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Jie Zhang, Alan R Light, Charles L Hoppel, Caitlin Campbell, Carol J Chandler, Dustin J Burnett, Elaine C Souza, Gretchen A Casazza, Ronald W Hughen, Nancy L Keim, John W Newman, Gary R Hunter, Jose R Fernandez, W Timothy Garvey, Mary-Ellen Harper, Oliver Fiehn, Sean H Adams
With insulin-resistance or type 2 diabetes mellitus, mismatches between mitochondrial fatty acid fuel delivery and oxidative phosphorylation/tricarboxylic acid cycle activity may contribute to inordinate accumulation of short- or medium-chain acylcarnitine fatty acid derivatives (markers of incomplete long-chain fatty acid oxidation [FAO]). We reasoned that incomplete FAO in muscle would be ameliorated concurrent with improved insulin sensitivity and fitness following a ∼14 wk training and weight loss intervention in obese, sedentary, insulin-resistant women...
October 12, 2016: Experimental Physiology
Yi-Ching Chen, Chia-Ju Tsai, Chia-Hsien Feng
A novel aqueous solvent-based dispersive liquid-liquid microextraction (AS-DLLME) method was combined with narrow-bore liquid chromatography and fluorescence detection for the determination of hydrophilic compounds. A remover (non-polar solvent) and extractant (aqueous solution) were introduced into the derivatization system (acetonitrile) to obtain a water-in-oil emulsion state that increased the mass transfer of analytes. As a proof of concept, three quaternary ammonium substances, including butyrobetaine, l-carnitine and acetyl-l-carnitine, were also used as analytes and determined in pharmaceuticals, personal care products, food and human plasma...
September 16, 2016: Journal of Chromatography. A
Hiroshi Fujimitsu, Akira Matsumoto, Sayaka Takubo, Akiko Fukui, Kazuma Okada, Isam A Mohamed Ahmed, Jiro Arima, Nobuhiro Mori
The report is the first of purification, overproduction, and characterization of a unique γ-butyrobetainyl CoA synthetase from soil-isolated Agrobacterium sp. 525a. The primary structure of the enzyme shares 70-95% identity with those of ATP-dependent microbial acyl-CoA synthetases of the Rhizobiaceae family. As distinctive characteristics of the enzyme of this study, ADP was released in the catalytic reaction process, whereas many acyl CoA synthetases are annotated as an AMP-forming enzyme. The apparent Km values for γ-butyrobetaine, CoA, and ATP were, respectively, 0...
August 2016: Bioscience, Biotechnology, and Biochemistry
Marieke G Schooneman, Riekelt H Houtkooper, Carla E M Hollak, Ronald J A Wanders, Frédéric M Vaz, Maarten R Soeters, Sander M Houten
AIM: Acylcarnitines are fatty acid oxidation (FAO) intermediates, which have been implicated in diet-induced insulin resistance. Elevated acylcarnitine levels are found in obese, insulin resistant humans and rodents, and coincide with lower free carnitine. We hypothesized that increasing free carnitine levels by administration of the carnitine precursor γ-butyrobetaine (γBB) could facilitate FAO, thereby improving insulin sensitivity. METHODS: C57BL/6N mice were fed with a high fat or chow diet with or without γBB supplementation (n=10 per group)...
August 2016: Biochimica et Biophysica Acta
Marius Trøseid, Johannes R Hov, Torunn Kristin Nestvold, Hanne Thoresen, Rolf K Berge, Asbjørn Svardal, Knut Tore Lappegård
BACKGROUND: Trimethylamine-N-oxide (TMAO) is formed in the liver from trimethylamine (TMA), a product exclusively generated by the gut microbiota from dietary phosphatidylcholine and carnitine. An alternative pathway of TMAO formation from carnitine is via the microbiota-dependent intermediate γ-butyrobetaine (γBB). Elevated TMAO levels are associated with cardiovascular disease (CVD), but little is known about TMAO in obesity. Given the proposed contribution of microbiota alterations in obesity and type 2 diabetes (T2D), we investigated the potential impact of obesity, lifestyle-induced weight loss, and bariatric surgery on plasma levels of TMAO, its microbiota-dependent intermediate γBB, and its diet-dependent precursors carnitine and choline...
May 2016: Metabolic Syndrome and related Disorders
Mona Ascha, Zeneng Wang, Mustafa S Ascha, Raed Dweik, Nizar N Zein, David Grove, J Mark Brown, Stephanie Marshall, Rocio Lopez, Ibrahim A Hanouneh
AIM: To identify plasma analytes using metabolomics that correlate with the diagnosis and severity of liver disease in patients with alcoholic hepatitis (AH). METHODS: We prospectively recruited patients with cirrhosis from AH (n = 23) and those with cirrhosis with acute decompensation (AD) from etiologies other than alcohol (n = 25). We used mass spectrometry to identify 29 metabolic compounds in plasma samples from fasted subjects. A receiver operating characteristics analysis was performed to assess the utility of biomarkers in distinguishing acute AH from alcoholic cirrhosis...
April 8, 2016: World Journal of Hepatology
Karolina Skagen, Marius Trøseid, Thor Ueland, Sverre Holm, Azhar Abbas, Ida Gregersen, Martin Kummen, Vigdis Bjerkeli, Frode Reier-Nilsen, David Russell, Asbjørn Svardal, Tom Hemming Karlsen, Pål Aukrust, Rolf K Berge, Johannes E R Hov, Bente Halvorsen, Mona Skjelland
BACKGROUND AND PURPOSE: γ-butyrobetaine (γBB) is a metabolite from dietary Carnitine, involved in the gut microbiota-dependent conversion from Carnitine to the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO). Orally ingested γBB has a pro-atherogenic effect in experimental studies, but γBB has not been studied in relation to atherosclerosis in humans. The aim of this study was to evaluate associations between serum levels of γBB, TMAO and their common precursors Carnitine and trimethyllysine (TML) and carotid atherosclerosis and adverse outcome...
April 2016: Atherosclerosis
Maija Dambrova, Marina Makrecka-Kuka, Reinis Vilskersts, Elina Makarova, Janis Kuka, Edgars Liepinsh
Meldonium (mildronate; 3-(2,2,2-trimethylhydrazinium)propionate; THP; MET-88) is a clinically used cardioprotective drug, which mechanism of action is based on the regulation of energy metabolism pathways through l-carnitine lowering effect. l-Carnitine biosynthesis enzyme γ-butyrobetaine hydroxylase and carnitine/organic cation transporter type 2 (OCTN2) are the main known drug targets of meldonium, and through inhibition of these activities meldonium induces adaptive changes in the cellular energy homeostasis...
February 2, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Jos J A G Kamps, Amjad Khan, Hwanho Choi, Robert K Lesniak, Jürgen Brem, Anna M Rydzik, Michael A McDonough, Christopher J Schofield, Timothy D W Claridge, Jasmin Mecinović
γ-Butyrobetaine hydroxylase (BBOX) is a non-heme Fe(II) - and 2-oxoglutarate-dependent oxygenase that catalyzes the stereoselective hydroxylation of an unactivated C-H bond of γ-butyrobetaine (γBB) in the final step of carnitine biosynthesis. BBOX contains an aromatic cage for the recognition of the positively charged trimethylammonium group of the γBB substrate. Enzyme binding and kinetic analyses on substrate analogues with P and As substituting for N in the trimethylammonium group show that the analogues are good BBOX substrates, which follow the efficiency trend N(+) >P(+) >As(+)...
January 22, 2016: Chemistry: a European Journal
Paul E Minkler, Maria S K Stoll, Stephen T Ingalls, Janos Kerner, Charles L Hoppel
Tandem MS "profiling" of acylcarnitines and amino acids was conceived as a first-tier screening method, and its application to expanded newborn screening has been enormously successful. However, unlike amino acid screening (which uses amino acid analysis as its second-tier validation of screening results), acylcarnitine "profiling" also assumed the role of second-tier validation, due to the lack of a generally accepted second-tier acylcarnitine determination method. In this report, we present results from the application of our validated UHPLC-MS/MS second-tier method for the quantification of total carnitine, free carnitine, butyrobetaine, and acylcarnitines to patient samples with known diagnoses: malonic acidemia, short-chain acyl-CoA dehydrogenase deficiency (SCADD) or isobutyryl-CoA dehydrogenase deficiency (IBD), 3-methyl-crotonyl carboxylase deficiency (3-MCC) or ß-ketothiolase deficiency (BKT), and methylmalonic acidemia (MMA)...
December 2015: Molecular Genetics and Metabolism
Bodil Bjørndal, Marie S Ramsvik, Carine Lindquist, Jan E Nordrehaug, Inge Bruheim, Asbjørn Svardal, Ottar Nygård, Rolf K Berge
Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lowering and anti-inflammatory effects of n-3 polyunsaturated fatty acids. However, other plasma risk factors linked to cardiovascular disease are less studied. This study aimed to penetrate the effect of a phospholipid-protein complex (PPC) from Antarctic krill on one-carbon metabolism and production of trimethylamine-N-oxide (TMAO) in rats. Male Wistar rats were fed isoenergetic control, 6%, or 11% PPC diets for four weeks...
September 2015: Marine Drugs
Paul E Minkler, Maria S K Stoll, Stephen T Ingalls, Janos Kerner, Charles L Hoppel
A validated quantitative method for the determination of free and total carnitine, butyrobetaine, and acylcarnitines is presented. The versatile method has four components: (1) isolation using strong cation-exchange solid-phase extraction, (2) derivatization with pentafluorophenacyl trifluoromethanesulfonate, (3) sequential ion-exchange/reversed-phase (ultra) high-performance liquid chromatography [(U)HPLC] using a strong cation-exchange trap in series with a fused-core HPLC column, and (4) detection with electrospray ionization multiple reaction monitoring (MRM) mass spectrometry (MS)...
September 1, 2015: Analytical Chemistry
Reinis Vilskersts, Janis Kuka, Edgars Liepinsh, Marina Makrecka-Kuka, Kristine Volska, Elina Makarova, Eduards Sevostjanovs, Helena Cirule, Solveiga Grinberga, Maija Dambrova
OBJECTIVE: The elevation of the levels of l-carnitine and its fatty acid esters, acylcarnitines, in tissue or plasma has been linked to the development of atherosclerosis. Recently, a potent inhibitor of l-carnitine biosynthesis and transport, methyl-γ-butyrobetaine (methyl-GBB), was discovered. In this study, we evaluated the effects of γ-butyrobetaine (GBB), l-carnitine and methyl-GBB administration on the progression of atherosclerosis. METHODS: Apolipoprotein E knockout (apoE(-/-)) mice were treated with methyl-GBB, l-carnitine or GBB for 4months...
September 2015: Vascular Pharmacology
Lorena Pochini, Mariafrancesca Scalise, Cesare Indiveri
OCTN1 was immuno-detected in the cervical cancer cell HeLa, in which the complete pattern of acetylcholine metabolizing enzymes is expressed. Comparison of immuno-staining intensity of HeLa OCTN1 with the purified recombinant human OCTN1 allowed measuring the specific OCTN1 concentration in the HeLa cell extract and, hence calculating the HeLa OCTN1 specific transport activity that was about 10 nmol×min(-1)×mg protein(-1), measured as uptake of [(3)H]acetylcholine in proteoliposomes reconstituted with HeLa extract...
November 2015: International Immunopharmacology
Juan A Campillo, Angel Sevilla, Marina Albentosa, Cristina Bernal, Ana B Lozano, Manuel Cánovas, Víctor M León
The Mar Menor is a coastal lagoon affected by the growth of intensive agriculture and urban development in the surrounding area. Large amounts of chemical pollutants from these areas are discharged into El Albujón, a permanent water-course flowing into the lagoon. Biomarkers such as the activity of acetylcholinesterase or antioxidant enzymes have been previously tested in this lagoon demonstrating the presence of neurotoxicity and oxidative stress in clams transplanted in sites affected by the dispersion of the effluent from El Albujón...
August 15, 2015: Science of the Total Environment
Solveiga Grinberga, Maija Dambrova, Gustavs Latkovskis, Ieva Strele, Ilze Konrade, Dace Hartmane, Eduards Sevostjanovs, Edgars Liepinsh, Osvalds Pugovics
An ultra-high-performance liquid chromatography-mass spectrometry (UPLC/MS/MS) method was developed and validated for the quantification of trimethylamine-N-oxide (TMAO) simultaneously with TMAO-related molecules L-carnitine and γ-butyrobetaine (GBB) in human blood plasma. The separation of analytes was achieved using a Hydrophilic interaction liquid chromatography (HILIC)-type column with ammonium acetate-acetonitrile as the mobile phase. TMAO determination was validated according to valid US Food and Drug Administration guidelines...
November 2015: Biomedical Chromatography: BMC
Dorothé Jenni Deusing, Melanie Beyrer, Elena Fitzenberger, Uwe Wenzel
Besides its function in transport of fatty acids into mitochondria in order to provide substrates for β-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 μM completely prevented the survival reduction that was caused by the application of 10 mM glucose...
May 8, 2015: Biochemical and Biophysical Research Communications
Robert A Koeth, Bruce S Levison, Miranda K Culley, Jennifer A Buffa, Zeneng Wang, Jill C Gregory, Elin Org, Yuping Wu, Lin Li, Jonathan D Smith, W H Wilson Tang, Joseph A DiDonato, Aldons J Lusis, Stanley L Hazen
L-carnitine, a nutrient in red meat, was recently reported to accelerate atherosclerosis via a metaorganismal pathway involving gut microbial trimethylamine (TMA) formation and host hepatic conversion into trimethylamine-N-oxide (TMAO). Herein, we show that following L-carnitine ingestion, γ-butyrobetaine (γBB) is produced as an intermediary metabolite by gut microbes at a site anatomically proximal to and at a rate ∼1,000-fold higher than the formation of TMA. Moreover, we show that γBB is the major gut microbial metabolite formed from dietary L-carnitine in mice, is converted into TMA and TMAO in a gut microbiota-dependent manner (like dietary L-carnitine), and accelerates atherosclerosis...
November 4, 2014: Cell Metabolism
Sandrine Paule Claus
γ-butyrobetaine has long been known as the precursor of endogenous L-carnitine synthesis. In this issue, Koeth et al. (2014) demonstrate that it is also a major metabolite of L-carnitine degradation by gut bacteria that precedes the enteric production of trimethylamine and trimethylamine-N-oxide.
November 4, 2014: Cell Metabolism
E Liepinsh, M Makrecka-Kuka, J Kuka, R Vilskersts, E Makarova, H Cirule, E Loza, D Lola, S Grinberga, O Pugovics, I Kalvins, M Dambrova
BACKGROUND AND PURPOSE: The important pathological consequences of ischaemic heart disease arise from the detrimental effects of the accumulation of long-chain acylcarnitines in the case of acute ischaemia-reperfusion. The aim of this study is to test whether decreasing the L-carnitine content represents an effective strategy to decrease accumulation of long-chain acylcarnitines and to reduce fatty acid oxidation in order to protect the heart against acute ischaemia-reperfusion injury...
March 2015: British Journal of Pharmacology
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