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Article ; Online: Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4.

McIntyre, Rebecca L / Molenaars, Marte / Schomakers, Bauke V / Gao, Arwen W / Kamble, Rashmi / Jongejan, Aldo / van Weeghel, Michel / van Kuilenburg, André B P / Possemato, Richard / Houtkooper, Riekelt H / Janssens, Georges E

Cell reports

2022 Volume 42, Issue 1, Page(s) 111928

Abstract: The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of ... ...

Abstract	The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.
MeSH term(s)	Animals ; Humans ; Zidovudine/pharmacology ; Zidovudine/therapeutic use ; Longevity ; Activating Transcription Factor 4 ; Caenorhabditis elegans/physiology ; Reverse Transcriptase Inhibitors/pharmacology ; Reverse Transcriptase Inhibitors/therapeutic use ; Retroviridae ; HIV Infections/drug therapy
Chemical Substances	Zidovudine (4B9XT59T7S) ; Activating Transcription Factor 4 (145891-90-3) ; Reverse Transcriptase Inhibitors
Language	English
Publishing date	2022-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.111928
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Article ; Online: Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infection.

Guo, Lihui / Appelman, Brent / Mooij-Kalverda, Kirsten / Houtkooper, Riekelt H / van Weeghel, Michel / Vaz, Frédéric M / Dijkhuis, Annemiek / Dekker, Tamara / Smids, Barbara S / Duitman, Jan Willem / Bugiani, Marianna / Brinkman, Paul / Sikkens, Jonne J / Lavell, H A Ayesha / Wüst, Rob C I / van Vugt, Michèle / Lutter, René

EBioMedicine

2023 Volume 94, Page(s) 104729

Abstract: Background: Post-acute sequela of SARS-CoV-2 infection (PASC) encompass fatigue, post-exertional malaise and cognitive problems. The abundant expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-2 (IDO2) in fatal/severe COVID-19, ...

Abstract	Background: Post-acute sequela of SARS-CoV-2 infection (PASC) encompass fatigue, post-exertional malaise and cognitive problems. The abundant expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-2 (IDO2) in fatal/severe COVID-19, led us to determine, in an exploratory observational study, whether IDO2 is expressed and active in PASC, and may correlate with pathophysiology. Methods: Plasma or serum, and peripheral blood mononuclear cells (PBMC) were obtained from well-characterized PASC patients and SARS-CoV-2-infected individuals without PASC. We assessed tryptophan and its degradation products by UPLC-MS/MS. IDO2 activity, its potential consequences, and the involvement of the aryl hydrocarbon receptor (AHR) in IDO2 expression were determined in PBMC from another PASC cohort by immunohistochemistry (IHC) for IDO2, IDO1, AHR, kynurenine metabolites, autophagy, and apoptosis. These PBMC were also analyzed by metabolomics and for mitochondrial functioning by respirometry. IHC was also performed on autopsy brain material from two PASC patients. Findings: IDO2 is expressed and active in PBMC from PASC patients, as well as in brain tissue, long after SARS-CoV-2 infection. This is paralleled by autophagy, and in blood cells by reduced mitochondrial functioning, reduced intracellular levels of amino acids and Krebs cycle-related compounds. IDO2 expression and activity is triggered by SARS-CoV-2-infection, but the severity of SARS-CoV-2-induced pathology appears related to the generated specific kynurenine metabolites. Ex vivo, IDO2 expression and autophagy can be halted by an AHR antagonist. Interpretation: SARS-CoV-2 infection triggers long-lasting IDO2 expression, which can be halted by an AHR antagonist. The specific kynurenine catabolites may relate to SARS-CoV-2-induced symptoms and pathology. Funding: None.
MeSH term(s)	Humans ; Chromatography, Liquid ; COVID-19/complications ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Kynurenine ; Leukocytes, Mononuclear/metabolism ; Post-Acute COVID-19 Syndrome ; SARS-CoV-2/metabolism ; Tandem Mass Spectrometry ; Tryptophan/metabolism
Chemical Substances	Indoleamine-Pyrrole 2,3,-Dioxygenase ; Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX) ; IDO2 protein, human
Language	English
Publishing date	2023-07-26
Publishing country	Netherlands
Document type	Observational Study ; Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2023.104729
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Zs.A 7090: Show issues

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Article ; Online: CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.

van Karnebeek, Clara D M / Tarailo-Graovac, Maja / Leen, René / Meinsma, Rutger / Correard, Solenne / Jansen-Meijer, Judith / Prykhozhij, Sergey V / Pena, Izabella A / Ban, Kevin / Schock, Sarah / Saxena, Vishal / Pras-Raves, Mia L / Drögemöller, Britt I / Grootemaat, Anita E / van der Wel, Nicole N / Dobritzsch, Doreen / Roseboom, Winfried / Schomakers, Bauke V / Jaspers, Yorrick R J /

Zoetekouw, Lida / Roelofsen, Jeroen / Ferreira, Carlos R / van der Lee, Robin / Ross, Colin J / Kochan, Jakub / McIntyre, Rebecca L / van Klinken, Jan B / van Weeghel, Michel / Kramer, Gertjan / Weschke, Bernhard / Labrune, Philippe / Willemsen, Michèl A / Riva, Daria / Garavaglia, Barbara / Moeschler, John B / Filiano, James J / Ekker, Marc / Berman, Jason N / Dyment, David / Vaz, Frédéric M / Wassermann, Wyeth W / Houtkooper, Riekelt H / van Kuilenburg, André B P

Genetics in medicine : official journal of the American College of Medical Genetics

2024 Volume 26, Issue 6, Page(s) 101104

Abstract: Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system.!## ...

Abstract	Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. Methods: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences. Results: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models. Conclusion: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.
Language	English
Publishing date	2024-02-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1016/j.gim.2024.101104
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Zs.A 5059: Show issues

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Article ; Online: NAD+-Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults.

Connell, N J / Grevendonk, L / Fealy, C E / Moonen-Kornips, E / Bruls, Y M H / Schrauwen-Hinderling, V B / de Vogel, J / Hageman, R / Geurts, J / Zapata-Perez, R / Houtkooper, R H / Havekes, B / Hoeks, J / Schrauwen, P

The Journal of nutrition

2021 Volume 151, Issue 10, Page(s) 2917–2931

Abstract: ... through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle ...

Abstract	Background: Boosting NAD+ via supplementation with niacin equivalents has been proposed as a potential modality capable of promoting healthy aging and negating age-dependent declines of skeletal muscle mass and function. Objectives: We investigated the efficacy of NAD+-precursor supplementation (tryptophan, nicotinic acid, and nicotinamide) on skeletal muscle mitochondrial function in physically compromised older adults. Methods: A randomized, double-blind, controlled trial was conducted in 14 (female/male: 4/10) community-dwelling, older adults with impaired physical function [age, 72.9 ± 4.0 years; BMI, 25.2 ± 2.3 kg/m2]. Participants were supplemented with 207.5 mg niacin equivalents/day [intervention (INT)] and a control product (CON) that did not contain niacin equivalents, each for 32 days. The primary outcomes tested were mitochondrial oxidative capacity and exercise efficiency, analyzed by means of paired Student's t-tests. Secondary outcomes, such as NAD+ concentrations, were analyzed accordingly. Results: Following supplementation, skeletal muscle NAD+ concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD+-precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD+ metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD+-precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Conclusions: Our findings are consistent with previous findings on NAD+ efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD+-precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034.
MeSH term(s)	Aged ; Dietary Supplements ; Female ; Humans ; Male ; Mitochondria ; Muscle, Skeletal/metabolism ; NAD/metabolism ; Niacin/pharmacology ; Niacinamide/pharmacology ; Tryptophan/metabolism
Chemical Substances	NAD (0U46U6E8UK) ; Niacinamide (25X51I8RD4) ; Niacin (2679MF687A) ; Tryptophan (8DUH1N11BX)
Language	English
Publishing date	2021-06-29
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	218373-0
ISSN	1541-6100 ; 0022-3166
ISSN (online)	1541-6100
ISSN	0022-3166
DOI	10.1093/jn/nxab193
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Article ; Online: A review of treatment modalities in gyrate atrophy of the choroid and retina (GACR).

Balfoort, Berith M / Buijs, Mark J N / Ten Asbroek, Anneloor L M A / Bergen, Arthur A B / Boon, Camiel J F / Ferreira, Elise A / Houtkooper, Riekelt H / Wagenmakers, Margreet A E M / Wanders, Ronald J A / Waterham, Hans R / Timmer, Corrie / van Karnebeek, Clara D / Brands, Marion M

Molecular genetics and metabolism

2021 Volume 134, Issue 1-2, Page(s) 96–116

Abstract: ... protein-restricted diets, pyridoxine supplementation, creatine or creatine precursor supplementation, l-lysine ...

Abstract	Gyrate atrophy of the choroid and retina (GACR) is a rare inborn error of amino acid metabolism caused by bi-allelic variations in OAT. GACR is characterised by vision decline in early life eventually leading to complete blindness, and high plasma ornithine levels. There is no curative treatment for GACR, although several therapeutic modalities aim to slow progression of the disease by targeting different steps within the ornithine pathway. No international treatment protocol is available. We systematically collected all international literature on therapeutic interventions in GACR to provide an overview of published treatment effects. Methods: Following the PRISMA guidelines, we conducted a systematic review of the English literature until December 22nd 2020. PubMed and Embase databases were searched for studies related to therapeutic interventions in patients with GACR. Results: A total of 33 studies (n = 107 patients) met the inclusion criteria. Most studies were designed as case reports (n = 27) or case series (n = 4). No randomised controlled trials or large cohort studies were found. Treatments applied were protein-restricted diets, pyridoxine supplementation, creatine or creatine precursor supplementation, l-lysine supplementation, and proline supplementation. Protein-restricted diets lowered ornithine levels ranging from 16.0-91.2%. Pyridoxine responsiveness was reported in 30% of included mutations. Lysine supplementation decreased ornithine levels with 21-34%. Quality assessment showed low to moderate quality of the articles. Conclusions: Based primarily on case reports ornithine levels can be reduced by using a protein restricted diet, pyridoxine supplementation (variation-dependent) and/or lysine supplementation. The lack of pre-defined clinical outcome measures and structural follow-up in all included studies impeded conclusions on clinical effectiveness. Future research should be aimed at 1) Unravelling the OAT biochemical pathway to identify other possible pathologic metabolites besides ornithine, 2) Pre-defining GACR specific clinical outcome measures, and 3) Establishing an international historical cohort.
MeSH term(s)	Choroid/drug effects ; Choroid/pathology ; Gyrate Atrophy/drug therapy ; Humans ; Metabolism, Inborn Errors/drug therapy ; Mutation ; Retina/drug effects ; Retina/pathology
Language	English
Publishing date	2021-07-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2021.07.010
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Article ; Online: mTOR-driven glycolysis governs induction of innate immune responses by bronchial epithelial cells exposed to the bacterial component flagellin.

Ramirez-Moral, I / Yu, X / Butler, J M / van Weeghel, M / Otto, N A / Ferreira, B Lima / Maele, L Van / Sirard, J C / de Vos, A F / de Jong, M D / Houtkooper, R H / van der Poll, T

Mucosal immunology

2021 Volume 14, Issue 3, Page(s) 594–604

Abstract: Human bronchial epithelial (HBE) cells play an essential role during bacterial infections of the airways by sensing pathogens and orchestrating protective immune responses. We here sought to determine which metabolic pathways are utilized by HBE cells to ...

Abstract	Human bronchial epithelial (HBE) cells play an essential role during bacterial infections of the airways by sensing pathogens and orchestrating protective immune responses. We here sought to determine which metabolic pathways are utilized by HBE cells to mount innate immune responses upon exposure to a relevant bacterial agonist. Stimulation of HBE cells by the bacterial component flagellin triggered activation of the mTOR pathway resulting in an increased glycolytic flux that sustained the secretory activity of immune mediators by HBE cells. The mTOR inhibitor rapamycin impeded glycolysis and limited flagellin-induced secretion of immune mediators. The role of the mTOR pathway was recapitulated in vivo in a mouse model of flagellin-triggered lung innate immune responses. These data demonstrate that metabolic reprogramming via the mTOR pathway modulates activation of the respiratory epithelium, identifying mTOR as a potential therapeutic target to modulate mucosal immunity in the context of bacterial infections.
MeSH term(s)	Animals ; Bronchi/pathology ; Cells, Cultured ; Cellular Reprogramming ; Disease Models, Animal ; Epithelial Cells/immunology ; Female ; Flagellin/metabolism ; Glycolysis ; Humans ; Immunity, Innate ; Klebsiella Infections/immunology ; Klebsiella pneumoniae/physiology ; Mice ; Mice, Inbred C57BL ; Pseudomonas Infections/immunology ; Pseudomonas aeruginosa/physiology ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Flagellin (12777-81-0) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2411370-0
ISSN	1935-3456 ; 1933-0219
ISSN (online)	1935-3456
ISSN	1933-0219
DOI	10.1038/s41385-021-00377-8
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Zs.A 6796: Show issues

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Article: Assessment of body composition in youths and relationship to sport.

Houtkooper, L B

International journal of sport nutrition

1996 Volume 6, Issue 2, Page(s) 146–164

Abstract: Body composition assessment techniques provide estimates of percent body fat (%BF), fat mass (FM), and fat-free mass (FFM) based on indirect assessment models and methods. Prediction equations for %BF developed using a two-component model based on adult ... ...

Abstract	Body composition assessment techniques provide estimates of percent body fat (%BF), fat mass (FM), and fat-free mass (FFM) based on indirect assessment models and methods. Prediction equations for %BF developed using a two-component model based on adult body composition constants with overestimate %BF in youths, especially prepubescent youths. Body composition prediction equations that have been validated and cross-validated using multiple-component criterion models which include measurements of body density and the water and mineral components of FFM provide the most accurate means for assessment of body composition in youths. Use of appropriate prediction equations and proper measurement techniques, for either bioelectrical impedance or skinfolds, results in body composition estimates with standard errors of estimate (prediction errors) of 3 to 4% BF and 2.0 to 2.5 kg of FFM. Poor measurement technique and inappropriate prediction equations will result in much larger prediction errors.
MeSH term(s)	Adipose Tissue ; Adolescent ; Anthropometry/methods ; Body Composition ; Child ; Densitometry ; Female ; Humans ; Male ; Models, Biological ; Sports
Language	English
Publishing date	1996-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1101115-4
ISSN	1543-2742 ; 1050-1606 ; 1526-484X
ISSN (online)	1543-2742
ISSN	1050-1606 ; 1526-484X
DOI	10.1123/ijsn.6.2.146
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Zs.A 4143: Show issues

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Article ; Online: Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30.

Liu, Yasmine J / McIntyre, Rebecca L / Janssens, Georges E / Williams, Evan G / Lan, Jiayi / van Weeghel, Michel / Schomakers, Bauke / van der Veen, Henk / van der Wel, Nicole N / Yao, Pallas / Mair, William B / Aebersold, Ruedi / MacInnes, Alyson W / Houtkooper, Riekelt H

The Journal of cell biology

2020 Volume 219, Issue 6

Abstract: Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented mitochondrial network. However, whether this link ... ...

Abstract	Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented mitochondrial network. However, whether this link between mitochondrial translation and morphology is causal in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by blocking fission or fusion synergizes with reduced mitochondrial translation to prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous disruption of fission and fusion abrogates the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic crosstalk between mitochondrial translation, mitochondrial dynamics, and lysosomal signaling in regulating longevity.
MeSH term(s)	Animals ; Autophagosomes/drug effects ; Autophagosomes/metabolism ; Autophagosomes/ultrastructure ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Gene Ontology ; Longevity/genetics ; Longevity/physiology ; Lysosomes/drug effects ; Lysosomes/metabolism ; Lysosomes/ultrastructure ; Microscopy, Electron, Transmission ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Dynamics/drug effects ; Protein Biosynthesis/drug effects ; Protein Biosynthesis/physiology ; Proteomics ; RNA Interference ; Reproduction/physiology ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Unfolded Protein Response/drug effects ; Unfolded Protein Response/genetics
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; Caenorhabditis elegans Proteins ; HLH-30 protein, C elegans
Language	English
Publishing date	2020-03-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201907067
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Ub I Zs.190: Show issues

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Article ; Online: Exploring the metabolic fate of medium-chain triglycerides in healthy individuals using a stable isotope tracer.

Knottnerus, Suzan J G / van Harskamp, Dewi / Schierbeek, Henk / Bleeker, Jeannette C / Crefcoeur, Loek L / Ferdinandusse, Sacha / van Goudoever, Johannes B / Houtkooper, Riekelt H / IJlst, Lodewijk / Langeveld, Mirjam / Wanders, Ronald J A / Vaz, Frédéric M / Wijburg, Frits A / Visser, Gepke

Clinical nutrition (Edinburgh, Scotland)

2020 Volume 40, Issue 3, Page(s) 1396–1404

Abstract: Background & aims: Medium chain triglyceride (MCT) supplementation is often recommended as treatment for patients with long-chain fatty acid β-oxidation (lcFAO) disorders, since they can be utilized as an energy source without the use of the defective ... ...

Abstract	Background & aims: Medium chain triglyceride (MCT) supplementation is often recommended as treatment for patients with long-chain fatty acid β-oxidation (lcFAO) disorders, since they can be utilized as an energy source without the use of the defective enzyme. However, studies in mice and preterm infants suggest that not all medium-chain fatty acids (MCFA) are oxidized and may undergo elongation to long-chain fatty acids (LCFA). In this single blinded study, we explored the metabolic fates of MCT in healthy individuals using a Method: Three healthy males in rest received on two test days a primed continuous infusion of glyceryl tri[1,2,3,4- Results: When provided as single energy source, an estimated 42% of administered MCT was converted to CO Conclusions: Although the relative MCT oxidation rate was higher when combined with carbohydrates and protein, quantitatively more MCT was oxidized when given an isocaloric meal with solely MCT. As these results were obtained in the resting state opposed to during exercise, it is too early to give a recommendation concerning the use of MCT in lcFAO disorders. The data show that in resting healthy individuals only a very small part of the MCT is traced back as LCFA in plasma, suggesting that MCT treatment does not result in a large LCFA burden, however further research on storage of MCT in tissues is warranted. Registration: The study was registered in the Nederlands Trialregister. Protocol ID: Trial NL7417 (NTR7650).
MeSH term(s)	Adult ; Breath Tests ; Caprylates ; Carbon Dioxide/metabolism ; Carbon Isotopes ; Diet ; Fatty Acids/blood ; Humans ; Isotope Labeling ; Male ; Oxidation-Reduction ; Triglycerides/administration & dosage ; Triglycerides/metabolism
Chemical Substances	Caprylates ; Carbon Isotopes ; Fatty Acids ; Triglycerides ; Carbon Dioxide (142M471B3J) ; tricaprylin (6P92858988)
Language	English
Publishing date	2020-09-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604812-2
ISSN	1532-1983 ; 0261-5614
ISSN (online)	1532-1983
ISSN	0261-5614
DOI	10.1016/j.clnu.2020.08.032
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Zs.A 1774: Show issues

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Article ; Online: Biotechnological production of reduced and oxidized NAD+ precursors

Zapata-Pérez, Rubén / García-Saura, Antonio Ginés / Scantlebery, Angelique M.L. / Schomakers, Bauke V. / Rabadán-Ros, Rubén / van Weeghel, Michel / Houtkooper, Riekelt H. / Sánchez-Ferrer, Álvaro

Food Research International. 20232023 Mar. 02, Feb. 02, v. 165 p.112560-

2023

Abstract: ... overexpressed soluble recombinant enzymes; (a) a NAD+ pyrophosphatase, (b) an NMN deamidase, and (c) a 5 ... replenishment strategies can be used. Among these, administration of vitamin B₃ derivatives (NAD⁺ precursors ...

Abstract	Dysregulation of nicotinamide adenine dinucleotide (NAD⁺) homeostasis by increased activity of NAD⁺ consumers or reduced NAD⁺ biosynthesis plays an important role in the onset of prevalent, often age-related, diseases, such as diabetes, neuropathies or nephropathies. To counteract such dysregulation, NAD⁺ replenishment strategies can be used. Among these, administration of vitamin B₃ derivatives (NAD⁺ precursors) has garnered attention in recent years. However, the high market price of these compounds and their limited availability, pose important limitations to their use in nutritional or biomedical applications. To overcome these limitations, we have designed an enzymatic method for the synthesis and purification of (1) the oxidized NAD⁺ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), (2) their reduced forms NMNH and NRH, and (3) their deaminated forms nicotinic acid mononucleotide (NaMN) and nicotinic acid riboside (NaR). Starting from NAD⁺ or NADH as substrates, we use a combination of three highly overexpressed soluble recombinant enzymes; (a) a NAD+ pyrophosphatase, (b) an NMN deamidase, and (c) a 5′-nucleotidase, to produce these six precursors. Finally, we validate the activity of the enzymatically produced molecules as NAD⁺ enhancers in cell culture.
Keywords	NAD (coenzyme) ; biosynthesis ; cell culture ; diabetes ; enzymatic treatment ; food research ; homeostasis ; market prices ; niacin ; nicotinamide ; oxidation ; peripheral nervous system diseases ; NAD precursor ; Enzymatic synthesis ; NaMN
Language	English
Dates of publication	2023-0202
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	1111695-x
ISSN	1873-7145 ; 0963-9969
ISSN (online)	1873-7145
ISSN	0963-9969
DOI	10.1016/j.foodres.2023.112560
Database	NAL-Catalogue (AGRICOLA)

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