycle and lead to an increase in the yield of l-glutamic acid via fermentation. We validated this hypothesis through a fermentation experiment involving a model l-glutamic acid-production strain, E. coli MG1655 ΔsucA in which the phosphoglycerate kinase gene had been amplified to cause accumulation of 3-phosphoglycerate. The observed increase in l-glutamic acid production verified the biologically meaningful predictive power of our dynamic metabolic simulation model. Conclusions In this study, dynamic simulation using a literature-based model was shown to be useful for elucidating the precise mechanisms involved in fermentation processes inside the cell. Further exhaustive sensitivity analysis will facilitate identification of novel factors involved in the metabolic regulation of amino acid fermentation. PMID

Systems and synthetic metabolic engineering for amino acid production - the heartbeat of industrial strain development.

PubMed

Becker, Judith; Wittmann, Christoph

2012-10-01

With a world market of more than four million tons per year, l-amino acids are among the most important products in industrial biotechnology. The recent years have seen a tremendous progress in the development of tailor-made strains for such products, intensively driven from systems metabolic engineering, which upgrades strain engineering into a concept of optimization on a global scale. This concept seems especially valuable for efficient amino acid production, demanding for a global modification of pathway fluxes - a challenge with regard to the high complexity of the underlying metabolism, superimposed by various layers of metabolic and transcriptional control. Copyright © 2011 Elsevier Ltd. All rights reserved.

Prepartum fatty acid supplementation in sheep I. Eicosapentaenoic and docosahexaenoic acid supplementation do not modify ewe and lamb metabolic status and performance through weaning.

PubMed

Coleman, D N; Rivera-Acevedo, K C; Relling, A E

2018-02-15

Fatty acids are involved in the regulation of many physiological pathways, including those involved in gene expression and energy metabolism. Through effects on these pathways, fatty acids may have lifelong impacts on offspring development and metabolism via maternal supplementation. Therefore, our objective was to investigate the impact of supplementing a source of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) during late gestation on productive and metabolic responses of ewes and their offspring. Eighty-four gestating ewes (28 pens) were blocked and randomly assigned to a diet with 0.39% added fat during the last 50 d of gestation (d -0). The fat sources were Ca salts of a palmitic fatty acid distillate (PFAD) or EPA + DHA. After lambing (d 1), all ewes and lambs were placed on the same pasture. The ewes were weighed and BCS was measured on d -50, -20, 30, and 60 (weaning) of the experiment. Blood samples were taken from the ewes on d -50, -20, 1 (lambing), 30, and 60. Milk yield and composition were measured at 30 d postpartum. Lambs were weighed and bled at d 1, 30, and 60, and ADG was calculated. All plasma samples were analyzed for glucose and NEFA. Ghrelin, prostaglandin E metabolites (PGEM), and the prostaglandin D2 metabolite 11β-PGF2α were measured in d -20 ewe samples. Insulin and adropin were measured in lamb samples at d 60. There was no difference on ewe BW (P = 0.48) or BCS (P = 0.55), or plasma concentrations of glucose (P = 0.57), NEFA (P = 0.44), ghrelin (P = 0.36), PGEM (P = 0.32), and 11β-PGF2α (P = 0.86) between ewes supplemented with PFAD or EPA + DHA. Neither milk yield nor its composition was different (P > 0.10) among treatments. Lambs born from ewes supplemented with PFAD or EPA + DHA did not have different BW (P = 0.22), ADG (P = 0.21) or plasma NEFA (P = 0.52), glucose (P = 0.50), insulin (P = 0.59), and adropin (P = 0.72) concentrations. These results suggest that supplementation of EPA and DHA

A study of the metabolism of l-αγ-diaminobutyric acid in a Xanthomonas species

PubMed Central

Rao, D. Rajagopal; Hariharan, K.; Vijayalakshmi, K. R.

1969-01-01

1. l-αγ-Diaminobutyric acid is metabolized in Xanthomonas sp. to aspartic β-semialdehyde, aspartic acid and oxaloacetic acid. 2. Aspartic β-semialdehyde is formed from diaminobutyric acid by a pyruvate-dependent γ-transamination. 3. The transaminase has a pH optimum of 9 and exhibits a high degree of substrate specificity, as analogues of diaminobutyric acid and pyruvate are inert in the system. The transaminase is inhibited by carbonyl-binding agents such as hydroxylamine. 4. Aspartic acid is formed from aspartic β-semialdehyde by an NAD+-dependent dehydrogenation. 5. The dehydrogenase has a pH optimum of 8·5 and is a thiol enzyme. It is specific for aspartic β-semialdehyde but analogues of NAD+ such as 3-acetylpyridine–adenine dinucleotide and deamino-NAD are partly active in the system. 6. The significance of these reactions is discussed in relation to diaminobutyric acid metabolism in plants and mammalian systems. PMID:4390206

Ursodeoxycholic Acid Ameliorates Fructose-Induced Metabolic Syndrome in Rats

PubMed Central

2014-01-01

The metabolic syndrome (MS) is characterized by insulin resistance, dyslipidemia and hypertension. It is associated with increased risk of cardiovascular diseases and type-2 diabetes. Consumption of fructose is linked to increased prevalence of MS. Ursodeoxycholic acid (UDCA) is a steroid bile acid with antioxidant, anti-inflammatory activities and has been shown to improve insulin resistance. The current study aims to investigate the effect of UDCA (150 mg/kg) on MS induced in rats by fructose administration (10%) in drinking water for 12 weeks. The effects of UDCA were compared to fenofibrate (100 mg/kg), an agonist of PPAR-α receptors. Treatment with UDCA or fenofibrate started from the 6th week after fructose administration once daily. Fructose administration resulted in significant increase in body weight, elevations of blood glucose, serum insulin, cholesterol, triglycerides, advanced glycation end products (AGEs), uric acid levels, insulin resistance index and blood pressure compared to control rats. Moreover, fructose increased oxidative stress in aortic tissues indicated by significant increases of malondialdehyde (MDA), expression of iNOS and reduction of reduced glutathione (GSH) content. These disturbances were associated with decreased eNOS expression, increased infiltration of leukocytes and loss of aortic vascular elasticity. Treatment with UDCA successfully ameliorated the deleterious effects of fructose. The protective effect of UDCA could be attributed to its ability to decrease uric acid level, improve insulin resistance and diminish oxidative stress in vascular tissues. These results might support possible clinical application of UDCA in MS patients especially those present with liver diseases, taking into account its tolerability and safety. However, further investigations on human subjects are needed before the clinical application of UDCA for this indication. PMID:25202970

Improved eicosapentaenoic acid production in Pythium splendens RBB-5 based on metabolic regulation analysis.

PubMed

Ren, Liang; Zhou, Pengpeng; Zhu, Yuanmin; Zhang, Ruijiao; Yu, Longjiang

2017-05-01

Eicosapentaenoic acid (EPA) is an essential polyunsaturated fatty acid for human beings. At present, the production of commercially available long-chain polyunsaturated fatty acids, mainly from wild-caught ocean fish, is struggling to meet the increasing demand for EPA. Production of EPA by microorganisms may be an alternative, effective and economical method. The oleaginous fungus Pythium splendens RBB-5 is a potential source of EPA, and thanks to the simple culture conditions required, high yields can be achieved in a facile manner. In the study, lipid metabolomics was performed in an attempt to enhance EPA biosynthesis in Pythium splendens. Synthetic, metabolic regulation and gene expression analyses were conducted to clarify the mechanism of EPA biosynthesis, and guide optimization of EPA production. The results showed that the Δ 6 desaturase pathway is the main EPA biosynthetic route in this organism, and ∆ 6 , ∆ 12 and Δ 17 desaturases are the rate-limiting enzymes. All the three desaturase genes were separately introduced into the parent strain to increase the flow of fatty acids into the Δ 6 desaturase pathway. Enhanced expression of these key enzymes, in combination with improved regulation of metabolism, resulted in a maximum yield of 1.43 g/L in the D12 transgenic strain, which represents a tenfold increase over the parent strain before optimization. This is the higher EPA production yield yet reported for a microbial system. Our findings may allow the production of EPA at an industrial scale, and the strategy employed could be used to increase the production of EPA or other lipids in oleaginous microorganisms.

On the cellular metabolism of the click chemistry probe 19-alkyne arachidonic acid[S

PubMed Central

Robichaud, Philippe Pierre; Poirier, Samuel J.; Boudreau, Luc H.; Doiron, Jérémie A.; Barnett, David A.; Boilard, Eric; Surette, Marc E.

2016-01-01

Alkyne and azide analogs of natural compounds that can be coupled to sensitive tags by click chemistry are powerful tools to study biological processes. Arachidonic acid (AA) is a FA precursor to biologically active compounds. 19-Alkyne-AA (AA-alk) is a sensitive clickable AA analog; however, its use as a surrogate to study AA metabolism requires further evaluation. In this study, AA-alk metabolism was compared with that of AA in human cells. Jurkat cell uptake of AA was 2-fold greater than that of AA-alk, but significantly more AA-Alk was elongated to 22:4. AA and AA-alk incorporation into and remodeling between phospholipid (PL) classes was identical indicating equivalent CoA-independent AA-PL remodeling. Platelets stimulated in the pre­sence of AA-alk synthesized significantly less 12-lipoxygenase (12-LOX) and cyclooxygenase products than in the presence of AA. Ionophore-stimulated neutrophils produced significantly more 5-LOX products in the presence of AA-alk than AA. Neutrophils stimulated with only exogenous AA-alk produced significantly less 5-LOX products compared with AA, and leukotriene B4 (LTB4)-alk was 12-fold less potent at stimulating neutrophil migration than LTB4, collectively indicative of weaker leukotriene B4 receptor 1 agonist activity of LTB4-alk. Overall, these results suggest that the use of AA-alk as a surrogate for the study of AA metabolism should be carried out with caution. PMID:27538823

Revising the Representation of Fatty Acid, Glycerolipid, and Glycerophospholipid Metabolism in the Consensus Model of Yeast Metabolism

PubMed Central

Aung, Hnin W.; Henry, Susan A.

2013-01-01

Abstract Genome-scale metabolic models are built using information from an organism's annotated genome and, correspondingly, information on reactions catalyzed by the set of metabolic enzymes encoded by the genome. These models have been successfully applied to guide metabolic engineering to increase production of metabolites of industrial interest. Congruity between simulated and experimental metabolic behavior is influenced by the accuracy of the representation of the metabolic network in the model. In the interest of applying the consensus model of Saccharomyces cerevisiae metabolism for increased productivity of triglycerides, we manually evaluated the representation of fatty acid, glycerophospholipid, and glycerolipid metabolism in the consensus model (Yeast v6.0). These areas of metabolism were chosen due to their tightly interconnected nature to triglyceride synthesis. Manual curation was facilitated by custom MATLAB functions that return information contained in the model for reactions associated with genes and metabolites within the stated areas of metabolism. Through manual curation, we have identified inconsistencies between information contained in the model and literature knowledge. These inconsistencies include incorrect gene-reaction associations, improper definition of substrates/products in reactions, inappropriate assignments of reaction directionality, nonfunctional β-oxidation pathways, and missing reactions relevant to the synthesis and degradation of triglycerides. Suggestions to amend these inconsistencies in the Yeast v6.0 model can be implemented through a MATLAB script provided in the Supplementary Materials, Supplementary Data S1 (Supplementary Data are available online at www.liebertpub.com/ind). PMID:24678285

Fatty Acid Synthesis and Pyruvate Metabolism Pathways Remain Active in Dihydroartemisinin-Induced Dormant Ring Stages of Plasmodium falciparum

PubMed Central

Chen, Nanhua; LaCrue, Alexis N.; Teuscher, Franka; Waters, Norman C.; Gatton, Michelle L.; Kyle, Dennis E.

2014-01-01

Artemisinin (ART)-based combination therapy (ACT) is used as the first-line treatment of uncomplicated falciparum malaria worldwide. However, despite high potency and rapid action, there is a high rate of recrudescence associated with ART monotherapy or ACT long before the recent emergence of ART resistance. ART-induced ring-stage dormancy and recovery have been implicated as possible causes of recrudescence; however, little is known about the characteristics of dormant parasites, including whether dormant parasites are metabolically active. We investigated the transcription of 12 genes encoding key enzymes in various metabolic pathways in P. falciparum during dihydroartemisinin (DHA)-induced dormancy and recovery. Transcription analysis showed an immediate downregulation for 10 genes following exposure to DHA but continued transcription of 2 genes encoding apicoplast and mitochondrial proteins. Transcription of several additional genes encoding apicoplast and mitochondrial proteins, particularly of genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, was also maintained. Additions of inhibitors for biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase of the fatty acid synthesis pathways delayed the recovery of dormant parasites by 6 and 4 days, respectively, following DHA treatment. Our results demonstrate that most metabolic pathways are downregulated in DHA-induced dormant parasites. In contrast, fatty acid and pyruvate metabolic pathways remain active. These findings highlight new targets to interrupt recovery of parasites from ART-induced dormancy and to reduce the rate of recrudescence following ART treatment. PMID:24913167

Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin-induced dormant ring stages of Plasmodium falciparum.

PubMed

Chen, Nanhua; LaCrue, Alexis N; Teuscher, Franka; Waters, Norman C; Gatton, Michelle L; Kyle, Dennis E; Cheng, Qin

2014-08-01

Artemisinin (ART)-based combination therapy (ACT) is used as the first-line treatment of uncomplicated falciparum malaria worldwide. However, despite high potency and rapid action, there is a high rate of recrudescence associated with ART monotherapy or ACT long before the recent emergence of ART resistance. ART-induced ring-stage dormancy and recovery have been implicated as possible causes of recrudescence; however, little is known about the characteristics of dormant parasites, including whether dormant parasites are metabolically active. We investigated the transcription of 12 genes encoding key enzymes in various metabolic pathways in P. falciparum during dihydroartemisinin (DHA)-induced dormancy and recovery. Transcription analysis showed an immediate downregulation for 10 genes following exposure to DHA but continued transcription of 2 genes encoding apicoplast and mitochondrial proteins. Transcription of several additional genes encoding apicoplast and mitochondrial proteins, particularly of genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, was also maintained. Additions of inhibitors for biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase of the fatty acid synthesis pathways delayed the recovery of dormant parasites by 6 and 4 days, respectively, following DHA treatment. Our results demonstrate that most metabolic pathways are downregulated in DHA-induced dormant parasites. In contrast, fatty acid and pyruvate metabolic pathways remain active. These findings highlight new targets to interrupt recovery of parasites from ART-induced dormancy and to reduce the rate of recrudescence following ART treatment. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

1H NMR-based metabolic profiling reveals the effects of fluoxetine on lipid and amino acid metabolism in astrocytes.

PubMed

Bai, Shunjie; Zhou, Chanjuan; Cheng, Pengfei; Fu, Yuying; Fang, Liang; Huang, Wen; Yu, Jia; Shao, Weihua; Wang, Xinfa; Liu, Meiling; Zhou, Jingjing; Xie, Peng

2015-04-15

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is a prescribed and effective antidepressant and generally used for the treatment of depression. Previous studies have revealed that the antidepressant mechanism of fluoxetine was related to astrocytes. However, the therapeutic mechanism underlying its mode of action in astrocytes remains largely unclear. In this study, primary astrocytes were exposed to 10 µM fluoxetine; 24 h post-treatment, a high-resolution proton nuclear magnetic resonance (1H NMR)-based metabolomic approach coupled with multivariate statistical analysis was used to characterize the metabolic variations of intracellular metabolites. The orthogonal partial least-squares discriminant analysis (OPLS-DA) score plots of the spectra demonstrated that the fluoxetine-treated astrocytes were significantly distinguished from the untreated controls. In total, 17 differential metabolites were identified to discriminate the two groups. These key metabolites were mainly involved in lipids, lipid metabolism-related molecules and amino acids. This is the first study to indicate that fluoxetine may exert antidepressant action by regulating the astrocyte's lipid and amino acid metabolism. These findings should aid our understanding of the biological mechanisms underlying fluoxetine therapy.

Metabolism of exogenous fatty acids, fatty acid-mediated cholesterol efflux, PKA and PKC pathways in boar sperm acrosome reaction.

PubMed

Hossain, Md Sharoare; Afrose, Sadia; Sawada, Tomio; Hamano, Koh-Ichi; Tsujii, Hirotada

2010-03-01

For understanding the roles of fatty acids on the induction of acrosome reaction which occurs under association of cholesterol efflux and PKA or PKC pathways in boar spermatozoa, metabolic fate of alone and combined radiolabeled 14 C-oleic acid and 3 H-linoleic acid incorporated in the sperm was compared, and behavior of cholesterol and effects of PKA and PKC inhibitors upon fatty acid-induced acrosome reaction were examined. Semen was collected from a Duroc boar, and the metabolic activities of fatty acids in the spermatozoa were measured using radioactive compounds and thin layer chromatography. Cholesterol efflux was measured with a cholesterol determination assay kit. Participation of fatty acids on the AR through PKA and PKC pathways was evaluated using a specific inhibitor of these enzymes. Incorporation rate of 14 C-oleic acid into the sperm lipids was significantly higher than that of 3 H-linoleic acid ( P < 0.05). The oxidation of 14 C-oleic acid was higher in combined radiolabeling rather than in one. The highest amounts of 3 H-linoleic acid and 14 C-oleic acid were recovered mainly in the triglycerides and phospholipids fraction, and 14 C-oleic acid distribution was higher than the 3 H-linoleic acid in both labeled ( P < 0.05) sperm lipids. In the 3 H-linoleic and 14 C-oleic acid combined radiolabeling, the incorporation rate of the radioactive fatty acids in all the lipid fractions increased 15 times more than the alone radiolabeling. Boar sperm utilize oleic acid to generate energy for hyperactivation ( P < 0.05). Supplementation of arachidonic acid significantly increased ( P < 0.05) cholesterol efflux in sperm. When spermatozoa were incubated with PKA or PKC inhibitors, there was a significant reduction of arachidonic acid-induced acrosome reaction (AR) ( P < 0.05), and inhibition by PKA inhibitor is stronger than that by PKC inhibitor. Incorporation of unsaturated fatty acids, especially oleic acid, into triglycerides and phospholipids provides

Nonessential fatty acids in formula fat blends influence essential fatty acid metabolism and composition in plasma and organ lipid classes in piglets.

PubMed

Wall, K M; Diersen-Schade, D; Innis, S M

1992-12-01

The n-6 and n-3 fatty acid status of developing organs is the cumulative result of the diet lipid composition and many complex events of lipid metabolism. Little information is available, however, on the potential effects of the saturated fatty acid chain length (8:0-16:0) or oleic acid (18:1) content of the diet on the subsequent metabolism of the essential fatty acids 18:2n-6 and 18:3n-3 and their elongated/desaturated products. The effects of feeding piglets formulas with fat blends containing either coconut oil (12:0 + 14:0) or medium chain triglycerides (MCT, 8:0 + 10:0) but similar levels of 18:1, 18:2n-6 and 18:3n-3, or MCT with high or low 18:1 but constant 18:2n-6 and 18:3n-3 on the fatty acid composition of plasma, liver and kidney triglycerides, phospholipids and cholesteryl esters, and of brain total lipid, were studied. Diet-induced changes in the fatty acid composition of lipid classes were generally similar for plasma, liver and kidney. Dietary 18:1 content was reflected in tissue lipids and was inversely associated with levels of 18:2n-6. Lower percentage of 18:2n-6, however, was not associated with lower levels of its elongated/desaturated product 20:4n-6 but was associated with higher levels of 22:6n-3. Feeding coconut oil vs. MCT resulted in lower 18:1 levels in all lipids, and higher percentages of 20:4n-6 in tissue phospholipid. Increasing the dietary n-6/n-3 ratio from 5 to 8 significantly increased tissue percentage of 18:2n-6 and decreased phospholipid 22:6n-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoid activity and metabolism with NaCl-induced low-grade metabolic acidosis and oral alkalization: results of two randomized controlled trials.

PubMed

Buehlmeier, Judith; Remer, Thomas; Frings-Meuthen, Petra; Maser-Gluth, Christiane; Heer, Martina

2016-04-01

Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid-base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases.

Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis.

PubMed

Roda, A; Aldini, R; Camborata, C; Spinozzi, S; Franco, P; Cont, M; D'Errico, A; Vasuri, F; Degiovanni, A; Maroni, L; Adorini, L

2017-07-01

Obeticholic acid (OCA) is a semisynthetic bile acid (BA) analog and potent farnesoid X receptor agonist approved to treat cholestasis. We evaluated the biodistribution and metabolism of OCA administered to carbon tetrachloride-induced cirrhotic rats. This was to ascertain if plasma and hepatic concentrations of OCA are potentially more harmful than those of endogenous BAs. After administration of OCA (30 mg/kg), we used liquid chromatography-mass spectrometry to measure OCA, its metabolites, and BAs at different timepoints in various organs and fluids. Plasma and hepatic concentrations of OCA and BAs were higher in cirrhotic rats than in controls. OCA and endogenous BAs had similar metabolic pathways in cirrhotic rats, although OCA hepatic and intestinal clearance were lower than in controls. BAs' qualitative and quantitative compositions were not modified by a single administration of OCA. In all the matrices studied, OCA concentrations were significantly lower than those of endogenous BAs, potentially much more cytotoxic. © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Production of succinic acid by metabolically engineered microorganisms.

PubMed

Ahn, Jung Ho; Jang, Yu-Sin; Lee, Sang Yup

2016-12-01

Succinic acid (SA) has been recognized as one of the most important bio-based building block chemicals due to its numerous potential applications. For the economical bio-based production of SA, extensive research works have been performed on developing microbial strains by metabolic engineering as well as fermentation and downstream processes. Here we review metabolic engineering strategies applied for bio-based production of SA using representative microorganisms, including Saccharomyces cerevisiae, Pichia kudriavzevii, Escherichia coli, Mannheimia succiniciproducens, Basfia succiniciproducens, Actinobacillus succinogenes, and Corynebacterium glutamicum. In particular, strategies employed for developing engineered strains of these microorganisms leading to the best performance indices (titer, yield, and productivity) are showcased based on the published papers as well as patents. Those processes currently under commercialization are also analyzed and future perspectives are provided. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hepatic Metabolism of Perfluorinated Carboxylic Acids and Polychlorotrifluoroethylene: A Nuclear Magnetic Resonance Investigation in Vivo

DTIC Science & Technology

1992-01-24

metabolism of perfluorooctanoic acid ( PFOA ) and perfluorodecanoic acid ( PFDA ) in rats. These studies are now complete and a manuscript was submitted to...effects of PFOA and PFDA on liver carbohydrate and high-energy phosphate metabolism in vivo. L ’F NMR Studies The studies involving a 19 F NMR...investigation of PFOA and PFDA in rat liver in vivo and various bodily fluids has been described previously and will not be reiterated here. There is, however

The Nitrogen Moieties of Dietary Nonessential Amino Acids Are Distinctively Metabolized in the Gut and Distributed to the Circulation in Rats.

PubMed

Nakamura, Hidehiro; Kawamata, Yasuko; Kuwahara, Tomomi; Sakai, Ryosei

2017-08-01

Background: Although previous growth studies in rodents have indicated the importance of dietary nonessential amino acids (NEAAs) as nitrogen sources, individual NEAAs have different growth-promoting activities. This phenomenon might be attributable to differences in the nitrogen metabolism of individual NEAAs. Objective: The aim of this study was to compare nitrogen metabolism across dietary NEAAs with the use of their 15 N isotopologues. Methods: Male Fischer rats (8 wk old) were given 1.0 g amino acid-defined diets containing either 15 N-labeled glutamate, glutamine (amino or amide), aspartate, alanine, proline, glycine, or serine hourly for 5-6 h. Then, steady-state amino acid concentrations and their 15 N enrichments in the gut and in portal and arterial plasma were measured by an amino acid analyzer and LC tandem mass spectrometry, respectively. Results: The intestinal 15 N distribution and portal-arterial balance of 15 N metabolites indicated that most dietary glutamate nitrogen (>90% of dietary input) was incorporated into various amino acids, including alanine, proline, and citrulline, in the gut. Dietary aspartate nitrogen, alanine nitrogen, and amino nitrogen of glutamine were distributed similarly to other amino acids both in the gut and in the circulation. In contrast, incorporation of the nitrogen moieties of dietary proline, serine, and glycine into other amino acids was less than that of other NEAAs, although interconversion between serine and glycine was very active. Cluster analysis of 15 N enrichment data also indicated that dietary glutamate nitrogen, aspartate nitrogen, alanine nitrogen, and the amino nitrogen of glutamine were distributed similarly to intestinal and circulating amino acids. Further, the analysis revealed close relations between intestinal and arterial 15 N enrichment for each amino acid. The steady-state 15 N enrichment of arterial amino acids indicated that substantial amounts of circulating amino acid nitrogen are derived

Palmitic acid follows a different metabolic pathway than oleic acid in human skeletal muscle cells; lower lipolysis rate despite an increased level of adipose triglyceride lipase.

PubMed

Bakke, Siril S; Moro, Cedric; Nikolić, Nataša; Hessvik, Nina P; Badin, Pierre-Marie; Lauvhaug, Line; Fredriksson, Katarina; Hesselink, Matthijs K C; Boekschoten, Mark V; Kersten, Sander; Gaster, Michael; Thoresen, G Hege; Rustan, Arild C

2012-10-01

Development of insulin resistance is positively associated with dietary saturated fatty acids and negatively associated with monounsaturated fatty acids. To clarify aspects of this difference we have compared the metabolism of oleic (OA, monounsaturated) and palmitic acids (PA, saturated) in human myotubes. Human myotubes were treated with 100μM OA or PA and the metabolism of [(14)C]-labeled fatty acid was studied. We observed that PA had a lower lipolysis rate than OA, despite a more than two-fold higher protein level of adipose triglyceride lipase after 24h incubation with PA. PA was less incorporated into triacylglycerol and more incorporated into phospholipids after 24h. Supporting this, incubation with compounds modifying lipolysis and reesterification pathways suggested a less influenced PA than OA metabolism. In addition, PA showed a lower accumulation than OA, though PA was oxidized to a relatively higher extent than OA. Gene set enrichment analysis revealed that 24h of PA treatment upregulated lipogenesis and fatty acid β-oxidation and downregulated oxidative phosphorylation compared to OA. The differences in lipid accumulation and lipolysis between OA and PA were eliminated in combination with eicosapentaenoic acid (polyunsaturated fatty acid). In conclusion, this study reveals that the two most abundant fatty acids in our diet are partitioned toward different metabolic pathways in muscle cells, and this may be relevant to understand the link between dietary fat and skeletal muscle insulin resistance. Copyright © 2012 Elsevier B.V. All rights reserved.

Effects of Lipoic Acid on High-Fat Diet-Induced Alteration of Synaptic Plasticity and Brain Glucose Metabolism: A PET/CT and 13C-NMR Study.

PubMed

Liu, Zhigang; Patil, Ishan; Sancheti, Harsh; Yin, Fei; Cadenas, Enrique

2017-07-14

High-fat diet (HFD)-induced obesity is accompanied by insulin resistance and compromised brain synaptic plasticity through the impairment of insulin-sensitive pathways regulating neuronal survival, learning, and memory. Lipoic acid is known to modulate the redox status of the cell and has insulin mimetic effects. This study was aimed at determining the effects of dietary administration of lipoic acid on a HFD-induced obesity model in terms of (a) insulin signaling, (b) brain glucose uptake and neuronal- and astrocytic metabolism, and (c) synaptic plasticity. 3-Month old C57BL/6J mice were divided into 4 groups exposed to their respective treatments for 9 weeks: (1) normal diet, (2) normal diet plus lipoic acid, (3) HFD, and (4) HFD plus lipoic acid. HFD resulted in higher body weight, development of insulin resistance, lower brain glucose uptake and glucose transporters, alterations in glycolytic and acetate metabolism in neurons and astrocytes, and ultimately synaptic plasticity loss evident by a decreased long-term potentiation (LTP). Lipoic acid treatment in mice on HFD prevented several HFD-induced metabolic changes and preserved synaptic plasticity. The metabolic and physiological changes in HFD-fed mice, including insulin resistance, brain glucose uptake and metabolism, and synaptic function, could be preserved by the insulin-like effect of lipoic acid.

Metabolic pathway engineering for fatty acid ethyl ester production in Saccharomyces cerevisiae using stable chromosomal integration.

PubMed

de Jong, Bouke Wim; Shi, Shuobo; Valle-Rodríguez, Juan Octavio; Siewers, Verena; Nielsen, Jens

2015-03-01

Fatty acid ethyl esters are fatty acid derived molecules similar to first generation biodiesel (fatty acid methyl esters; FAMEs) which can be produced in a microbial cell factory. Saccharomyces cerevisiae is a suitable candidate for microbial large scale and long term cultivations, which is the typical industrial production setting for biofuels. It is crucial to conserve the metabolic design of the cell factory during industrial cultivation conditions that require extensive propagation. Genetic modifications therefore have to be introduced in a stable manner. Here, several metabolic engineering strategies for improved production of fatty acid ethyl esters in S. cerevisiae were combined and the genes were stably expressed from the organisms' chromosomes. A wax ester synthase (ws2) was expressed in different yeast strains with an engineered acetyl-CoA and fatty acid metabolism. Thus, we compared expression of ws2 with and without overexpression of alcohol dehydrogenase (ADH2), acetaldehyde dehydrogenase (ALD6) and acetyl-CoA synthetase (acs SE (L641P) ) and further evaluated additional overexpression of a mutant version of acetyl-CoA decarboxylase (ACC1 (S1157A,S659A) ) and the acyl-CoA binding protein (ACB1). The combined engineering efforts of the implementation of ws2, ADH2, ALD6 and acs SE (L641P) , ACC1 (S1157A,S659A) and ACB1 in a S. cerevisiae strain lacking storage lipid formation (are1Δ, are2Δ, dga1Δ and lro1Δ) and β-oxidation (pox1Δ) resulted in a 4.1-fold improvement compared with sole expression of ws2 in S. cerevisiae.

Metabolism of fatty acids and lipid hydroperoxides in human body monitoring with Fourier transform Infrared Spectroscopy.

PubMed

Yoshida, Satoshi; Zhang, Qin-Zeng; Sakuyama, Shu; Matsushima, Satoshi

2009-07-24

The metabolism of dietary fatty acids in human has been measured so far using human blood cells and stable-isotope labeled fatty acids, however, no direct data was available for human peripheral tissues and other major organs. To realize the role of dietary fatty acids in human health and diseases, it would be eager to develop convenient and suitable method to monitor fatty acid metabolism in human. We have developed the measurement system in situ for human lip surface lipids using the Fourier transform infrared spectroscopy (FTIR) - attenuated total reflection (ATR) detection system with special adaptor to monitor metabolic changes of lipids in human body. As human lip surface lipids may not be much affected by skin sebum constituents and may be affected directly by the lipid constituents of diet, we could detect changes of FTIR-ATR spectra, especially at 3005 to approximately 3015 cm(-1), of lip surface polyunsaturated fatty acids in a duration time-dependent manner after intake of the docosahexaenoic acid (DHA)-containing triglyceride diet. The ingested DHA appeared on the lip surface and was detected by FTIR-ATR directly and non-invasively. It was found that the metabolic rates of DHA for male volunteer subjects with age 60s were much lower than those with age 20s. Lipid hydroperoxides were found in lip lipids which were extracted from the lip surface using a mixture of ethanol/ethylpropionate/iso-octane solvents, and were the highest in the content just before noon. The changes of lipid hydroperoxides were detected also in situ with FTIR-ATR at 968 cm(-1). The measurements of lip surface lipids with FTIR-ATR technique may advance the investigation of human lipid metabolism in situ non-invasively.

Genome wide identification of microRNAs involved in fatty acid and lipid metabolism of Brassica napus by small RNA and degradome sequencing.

PubMed

Wang, Zhiwei; Qiao, Yan; Zhang, Jingjing; Shi, Wenhui; Zhang, Jinwen

2017-07-01

Rapeseed (Brassica napus) is an important cash crop considered as the third largest oil crop worldwide. Rapeseed oil contains various saturation or unsaturation fatty acids, these fatty acids, whose could incorporation with TAG form into lipids stored in seeds play various roles in the metabolic activity. The different fatty acids in B. napus seeds determine oil quality, define if the oil is edible or must be used as industrial material. miRNAs are kind of non-coding sRNAs that could regulate gene expressions through post-transcriptional modification to their target transcripts playing important roles in plant metabolic activities. We employed high-throughput sequencing to identify the miRNAs and their target transcripts involved in fatty acids and lipids metabolism in different development of B. napus seeds. As a result, we identified 826 miRNA sequences, including 523 conserved and 303 newly miRNAs. From the degradome sequencing, we found 589 mRNA could be targeted by 236 miRNAs, it includes 49 novel miRNAs and 187 conserved miRNAs. The miRNA-target couple suggests that bna-5p-163957_18, bna-5p-396192_7, miR9563a-p3, miR9563b-p5, miR838-p3, miR156e-p3, miR159c and miR1134 could target PDP, LACS9, MFPA, ADSL1, ACO32, C0401, GDL73, PlCD6, OLEO3 and WSD1. These target transcripts are involving in acetyl-CoA generate and carbon chain desaturase, regulating the levels of very long chain fatty acids, β-oxidation and lipids transport and metabolism process. At the same, we employed the q-PCR to valid the expression of miRNAs and their target transcripts that involve in fatty acid and lipid metabolism, the result suggested that the miRNA and their transcript expression are negative correlation, which in accord with the expression of miRNA and its target transcript. The study findings suggest that the identified miRNA may play important role in the fatty acids and lipids metabolism in seeds of B. napus. Copyright © 2017 The Author(s). Published by Elsevier B.V. All

Glucose and amino acid metabolism in rat brain during sustained hypoglycemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wong, K.L.; Tyce, G.M.

1983-04-01

The metabolism of glucose in brains during sustained hypoglycemia was studied. (U-/sup 14/C)Glucose (20 microCi) was injected into control rats, and into rats at 2.5 hr after a bolus injection of 2 units of insulin followed by a continuous infusion of 0.2 units/100 g rat/hr. This regimen of insulin injection was found to result in steady-state plasma glucose levels between 2.5 and 3.5 mumol per ml. In the brains of control rats carbon was transferred rapidly from glucose to glutamate, glutamine, gamma-aminobutyric acid and aspartate and this carbon was retained in the amino acids for at least 60 min. Inmore » the brains of hypoglycemic rats, the conversion of carbon from glucose to amino acids was increased in the first 15 min after injection. After 15 min, the specific activity of the amino acids decreased in insulin-treated rats but not in the controls. The concentrations of alanine, glutamate, and gamma-amino-butyric acid decreased, and the concentration of aspartate increased, in the brains of the hypoglycemic rats. The concentration of pyridoxal-5'-phosphate, a cofactor in many of the reactions whereby these amino acids are formed from tricarboxylic acid cycle intermediates, was less in the insulin-treated rats than in the controls. These data provide evidence that glutamate, glutamine, aspartate, and GABA can serve as energy sources in brain during insulin-induced hypoglycemia.« less

Phase I Metabolic Stability and Electrophilic Reactivity of 2-Phenylaminophenylacetic Acid Derived Compounds.

PubMed

Pang, Yi Yun; Tan, Yee Min; Chan, Eric Chun Yong; Ho, Han Kiat

2016-07-18

Diclofenac and lumiracoxib are two highly analogous 2-phenylaminophenylacetic acid anti-inflammatory drugs exhibiting occasional dose-limiting hepatotoxicities. Prior data indicate that bioactivation and reactive metabolite formation play roles in the observed toxicity, but the exact chemical influence of the substituents remains elusive. In order to elucidate the role of chemical influence on metabolism related toxicity, metabolic stability and electrophilic reactivity were investigated for a series of structurally related analogues and their resulting metabolites. The resulting analogues embody progressive physiochemical changes through varying halogeno- and aliphatic substituents at two positions and were subjected to in vitro human liver microsomal metabolic stability and cell-based GSH depletion assays (to measure electrophilic reactivity). LC-MS/MS analysis of the GSH trapped reactive intermediates derived from the analogues was then used to identify the putative structures of reactive metabolites. We found that chemical modifications of the structural backbone led to noticeable perturbations of metabolic stability, electrophilic reactivity, and structures and composition of reactive metabolites. With the acquired data, the relationships between stability, reactivity, and toxicity were investigated in an attempt to correlate between Phase I metabolism and in vitro toxicity. A positive correlation was identified between reactivity and in vitro toxicity, indicating that electrophilic reactivity can be an indicator for in vitro toxicity. All in all, the effect of substituents on the structures and reactivity of the metabolites, however subtle the changes, should be taken into consideration during future drug design involving similar chemical features.

Correlation between citric acid and nitrate metabolisms during CAM cycle in the atmospheric bromeliad Tillandsia pohliana.

PubMed

Freschi, Luciano; Rodrigues, Maria Aurineide; Tiné, Marco Aurélio Silva; Mercier, Helenice

2010-12-15

Crassulacean acid metabolism (CAM) confers crucial adaptations for plants living under frequent environmental stresses. A wide metabolic plasticity can be found among CAM species regarding the type of storage carbohydrate, organic acid accumulated at night and decarboxylating system. Consequently, many aspects of the CAM pathway control are still elusive while the impact of this photosynthetic adaptation on nitrogen metabolism has remained largely unexplored. In this study, we investigated a possible link between the CAM cycle and the nitrogen assimilation in the atmospheric bromeliad Tillandsia pohliana by simultaneously characterizing the diel changes in key enzyme activities and metabolite levels of both organic acid and nitrate metabolisms. The results revealed that T. pohliana performed a typical CAM cycle in which phosphoenolpyruvate carboxylase and phosphoenolpyruvate carboxykinase phosphorylation seemed to play a crucial role to avoid futile cycles of carboxylation and decarboxylation. Unlike all other bromeliads previously investigated, almost equimolar concentrations of malate and citrate were accumulated at night. Moreover, a marked nocturnal depletion in the starch reservoirs and an atypical pattern of nitrate reduction restricted to the nighttime were also observed. Since reduction and assimilation of nitrate requires a massive supply of reducing power and energy and considering that T. pohliana lives overexposed to the sunlight, we hypothesize that citrate decarboxylation might be an accessory mechanism to increase internal CO₂ concentration during the day while its biosynthesis could provide NADH and ATP for nocturnal assimilation of nitrate. Therefore, besides delivering photoprotection during the day, citrate might represent a key component connecting both CAM pathway and nitrogen metabolism in T. pohliana; a scenario that certainly deserves further study not only in this species but also in other CAM plants that nocturnally accumulate citrate

Improvement in cardiac function and free fatty acid metabolism in a case of dilated cardiomyopathy with CD36 deficiency.

PubMed

Hirooka, K; Yasumura, Y; Ishida, Y; Komamura, K; Hanatani, A; Nakatani, S; Yamagishi, M; Miyatake, K

2000-09-01

A 27-year-old man diagnosed as having dilated cardiomyopathy (DCM) without myocardial accumulation of 123I-beta-methyl-iodophenylpentadecanoic acid, and he was found to have type I CD36 deficiency. This abnormality of cardiac free fatty acid metabolism was also confirmed by other methods: 18F-fluoro-2-deoxyglucose positron emission tomography, measurements of myocardial respiratory quotient and cardiac fatty acid uptake. Although the type I CD36 deficiency was reconfirmed after 3 months, the abnormal free fatty acid metabolism improved after carvedilol therapy and was accompanied by improved cardiac function. Apart from a cause-and-effect relationship, carvedilol can improve cardiac function and increase free fatty acid metabolism in patients with both DCM and CD36 deficiency.

Roles of Chlorogenic Acid on Regulating Glucose and Lipids Metabolism: A Review

PubMed Central

Meng, Shengxi; Cao, Jianmei; Feng, Qin; Peng, Jinghua; Hu, Yiyang

2013-01-01

Intracellular glucose and lipid metabolic homeostasis is vital for maintaining basic life activities of a cell or an organism. Glucose and lipid metabolic disorders are closely related with the occurrence and progression of diabetes, obesity, hepatic steatosis, cardiovascular disease, and cancer. Chlorogenic acid (CGA), one of the most abundant polyphenol compounds in the human diet, is a group of phenolic secondary metabolites produced by certain plant species and is an important component of coffee. Accumulating evidence has demonstrated that CGA exerts many biological properties, including antibacterial, antioxidant, and anticarcinogenic activities. Recently, the roles and applications of CGA, particularly in relation to glucose and lipid metabolism, have been highlighted. This review addresses current studies investigating the roles of CGA in glucose and lipid metabolism. PMID:24062792

Geobiochemistry of metabolism: Standard state thermodynamic properties of the citric acid cycle

NASA Astrophysics Data System (ADS)

Canovas, Peter A.; Shock, Everett L.

2016-12-01

Integrating microbial metabolism into geochemical modeling allows assessments of energy and mass transfer between the geosphere and the microbial biosphere. Energy and power supplies and demands can be assessed from analytical geochemical data given thermodynamic data for compounds involved in catabolism and anabolism. Results are reported here from a critique of the available standard state thermodynamic data for organic acids and acid anions involved in the citric acid cycle (also known as the tricarboxylic acid cycle or the Krebs cycle). The development of methods for estimating standard state data unavailable from experiments is described, together with methods to predict corresponding values at elevated temperatures and pressures using the revised Helgeson-Kirkham-Flowers (HKF) equation of state for aqueous species. Internal consistency is maintained with standard state thermodynamic data for organic and inorganic aqueous species commonly used in geochemical modeling efforts. Standard state data and revised-HKF parameters are used to predict equilibrium dissociation constants for the organic acids in the citric acid cycle, and to assess standard Gibbs energies of reactions for each step in the cycle at elevated temperatures and pressures. The results presented here can be used with analytical data from natural and experimental systems to assess the energy and power demands of microorganisms throughout the habitable ranges of pressure and temperature, and to assess the consequences of abiotic organic compound alteration processes at conditions of subsurface aquifers, sedimentary basins, hydrothermal systems, meteorite parent bodies, and ocean worlds throughout the solar system.

Three Conazoles Increase Hepatic Microsomal Retinoic Acid Metabolism and Decrease Mouse Hepatic Retinoic Acid Levels In Vivo

EPA Science Inventory

Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with...

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

PubMed Central

Frey, Julie L.; Li, Zhu; Ellis, Jessica M.; Zhang, Qian; Farber, Charles R.; Aja, Susan; Wolfgang, Michael J.; Clemens, Thomas L.

2015-01-01

The Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of β-catenin and thereby induce the expression of key enzymes required for fatty acid β-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism. PMID:25802278

The human microbiome and bile acid metabolism: dysbiosis, dysmetabolism, disease and intervention.

PubMed

Jones, Mitchell L; Martoni, Christopher J; Ganopolsky, Jorge G; Labbé, Alain; Prakash, Satya

2014-04-01

Recent evidence indicates that the human gut microbiome plays a significant role in health and disease. Dysbiosis, defined as a pathological imbalance in a microbial community, is becoming increasingly appreciated as a 'central environmental factor' that is both associated with complex phenotypes and affected by host genetics, diet and antibiotic use. More recently, a link has been established between the dysmetabolism of bile acids (BAs) in the gut to dysbiosis. BAs, which are transformed by the gut microbiota, have been shown to regulate intestinal homeostasis and are recognized as signaling molecules in a wide range of metabolic processes. This review will examine the connection between BA metabolism as it relates to the gut microbiome and its implication in health and disease. A disrupted gut microbiome, including a reduction of bile salt hydrolase (BSH)-active bacteria, can significantly impair the metabolism of BAs and may result in an inability to maintain glucose homeostasis as well as normal cholesterol breakdown and excretion. To better understand the link between dysbiosis, BA dysmetabolism and chronic degenerative disease, large-scale metagenomic sequencing studies, metatranscriptomics, metaproteomics and metabolomics should continue to catalog functional diversity in the gastrointestinal tract of both healthy and diseased populations. Further, BSH-active probiotics should continue to be explored as treatment options to help restore metabolic levels.

Effect of α-linolenic acid and DHA intake on lipogenesis and gene expression involved in fatty acid metabolism in growing-finishing pigs.

PubMed

De Tonnac, A; Labussière, E; Vincent, A; Mourot, J

2016-07-01

The regulation of lipogenesis mechanisms related to consumption of n-3 PUFA is poorly understood. The aim of the present study was to find out whether α-linolenic acid (ALA) or DHA uptake can have an effect on activities and gene expressions of enzymes involved in lipid metabolism in the liver, subcutaneous adipose tissue and longissimus dorsi (LD) muscle of growing-finishing pigs. Six groups of ten pigs received one of six experimental diets supplemented with rapeseed oil in the control diet, extruded linseed, microalgae or a mixture of both to implement different levels of ALA and DHA with the same content in total n-3. Results were analysed for linear and quadratic effects of DHA intake. The results showed that activities of malic enzyme (ME) and fatty acid synthase (FAS) decreased linearly in the liver with dietary DHA. Although the expression of the genes of these enzymes and their activities were poorly correlated, ME and FAS expressions also decreased linearly with DHA intake. The intake of DHA down-regulates the expressions of other genes involved in fatty acid (FA) metabolism in some tissues of pigs, such as fatty acid desaturase 2 and sterol-regulatory element binding transcription factor 1 in the liver and 2,4-dienoyl CoA reductase 2 in the LD muscle. FA oxidation in the LD muscle and FA synthesis decreased in the liver with increasing amount of dietary DHA, whereas a retroconversion of DHA into EPA seems to be set up in this last tissue.

Consumption of pomegranate juice decreases blood lipid peroxidation and levels of arachidonic acid in women with metabolic syndrome.

PubMed

Kojadinovic, Milica I; Arsic, Aleksandra C; Debeljak-Martacic, Jasmina D; Konic-Ristic, Aleksandra I; Kardum, Nevena Dj; Popovic, Tamara B; Glibetic, Marija D

2017-04-01

Pomegranate juice is a rich source of polyphenols and is thus a promising dietary antioxidant with numerous health-promoting effects. These include a beneficial impact on cardiovascular health that could be partly attributed to the effects of polyphenols on lipid metabolism. The aim of this study was to investigate whether consumption of pomegranate juice for 6 weeks could modify lipid peroxidation and phospholipid fatty acid composition of plasma and erythrocytes in subjects with metabolic syndrome. Twenty-three women, aged 40-60 years, were enrolled and randomly assigned into two groups: the intervention group, in which each participant consumed 300 mL of juice per day for 6 weeks; and a control group. A statistically significant decrease in the relative amount of arachidonic acid (P < 0.05) and an increase in the relative amount of saturated fatty acids (P < 0.05) were observed in the intervention group at the end of the consumption period. In addition, pomegranate juice significantly increased the relative amount of total mono-unsaturated fatty acids (P < 0.05), and significantly decreased the levels of thiobarbituric acid reactive substances in erythrocytes (P < 0.05). The status of blood lipids and the values for blood pressure were not changed during the study. The results obtained indicate a positive impact of the consumption of pomegranate juice on lipid peroxidation and fatty acid status in subjects with metabolic syndrome and suggest potential anti-inflammatory and cardio-protective effects. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Paradigm shift - Metabolic transformation of docosahexaenoic and eicosapentaenoic acids to bioactives exemplify the promise of fatty acid drug discovery.

PubMed

Halade, Ganesh V; Black, Laurence M; Verma, Mahendra Kumar

Fatty acid drug discovery (FADD) is defined as the identification of novel, specialized bioactive mediators that are derived from fatty acids and have precise pharmacological/therapeutic potential. A number of reports indicate that dietary intake of omega-3 fatty acids and limited intake of omega-6 promotes overall health benefits. In 1929, Burr and Burr indicated the significant role of essential fatty acids for survival and functional health of many organs. In reference to specific dietary benefits of differential omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids (DHA and EPA) are transformed to monohydroxy, dihydroxy, trihydroxy, and other complex mediators during infection, injury, and exercise to resolve inflammation. The presented FADD approach describes the metabolic transformation of DHA and EPA in response to injury, infection, and exercise to govern uncontrolled inflammation. Metabolic transformation of DHA and EPA into a number of pro-resolving molecules exemplifies a novel, inexpensive approach compared to traditional, expensive drug discovery. DHA and EPA have been recommended for prevention of cardiovascular disease since 1970. Therefore, the FADD approach is relevant to cardiovascular disease and resolution of inflammation in many injury models. Future research demands identification of novel action targets, receptors for biomolecules, mechanism(s), and drug-interactions with resolvins in order to maintain homeostasis. Copyright © 2018 Elsevier Inc. All rights reserved.

Metabolism of 13-cis-retinoic acid by a rat liver 9000g supernatant preparation.

PubMed

Vane, F M; Buggé, C J; Williams, T H

1982-01-01

The in vitro metabolites formed on incubation of 13-cis-retinoic acid (13-cis-RA, isotretinoin) with a 9000g rat liver supernatant system were isolated by HPLC and identified by their mass and NMR spectra. The major metabolic pathway was hydroxylation at C4 to give 4-hydroxy-13-cis-RA, which was rapidly oxidized to 4-oxo-13-cis-RA, the major isolated metabolite. Further metabolism of this 4-oxo metabolite led to two novel compounds, 2-hydroxy-4-oxo-13-cis-RA and 3-hydroxy-4-oxo-13-cis-RA. In addition, small amounts of 13-cis-RA and 4-oxo-13-cis-RA were enzymatically converted to their all-trans isomers. Support for these pathways was obtained by the metabolism of reference samples of 4-hydroxy-13-cis-RA, 4-oxo-13-cis-RA, all-trans-RA, and 4-oxo-all-trans-RA. The predominant formation of 4-oxo metabolites of 13-cis-RA in this in vitro rat system and the results from previously reported in vivo metabolism studies suggest that oxidation at C4 is a major metabolic pathway of 13-cis-RA in both rats and humans.

Metabolic Reprogramming of Macrophages Exposed to Silk, Poly(lactic-co-glycolic acid), and Silica Nanoparticles.

PubMed

Saborano, Raquel; Wongpinyochit, Thidarat; Totten, John D; Johnston, Blair F; Seib, F Philipp; Duarte, Iola F

2017-07-01

Monitoring macrophage metabolism in response to nanoparticle exposure provides new insights into biological outcomes, such as inflammation or toxicity, and supports the design of tailored nanomedicines. This paper describes the metabolic signature of macrophages exposed to nanoparticles ranging in diameter from 100 to 125 nm and made from silk, poly(lactic-co-glycolic acid) or silica. Nanoparticles of this size and type are currently at various stages of preclinical and clinical development for drug delivery applications. 1 H NMR analysis of cell extracts and culture media is used to quantify the changes in the intracellular and extracellular metabolomes of macrophages in response to nanoparticle exposure. Increased glycolytic activity, an altered tricarboxylic acid cycle, and reduced ATP generation are consistent with a proinflammatory phenotype. Furthermore, amino acids possibly arising from autophagy, the creatine kinase/phosphocreatine system, and a few osmolytes and antioxidants emerge as important players in the metabolic reprogramming of macrophages exposed to nanoparticles. This metabolic signature is a common response to all nanoparticles tested; however, the direction and magnitude of some variations are clearly nanoparticle specific, indicating material-induced biological specificity. Overall, metabolic reprogramming of macrophages can be achieved with nanoparticle treatments, modulated through the choice of the material, and monitored using 1 H NMR metabolomics. © 2017 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Long-chain n-3 fatty acids enhance neonatal insulin-regulated protein metabolism in piglets by differentially altering muscle lipid composition

PubMed Central

Bergeron, Karen; Julien, Pierre; Davis, Teresa A.; Myre, Alexandre; Thivierge, M. Carole

2009-01-01

This study investigated the role of long-chain n-3 polyunsaturated fatty acids (LCn-3PUFAs) of muscle phospholipids in the regulation of neonatal metabolism. Twenty-eight piglets were weaned at 2 days of age and raised on one of two milk formulas that consisted of either a control formula supplying 0% or a formula containing 3.5% LCn-3PUFAs until 10 or 28 days of age. There was a developmental decline in the insulin sensitivity of amino acid disposal in control pigs during the first month of life, with a slope of −2.24 μmol·kg−1·h−1 (P = 0.01) per unit of insulin increment, as assessed using hyperinsulinemic-euglycemic-euaminoacidemic clamps. LCn-3PUFA feeding blunted this developmental decline, resulting in differing insulin sensitivities (P < 0.001). When protein metabolism was assessed under parenteral feeding-induced hyperinsulinemia, LCn-3PUFAs reduced by 16% whole body oxidative losses of amino acids (from 238 to 231 μmol·kg−1·h−1; P = 0.06), allowing 41% more amino acids to accrete into body proteins (from 90 to 127 μmol·kg−1·h−1; P = 0.06). The fractional synthetic rate of muscle mixed proteins remained unaltered by the LCn-3PUFA feeding. However, LCn-3PUFAs retarded a developmental increase in the essential-to-nonessential amino acid ratio of the muscle intracellular free pool (P = 0.05). Overall, alterations in metabolism were concomitant with a preferential incorporation of LCn-3PUFAs into muscle total membrane phospholipids (P < 0.001), in contrast to intramuscular triglycerides. These results underscore the potential role of LCn-3PUFAs as regulators of different aspects of protein metabolism in the neonate. PMID:17673528

Omega-3 and omega-6 polyunsaturated fatty acids: Dietary sources, metabolism, and significance - A review.

PubMed

Saini, Ramesh Kumar; Keum, Young-Soo

2018-06-15

Linoleic acid (LA) (n-6) and α-linolenic acid (ALA) (n-3) are essential fatty acids (EFAs) as they cannot be synthesized by humans or other higher animals. In the human body, these fatty acids (FAs) give rise to arachidonic acid (ARA, n-6), eicosapentaenoic acid (EPA, n-3), and docosahexaenoic acid (DHA, n-3) that play key roles in regulating body homeostasis. Locally acting bioactive signaling lipids called eicosanoids derived from these FAs also regulate diverse homeostatic processes. In general, ARA gives rise to pro-inflammatory eicosanoids whereas EPA and DHA give rise to anti-inflammatory eicosanoids. Thus, a proportionally higher consumption of n-3 PUFAs can protect us against inflammatory diseases, cancer, cardiovascular diseases, and other chronic diseases. The present review summarizes major sources, intake, and global consumption of n-3 and n-6 PUFAs. Their metabolism to biosynthesize long-chain PUFAs and eicosanoids and their roles in brain metabolism, cardiovascular disease, obesity, cancer, and bone health are also discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of Selenium on Lipid and Amino Acid Metabolism in Yeast Cells.

PubMed

Kieliszek, Marek; Błażejak, Stanisław; Bzducha-Wróbel, Anna; Kot, Anna M

2018-04-19

This article discusses the effect of selenium in aqueous solutions on aspects of lipid and amino acid metabolism in the cell biomass of Saccharomyces cerevisiae MYA-2200 and Candida utilis ATCC 9950 yeasts. The yeast biomass was obtained by using waste products (potato wastewater and glycerol). Selenium, at a dose of 20 mg/L of aqueous solution, affected the differentiation of cellular morphology. Yeast enriched with selenium was characterized by a large functional diversity in terms of protein and amino acid content. The protein content in the biomass of S. cerevisiae enriched with selenium (42.6%) decreased slightly as compared to that in the control sample without additional selenium supplementation (48.4%). Moreover, yeasts of both strains enriched with selenium contained a large amount of glutamic acid, aspartic acid, lysine, and leucine. Analysis of fatty acid profiles in S. cerevisiae yeast supplemented with selenium showed an increase in the unsaturated fatty acid content (e.g., C18:1). The presence of margaric acid (C17:0) and hexadecanoic acid (C17:1) was found in the C. utilis biomass enriched with selenium, in contrast to that of S. cerevisiae. These results indicate that selenium may induce lipid peroxidation, which consequently affects the loss of integrity of the cytoplasmic membrane. Yeast enriched with selenium with optimal amino acid and lipid composition can be used to prepare a novel formula of dietary supplements, which can be applied directly to various diets for both humans and animals.

The dynamics of folic acid metabolism in an adult given a small tracer dose of 14C-folic acid.

PubMed

Clifford, A J; Arjomand, A; Dueker, S R; Schneider, P D; Buchholz, B A; Vogel, J S

1998-01-01

Folate is an essential nutrient that is involved in many metabolic pathways, including amino acid interconversions and nucleotide (DNA) synthesis. In genetically susceptible individuals and populations, dysfunction of folate metabolism is associated with severe illness. Despite the importance of folate, major gaps exist in our quantitative understanding of folate metabolism in humans. The gaps exist because folate metabolism is complex, a suitable animal model that mimics human folate metabolism has not been identified, and suitable experimental protocols for in vivo studies in humans are not developed. In general, previous studies of folate metabolism have used large doses of high specific activity tritium and 14C-labeled folates in clinical patients. While stable isotopes such as deuterium and 13C-labeled folate are viewed as ethical alternatives to radiolabeled folates for studying metabolism, the lack of sensitive mass spectrometry methods to quantify them has impeded advancement of the field using this approach. In this chapter, we describe a new approach that uses a major analytical breakthrough, Accelerator Mass Spectrometry (AMS). Because AMS can detect attomole concentrations of 14C, small radioactive dosages (nCi) can be safely administered to humans and traced over long periods of time. The needed dosages are sufficiently small that the total radiation exposure is only a fraction of the natural annual background radiation of Americans, and the generated laboratory waste may legally be classified non-radioactive in many cases. The availability of AMS has permitted the longest (202 d) and most detailed study to date of folate metabolism in a healthy adult human volunteer. Here we demonstrate the feasibility of our approach and illustrate its potential by determining empirical kinetic values of folate metabolism. Our data indicate that the mean sojourn time for folate is in the range of 93 to 120 d. It took > or = 350 d for the absorbed portion of small

Bioactive Compounds Derived from the Yeast Metabolism of Aromatic Amino Acids during Alcoholic Fermentation

PubMed Central

Guillamon, Jose Manuel; Torija, Maria Jesus; Beltran, Gemma; Troncoso, Ana M.; Garcia-Parrilla, M. Carmen

2014-01-01

Metabolites resulting from nitrogen metabolism in yeast are currently found in some fermented beverages such as wine and beer. Their study has recently attracted the attention of researchers. Some metabolites derived from aromatic amino acids are bioactive compounds that can behave as hormones or even mimic their role in humans and may also act as regulators in yeast. Although the metabolic pathways for their formation are well known, the physiological significance is still far from being understood. The understanding of this relevance will be a key element in managing the production of these compounds under controlled conditions, to offer fermented food with specific enrichment in these compounds or even to use the yeast as nutritional complements. PMID:24895623

Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation.

PubMed

Makowski, Liza; Noland, Robert C; Koves, Timothy R; Xing, Weibing; Ilkayeva, Olga R; Muehlbauer, Michael J; Stevens, Robert D; Muoio, Deborah M

2009-02-01

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a master transcriptional regulator of beta-oxidation and a prominent target of hypolipidemic drugs. To gain deeper insights into the systemic consequences of impaired fat catabolism, we used quantitative, mass spectrometry-based metabolic profiling to investigate the fed-to-fasted transition in PPARalpha(+/+) and PPARalpha(-/-) mice. Compared to PPARalpha(+/+) animals, acylcarnitine profiles of PPARalpha(-/-) mice revealed 2- to 4-fold accumulation of long-chain species in the plasma, whereas short-chain species were reduced by as much as 69% in plasma, liver, and skeletal muscle. These results reflect a metabolic bottleneck downstream of carnitine palmitoyltransferase-1, a mitochondrial enzyme that catalyzes the first step in beta-oxidation. Organic and amino acid profiles of starved PPARalpha(-/-) mice suggested compromised citric acid cycle flux, enhanced urea cycle activity, and increased amino acid catabolism. PPARalpha(-/-) mice had 40-50% lower plasma and tissue levels of free carnitine, corresponding with diminished hepatic expression of genes involved in carnitine biosynthesis and transport. One week of oral carnitine supplementation conferred partial metabolic recovery in the PPARalpha(-/-) mice. In summary, comprehensive metabolic profiling revealed novel biomarkers of defective fat oxidation, while also highlighting the potential value of supplemental carnitine as a therapy and diagnostic tool for metabolic disorders.

Effects of metabolic pathway precursors and polydimethylsiloxane (PDMS) on poly-(gamma)-glutamic acid production by Bacillus subtilis BL53.

PubMed

de Cesaro, Alessandra; da Silva, Suse Botelho; Ayub, Marco Antônio Záchia

2014-09-01

The aims of this study were to evaluate the effects of the addition of metabolic precursors and polydimethylsiloxane (PDMS) as an oxygen carrier to cultures of Bacillus subtilis BL53 during the production of γ-PGA. Kinetics analyses of cultivations of different media showed that B. subtilis BL53 is an exogenous glutamic acid-dependent strain. When the metabolic pathway precursors of γ-PGA synthesis, L-glutamine and a-ketoglutaric acid, were added to the culture medium, production of the biopolymer was increased by 20 % considering the medium without these precursors. The addition of 10 % of the oxygen carrier PDMS to cultures caused a two-fold increase in the volumetric oxygen mass transfer coefficient (kLa), improving γ-PGA production and productivity. Finally, bioreactor cultures of B. subtilis BL53 adopting the combination of optimized medium E, added of glutamine, α-ketoglutaric acid, and PDMS, showed a productivity of 1 g L(-1) h(-1) of g-PGA after only 24 h of cultivation. Results of this study suggest that the use of metabolic pathway precursors glutamine and a-ketolgutaric acid, combined with the addition of PDMS as an oxygen carrier in bioreactors, can improve γ-PGA production and productivity by Bacillus strains .

Flower abscission in Vitis vinifera L. triggered by gibberellic acid and shade discloses differences in the underlying metabolic pathways

PubMed Central

Domingos, Sara; Scafidi, Pietro; Cardoso, Vania; Leitao, Antonio E.; Di Lorenzo, Rosario; Oliveira, Cristina M.; Goulao, Luis F.

2015-01-01

Understanding abscission is both a biological and an agronomic challenge. Flower abscission induced independently by shade and gibberellic acid (GAc) sprays was monitored in grapevine (Vitis vinifera L.) growing under a soilless greenhouse system during two seasonal growing conditions, in an early and late production cycle. Physiological and metabolic changes triggered by each of the two distinct stimuli were determined. Environmental conditions exerted a significant effect on fruit set as showed by the higher natural drop rate recorded in the late production cycle with respect to the early cycle. Shade and GAc treatments increased the percentage of flower drop compared to the control, and at a similar degree, during the late production cycle. The reduction of leaf gas exchanges under shade conditions was not observed in GAc treated vines. The metabolic profile assessed in samples collected during the late cycle differently affected primary and secondary metabolisms and showed that most of the treatment-resulting variations occurred in opposite trends in inflorescences unbalanced in either hormonal or energy deficit abscission-inducing signals. Particularly concerning carbohydrates metabolism, sucrose, glucose, tricarboxylic acid metabolites and intermediates of the raffinose family oligosaccharides pathway were lower in shaded and higher in GAc samples. Altered oxidative stress remediation mechanisms and indolacetic acid (IAA) concentration were identified as abscission signatures common to both stimuli. According to the global analysis performed, we report that grape flower abscission mechanisms triggered by GAc application and C-starvation are not based on the same metabolic pathways. PMID:26157448

Metabolic Engineering for Enhanced Medium Chain Omega Hydroxy Fatty Acid Production in Escherichia coli

PubMed Central

Xiao, Kang; Yue, Xiu-Hong; Chen, Wen-Chao; Zhou, Xue-Rong; Wang, Lian; Xu, Lin; Huang, Feng-Hong; Wan, Xia

2018-01-01

Medium chain hydroxy fatty acids (HFAs) at ω-1, 2, or 3 positions (ω-1/2/3) are rare in nature but are attractive due to their potential applications in industry. They can be metabolically engineered in Escherichia coli, however, the current yield is low. In this study, metabolic engineering with P450BM3 monooxygenase was applied to regulate both the chain length and sub-terminal position of HFA products in E. coli, leading to increased yield. Five acyl-acyl carrier protein thioesterases from plants and bacteria were first evaluated for regulating the chain length of fatty acids. Co-expression of the selected thioesterase gene CcFatB1 with a fatty acid metabolism regulator fadR and monooxygenase P450BM3 boosted the production of HFAs especially ω-3-OH-C14:1, in both the wild type and fadD deficient strain. Supplementing renewable glycerol to reduce the usage of glucose as a carbon source further increased the HFAs production to 144 mg/L, representing the highest titer of such HFAs obtained in E. coli under the comparable conditions. This study illustrated an improved metabolic strategy for medium chain ω-1/2/3 HFAs production in E. coli. In addition, the produced HFAs were mostly secreted into culture media, which eased its recovery. PMID:29467747

Conditional knock-out of lipoic acid protein ligase 1 reveals redundancy pathway for lipoic acid metabolism in Plasmodium berghei malaria parasite.

PubMed

Wang, Min; Wang, Qiong; Gao, Xiang; Su, Zhong

2017-06-27

Lipoic acid is a cofactor for α-keto acid dehydrogenase system that is involved in the central energy metabolism. In the apicomplexan parasite, Plasmodium, lipoic acid protein ligase 1 (LplA1) and LplA2 catalyse the ligation of acquired lipoic acid to the dehydrogenase complexes in the mitochondrion. The enzymes LipB and LipA mediate lipoic acid synthesis and ligation to the enzymes in the apicoplast. These enzymes in the lipoic acid metabolism machinery have been shown to play important roles in the biology of Plasmodium parasites, but the relationship between the enzymes is not fully elucidated. We used an anhydrotetracycline (ATc)-inducible transcription system to generate transgenic P. berghei parasites in which the lplA1 gene was conditionally knocked out (LplA1-cKO). Phenotypic changes and the lplA1 and lplA2 gene expression profiles of cloned LplA1-cKO parasites were analysed. LplA1-cKO parasites showed severely impaired growth in vivo in the first 8 days of infection, and retarded blood-stage development in vitro, in the absence of ATc. However, these parasites resumed viability in the late stage of infection and mounted high levels of parasitemia leading to the death of the hosts. Although lplA1 mRNA expression was regulated tightly by ATc during the whole course of infection, lplA2 mRNA expression was significantly increased in the late stage of infection only in the LplA1-cKO parasites that were not exposed to ATc. The lplA2 gene can be activated as an alternative pathway to compensate for the loss of LplA1 activity and to maintain lipoic acid metabolism.

PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation

PubMed Central

Patsoukis, Nikolaos; Bardhan, Kankana; Chatterjee, Pranam; Sari, Duygu; Liu, Bianling; Bell, Lauren N.; Karoly, Edward D.; Freeman, Gordon J.; Petkova, Victoria; Seth, Pankaj; Li, Lequn; Boussiotis, Vassiliki A.

2015-01-01

During activation, T cells undergo metabolic reprogramming, which imprints distinct functional fates. We determined that on PD-1 ligation, activated T cells are unable to engage in glycolysis or amino acid metabolism but have an increased rate of fatty acid β-oxidation (FAO). PD-1 promotes FAO of endogenous lipids by increasing expression of CPT1A, and inducing lipolysis as indicated by elevation of the lipase ATGL, the lipolysis marker glycerol and release of fatty acids. Conversely, CTLA-4 inhibits glycolysis without augmenting FAO, suggesting that CTLA-4 sustains the metabolic profile of non-activated cells. Because T cells utilize glycolysis during differentiation to effectors, our findings reveal a metabolic mechanism responsible for PD-1-mediated blockade of T-effector cell differentiation. The enhancement of FAO provides a mechanistic explanation for the longevity of T cells receiving PD-1 signals in patients with chronic infections and cancer, and for their capacity to be reinvigorated by PD-1 blockade. PMID:25809635

1H NMR-Based Metabolic Profiling Reveals the Effects of Fluoxetine on Lipid and Amino Acid Metabolism in Astrocytes

PubMed Central

Bai, Shunjie; Zhou, Chanjuan; Cheng, Pengfei; Fu, Yuying; Fang, Liang; Huang, Wen; Yu, Jia; Shao, Weihua; Wang, Xinfa; Liu, Meiling; Zhou, Jingjing; Xie, Peng

2015-01-01

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is a prescribed and effective antidepressant and generally used for the treatment of depression. Previous studies have revealed that the antidepressant mechanism of fluoxetine was related to astrocytes. However, the therapeutic mechanism underlying its mode of action in astrocytes remains largely unclear. In this study, primary astrocytes were exposed to 10 µM fluoxetine; 24 h post-treatment, a high-resolution proton nuclear magnetic resonance (1H NMR)-based metabolomic approach coupled with multivariate statistical analysis was used to characterize the metabolic variations of intracellular metabolites. The orthogonal partial least-squares discriminant analysis (OPLS-DA) score plots of the spectra demonstrated that the fluoxetine-treated astrocytes were significantly distinguished from the untreated controls. In total, 17 differential metabolites were identified to discriminate the two groups. These key metabolites were mainly involved in lipids, lipid metabolism-related molecules and amino acids. This is the first study to indicate that fluoxetine may exert antidepressant action by regulating the astrocyte’s lipid and amino acid metabolism. These findings should aid our understanding of the biological mechanisms underlying fluoxetine therapy. PMID:25884334

Rapid LC-MS/MS profiling of protein amino acids and metabolically related compounds for large-scale assessment of metabolic phenotypes.

PubMed

Gu, Liping; Jones, A Daniel; Last, Robert L

2012-01-01

Amino acids extracted from a biological matrix can be resolved and measured using a 6-min per sample method through high-performance liquid chromatography with a short C18 column and rapid gradient using the ion-pairing reagent perfluoroheptanoic acid. LC-tandem mass spectrometry with multiple reaction monitoring (MRM) transitions selective for each compound allows simultaneous quantification of the 20 proteinogenic amino acids and 5 metabolically related compounds. Distinct MRM transitions were also established for selective detection of the isomers leucine/isoleucine and threonine/homoserine.

Analysis of L-glutamic acid fermentation by using a dynamic metabolic simulation model of Escherichia coli.

PubMed

Nishio, Yousuke; Ogishima, Soichi; Ichikawa, Masao; Yamada, Yohei; Usuda, Yoshihiro; Masuda, Tadashi; Tanaka, Hiroshi

2013-09-22

Understanding the process of amino acid fermentation as a comprehensive system is a challenging task. Previously, we developed a literature-based dynamic simulation model, which included transcriptional regulation, transcription, translation, and enzymatic reactions related to glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and the anaplerotic pathway of Escherichia coli. During simulation, cell growth was defined such as to reproduce the experimental cell growth profile of fed-batch cultivation in jar fermenters. However, to confirm the biological appropriateness of our model, sensitivity analysis and experimental validation were required. We constructed an L-glutamic acid fermentation simulation model by removing sucAB, a gene encoding α-ketoglutarate dehydrogenase. We then performed systematic sensitivity analysis for L-glutamic acid production; the results of this process corresponded with previous experimental data regarding L-glutamic acid fermentation. Furthermore, it allowed us to predicted the possibility that accumulation of 3-phosphoglycerate in the cell would regulate the carbon flux into the TCA cycle and lead to an increase in the yield of L-glutamic acid via fermentation. We validated this hypothesis through a fermentation experiment involving a model L-glutamic acid-production strain, E. coli MG1655 ΔsucA in which the phosphoglycerate kinase gene had been amplified to cause accumulation of 3-phosphoglycerate. The observed increase in L-glutamic acid production verified the biologically meaningful predictive power of our dynamic metabolic simulation model. In this study, dynamic simulation using a literature-based model was shown to be useful for elucidating the precise mechanisms involved in fermentation processes inside the cell. Further exhaustive sensitivity analysis will facilitate identification of novel factors involved in the metabolic regulation of amino acid fermentation.

Fatty Acids in Membranes as Homeostatic, Metabolic and Nutritional Biomarkers: Recent Advancements in Analytics and Diagnostics.

PubMed

Ferreri, Carla; Masi, Annalisa; Sansone, Anna; Giacometti, Giorgia; Larocca, Anna Vita; Menounou, Georgia; Scanferlato, Roberta; Tortorella, Silvia; Rota, Domenico; Conti, Marco; Deplano, Simone; Louka, Maria; Maranini, Anna Rosaria; Salati, Arianna; Sunda, Valentina; Chatgilialoglu, Chryssostomos

2016-12-22

Fatty acids, as structural components of membranes and inflammation/anti-inflammatory mediators, have well-known protective and regulatory effects. They are studied as biomarkers of pathological conditions, as well as saturated and unsaturated hydrophobic moieties in membrane phospholipids that contribute to homeostasis and physiological functions. Lifestyle, nutrition, metabolism and stress-with an excess of radical and oxidative processes-cause fatty acid changes that are examined in the human body using blood lipids. Fatty acid-based membrane lipidomics represents a powerful diagnostic tool for assessing the quantity and quality of fatty acid constituents and also for the follow-up of the membrane fatty acid remodeling that is associated with different physiological and pathological conditions. This review focuses on fatty acid biomarkers with two examples of recent lipidomic research and health applications: (i) monounsaturated fatty acids and the analytical challenge offered by hexadecenoic fatty acids (C16:1); and (ii) the cohort of 10 fatty acids in phospholipids of red blood cell membranes and its connections to metabolic and nutritional status in healthy and diseased subjects.

Fatty Acids in Membranes as Homeostatic, Metabolic and Nutritional Biomarkers: Recent Advancements in Analytics and Diagnostics

PubMed Central

Ferreri, Carla; Masi, Annalisa; Sansone, Anna; Giacometti, Giorgia; Larocca, Anna Vita; Menounou, Georgia; Scanferlato, Roberta; Tortorella, Silvia; Rota, Domenico; Conti, Marco; Deplano, Simone; Louka, Maria; Maranini, Anna Rosaria; Salati, Arianna; Sunda, Valentina; Chatgilialoglu, Chryssostomos

2016-01-01

Fatty acids, as structural components of membranes and inflammation/anti-inflammatory mediators, have well-known protective and regulatory effects. They are studied as biomarkers of pathological conditions, as well as saturated and unsaturated hydrophobic moieties in membrane phospholipids that contribute to homeostasis and physiological functions. Lifestyle, nutrition, metabolism and stress—with an excess of radical and oxidative processes—cause fatty acid changes that are examined in the human body using blood lipids. Fatty acid-based membrane lipidomics represents a powerful diagnostic tool for assessing the quantity and quality of fatty acid constituents and also for the follow-up of the membrane fatty acid remodeling that is associated with different physiological and pathological conditions. This review focuses on fatty acid biomarkers with two examples of recent lipidomic research and health applications: (i) monounsaturated fatty acids and the analytical challenge offered by hexadecenoic fatty acids (C16:1); and (ii) the cohort of 10 fatty acids in phospholipids of red blood cell membranes and its connections to metabolic and nutritional status in healthy and diseased subjects. PMID:28025506

[Influence of conjugated linoleic acids on metabolic processes in cells and tissues].

PubMed

Siwiec, Ewa; Stachowska, Ewa

2017-01-01

Conjugated linoleic acids (CLA) are constitutional and geometric isomers of this acid. The most commonly consumed geometric isomers are cis-9,trans-11 (c9, t11) CLA and trans-10, cis-12 (t10,c12) CLA. These isomers together with trans-9,trans-11 CLA and trans-10,trans-12 CLA constitute about 90% of all CLA in natural products. Different structure of the isomers affects their functions in the body. Differences in the effects on organs and tissues are sometimes small and sometimes opposed, sometimes the isomers work synergistically. Diverse influence has been shown mainly in neoplastic processes and lipid metabolism. For example, differences in inhibition of proliferation of prostate cancer cells are explained by different pathways: t10,c12 CLA acts on apoptosis and cell cycle control genes, while c9,t11 CLA regulates genes involved in metabolism of arachidonic acid with subsequent impairment of eicosanoids synthesis. Other studies have shown that t10,c12 CLA, but not c9,t11 CLA, can induce fat reduction in adipose tissue and apoptosis of adipocytes in mice.

Folic acid mitigated cardiac dysfunction by normalizing the levels of tissue inhibitor of metalloproteinase and homocysteine-metabolizing enzymes postmyocardial infarction in mice

PubMed Central

Qipshidze, Natia; Tyagi, Neetu; Sen, Utpal; Givvimani, Srikanth; Metreveli, Naira; Lominadze, David

2010-01-01

Myocardial infarction (MI) results in significant metabolic derangement, causing accumulation of metabolic by product, such as homocysteine (Hcy). Hcy is a nonprotein amino acid generated during nucleic acid methylation and demethylation of methionine. Folic acid (FA) decreases Hcy levels by remethylating the Hcy to methionine, by 5-methylene tetrahydrofolate reductase (5-MTHFR). Although clinical trials were inconclusive regarding the role of Hcy in MI, in animal models, the levels of 5-MTHFR were decreased, and FA mitigated the MI injury. We hypothesized that FA mitigated MI-induced injury, in part, by mitigating cardiac remodeling during chronic heart failure. Thus, MI was induced in 12-wk-old male C57BL/J mice by ligating the left anterior descending artery, and FA (0.03 g/l in drinking water) was administered for 4 wk after the surgery. Cardiac function was assessed by echocardiography and by a Millar pressure-volume catheter. The levels of Hcy-metabolizing enzymes, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 5-MTHFR, were estimated by Western blot analyses. The results suggest that FA administered post-MI significantly improved cardiac ejection fraction and induced tissue inhibitor of metalloproteinase, CBS, CSE, and 5-MTHFR. We showed that FA supplementation resulted in significant improvement of myocardial function after MI. The study eluted the importance of homocysteine (Hcy) metabolism and FA supplementation in cardiovascular disease. PMID:20802128

Association Between Uric Acid and Metabolic Syndrome in Elderly Women.

PubMed

Wang, Hui-Juan; Shi, Lei-Zhi; Liu, Cun-Fei; Liu, Shi-Min; Shi, Song-Tao

2018-01-01

To investigate the relationship between uric acid and metabolic syndrome (MetS) in elderly women. A total of 468 women aged ≥60 years participating in a health examination were enrolled. The association between uric acid and MetS and its individual variables was evaluated by univariate and multivariate logistic regression models. A dose-response relationship was observed for the prevalence of MetS and uric acid quartiles. Subjects in the second, third and fourth quartile of uric acid had a 2.23-fold, 2.25-fold and 4.41-fold increased risk, respectively, of MetS than those in the first uric acid quartile (p for trend <0.001). Furthermore, each 1 mg/dl increment of serum uric acid level had a 1.38-fold increased risk of MetS (OR 1.38; 95% CI, 1.14-1.69; p=0.001). Our present study demonstrated that elevated uric acid was positively associated with the prevalence of MetS in elderly women. Further random control trials are needed to elucidate the effectiveness of treatment of hyperuricaemia in reducing the incidence of MetS in elderly women.

Increased missense mutation burden of Fatty Acid metabolism related genes in nunavik inuit population.

PubMed

Zhou, Sirui; Xiong, Lan; Xie, Pingxing; Ambalavanan, Amirthagowri; Bourassa, Cynthia V; Dionne-Laporte, Alexandre; Spiegelman, Dan; Turcotte Gauthier, Maude; Henrion, Edouard; Diallo, Ousmane; Dion, Patrick A; Rouleau, Guy A

2015-01-01

Nunavik Inuit (northern Quebec, Canada) reside along the arctic coastline where for generations their daily energy intake has mainly been derived from animal fat. Given this particular diet it has been hypothesized that natural selection would lead to population specific allele frequency differences and unique variants in genes related to fatty acid metabolism. A group of genes, namely CPT1A, CPT1B, CPT1C, CPT2, CRAT and CROT, encode for three carnitine acyltransferases that are important for the oxidation of fatty acids, a critical step in their metabolism. Exome sequencing and SNP array genotyping were used to examine the genetic variations in the six genes encoding for the carnitine acyltransferases in 113 Nunavik Inuit individuals. Altogether ten missense variants were found in genes CPT1A, CPT1B, CPT1C, CPT2 and CRAT, including three novel variants and one Inuit specific variant CPT1A p.P479L (rs80356779). The latter has the highest frequency (0.955) compared to other Inuit populations. We found that by comparison to Asians or Europeans, the Nunavik Inuit have an increased mutation burden in CPT1A, CPT2 and CRAT; there is also a high level of population differentiation based on carnitine acyltransferase gene variations between Nunavik Inuit and Asians. The increased number and frequency of deleterious variants in these fatty acid metabolism genes in Nunavik Inuit may be the result of genetic adaptation to their diet and/or the extremely cold climate. In addition, the identification of these variants may help to understand some of the specific health risks of Nunavik Inuit.

Differences in elongation of very long chain fatty acids and fatty acid metabolism between triple-negative and hormone receptor-positive breast cancer.

PubMed

Yamashita, Yuji; Nishiumi, Shin; Kono, Seishi; Takao, Shintaro; Azuma, Takeshi; Yoshida, Masaru

2017-08-29

Triple-negative breast cancer (TN) is more aggressive than other subtypes of breast cancer and has a lower survival rate. Furthermore, detailed biological information about the disease is lacking. This study investigated characteristics of metabolic pathways in TN. We performed the metabolome analysis of 74 breast cancer tissues and the corresponding normal breast tissues using LC/MS. Furthermore, we classified the breast cancer tissues into ER-positive, PgR-positive, HER2-negative breast cancer (EP+H-) and TN, and then the differences in their metabolic pathways were investigated. The RT-PCR and immunostaining were carried out to examine the expression of ELOVL1, 2, 3, 4, 5, 6, and 7. We identified 142 of hydrophilic metabolites and 278 of hydrophobic lipid metabolites in breast tissues. We found the differences between breast cancer and normal breast tissues in choline metabolism, glutamine metabolism, lipid metabolism, and so on. Most characteristic of comparison between EP+H- and TN were differences in fatty acid metabolism was which were related to the elongation of very long chain fatty acids were detected between TN and EP+H-. Real-time RT-PCR showed that the mRNA expression levels of ELOVL1, 5, and 6 were significantly upregulated by 8.5-, 4.6- and 7.0-fold, respectively, in the TN tumors compared with their levels in the corresponding normal breast tissue samples. Similarly, the mRNA expression levels of ELOVL1, 5, and 6 were also significantly higher in the EP+H- tissues than in the corresponding normal breast tissues (by 4.9-, 3.4-, and 2.1-fold, respectively). The mRNA expression level of ELOVL6 was 2.6-fold higher in the TN tumors than in the EP+H- tumors. During immunostaining, the TN and EP+H- tumors demonstrated stronger ELOVL1 and 6 staining than the corresponding normal breast tissues, but ELOVL5 was not stained strongly in the TN or EP+H- tumors. Furthermore, the TN tumors exhibited stronger ELOVL1 and 6 staining than the EP+H- tumors. Marked