108 results on '"Denis, Simone"'
Search Results
2. Author Correction: Upregulation of the AMPK-FOXO1-PDK4 pathway is a primary mechanism of pyruvate dehydrogenase activity reduction in tafazzin-deficient cells
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Liang, Zhuqing, Ralph-Epps, Tyler, Schmidtke, Michael W., Lazcano, Pablo, Denis, Simone W., Balážová, Mária, Teixeira da Rosa, Jr., Nevton, Chakkour, Mohamed, Hazime, Sanaa, Ren, Mindong, Schlame, Michael, Houtkooper, Riekelt H., and Greenberg, Miriam L.
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- 2024
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3. Upregulation of the AMPK-FOXO1-PDK4 pathway is a primary mechanism of pyruvate dehydrogenase activity reduction in tafazzin-deficient cells
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Liang, Zhuqing, Ralph-Epps, Tyler, Schmidtke, Michael W., Lazcano, Pablo, Denis, Simone W., Balážová, Mária, Teixeira da Rosa, Jr., Nevton, Chakkour, Mohamed, Hazime, Sanaa, Ren, Mindong, Schlame, Michael, Houtkooper, Riekelt H., and Greenberg, Miriam L.
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- 2024
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4. Tracer‐based lipidomics enables the discovery of disease‐specific candidate biomarkers in mitochondrial β‐oxidation disorders.
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Schwantje, Marit, Mosegaard, Signe, Knottnerus, Suzan J. G., van Klinken, Jan Bert, Wanders, Ronald J., van Lenthe, Henk, Hermans, Jill, IJlst, Lodewijk, Denis, Simone W., Jaspers, Yorrick R. J., Fuchs, Sabine A., Houtkooper, Riekelt H., Ferdinandusse, Sacha, and Vaz, Frédéric M.
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- 2024
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5. ACOX3 Dysfunction as a Potential Cause of Recurrent Spontaneous Vasospasm of Internal Carotid Artery
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Kim, Joon-Tae, Won, So Yeon, Kang, KyungWook, Kim, Sang-Hoon, Park, Man-Seok, Choi, Kang-Ho, Nam, Tai-Seung, Denis, Simone W., Ferdinandusse, Sacha, Lee, Ji Eun, Choi, Seok-Yong, and Kim, Myeong-Kyu
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- 2020
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6. Barth syndrome cells display widespread remodeling of mitochondrial complexes without affecting metabolic flux distribution
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Chatzispyrou, Iliana A., Guerrero-Castillo, Sergio, Held, Ntsiki M., Ruiter, Jos P.N., Denis, Simone W., IJlst, Lodewijk, Wanders, Ronald J., van Weeghel, Michel, Ferdinandusse, Sacha, Vaz, Frédéric M., Brandt, Ulrich, and Houtkooper, Riekelt H.
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- 2018
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7. Acute detachment of hexokinase II from mitochondria modestly increases oxygen consumption of the intact mouse heart
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Nederlof, Rianne, Denis, Simone, Lauzier, Benjamin, Rosiers, Christine Des, Laakso, Markku, Hagen, Jacob, Argmann, Carmen, Wanders, Ronald, Houtkooper, Riekelt H., Hollmann, Markus W., Houten, Sander M., and Zuurbier, Coert J.
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- 2017
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8. Clinical heterogeneity of mitochondrial NAD kinase deficiency caused by a NADK2 start loss variant
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Pomerantz, Daniel J., Ferdinandusse, Sacha, Cogan, Joy, Cooper, David N., Reimschisel, Tyler, Robertson, Amy, Bican, Anna, McGregor, Tracy, Gauthier, Jackie, Millington, David S., Andrae, Jaime L. W., Tschannen, Michael R., Helbling, Daniel C., Demos, Wendy M., Denis, Simone, Wanders, Ronald J. A., Newman, John N., Hamid, Rizwan, and Phillips, John A., III
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- 2018
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9. Pyruvate dehydrogenase complex plays a central role in brown adipocyte energy expenditure and fuel utilization during short-term beta-adrenergic activation
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Held, Ntsiki M., Kuipers, Eline N., van Weeghel, Michel, van Klinken, Jan Bert, Denis, Simone W., Lombès, Marc, Wanders, Ronald J., Vaz, Frédéric M., Rensen, Patrick C. N., Verhoeven, Arthur J., Boon, Mariëtte R., and Houtkooper, Riekelt H.
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- 2018
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10. Lower Metabolic Potential and Impaired Metabolic Flexibility in Human Lymph Node Stromal Cells from Patients with Rheumatoid Arthritis.
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de Jong, Tineke A., Semmelink, Johanna F., Denis, Simone W., Bolt, Janne W., Maas, Mario, van de Sande, Marleen G. H., Houtkooper, Riekelt H. L., and van Baarsen, Lisa G. M.
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STROMAL cells ,LYMPH nodes ,RHEUMATOID arthritis ,RESPIRATION ,FATTY acid oxidation ,IMMUNOLOGICAL tolerance ,AUTOANTIBODIES - Abstract
Cellular metabolism is important for determining cell function and shaping immune responses. Studies have shown a crucial role for stromal cells in steering proper immune responses in the lymph node microenvironment. These lymph node stromal cells (LNSCs) tightly regulate immune tolerance. We hypothesize that malfunctioning LNSCs create a microenvironment in which normal immune responses are not properly controlled, possibly leading to the development of autoimmune diseases such as rheumatoid arthritis (RA). Therefore, we set out to determine their metabolic profile during health and systemic autoimmunity. We included autoantibody positive individuals at risk of developing RA (RA-risk individuals), RA patients and healthy volunteers. All study subjects underwent lymph node biopsy sampling. Mitochondrial function in cultured LNSCs was assessed by quantitative PCR, flow cytometry, Seahorse and oleate oxidation assays. Overall, mitochondrial respiration was lower in RA(-risk) LNSCs compared with healthy LNSCs, while metabolic potential was only lower in RA LNSCs. To maintain basal mitochondrial respiration, all LNSCs were mostly dependent on fatty acid oxidation. However, RA(-risk) LNSCs were also dependent on glutamine oxidation. Finally, we showed that RA LNSCs have impaired metabolic flexibility. Our results show that the metabolic landscape of LNSCs is not only altered during established disease, but partly already in individuals at risk of developing RA. Future studies are needed to investigate the impact of restoring metabolic capacity in LNSC-mediated immunomodulation and disease progression. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Carnitine supplementation attenuates myocardial lipid accumulation in long-chain acyl-CoA dehydrogenase knockout mice
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Bakermans, Adrianus J., van Weeghel, Michel, Denis, Simone, Nicolay, Klaas, Prompers, Jeanine J., and Houten, Sander M.
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- 2013
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12. A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3
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Ferdinandusse, Sacha, Jimenez-Sanchez, Gerardo, Koster, Janet, Denis, Simone, Van Roermund, Carlo W., Silva-Zolezzi, Irma, Moser, Ann B., Visser, Wouter F., Gulluoglu, Mine, Durmaz, Ozlem, Demirkol, Mubeccel, Waterham, Hans R., Gökcay, Gülden, Wanders, Ronald J.A., and Valle, David
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- 2015
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13. Mannose-Binding Lectin Is Required for the Effective Clearance of Apoptotic Cells by Adipose Tissue Macrophages During Obesity
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Stienstra, Rinke, Dijk, Wieneke, van Beek, Lianne, Jansen, Henry, Heemskerk, Mattijs, Houtkooper, Riekelt H., Denis, Simone, van Harmelen, Vanessa, Willems van Dijk, Ko, Tack, Cees J., and Kersten, Sander
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- 2014
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14. Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia
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Houten, Sander M., Denis, Simone, te Brinke, Heleen, Jongejan, Aldo, van Kampen, Antoine H.C., Bradley, Edward J., Baas, Frank, Hennekam, Raoul C.M., Millington, David S., Young, Sarah P., Frazier, Dianne M., Gucsavas-Calikoglu, Muge, and Wanders, Ronald J.A.
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- 2014
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15. Detection of nonsterol isoprenoids by HPLC–MS/MS
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Henneman, Linda, van Cruchten, Arno G., Denis, Simone W., Amolins, Michael W., Placzek, Andrew T., Gibbs, Richard A., Kulik, Willem, and Waterham, Hans R.
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- 2008
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16. Time‐restricted feeding during the inactive phase abolishes the daily rhythm in mitochondrial respiration in rat skeletal muscle.
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de Goede, Paul, Wüst, Rob C. I., Schomakers, Bauke V., Denis, Simone, Vaz, Frédéric M., Pras‐Raves, Mia L., van Weeghel, Michel, Yi, Chun‐Xia, Kalsbeek, Andries, and Houtkooper, Riekelt H.
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- 2022
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17. Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects
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Houten, Sander M., Herrema, Hilde, te Brinke, Heleen, Denis, Simone, Ruiter, Jos P.N., van Dijk, Theo H., Argmann, Carmen A., Ottenhoff, Roelof, Müller, Michael, Groen, Albert K., Kuipers, Folkert, Reijngoud, Dirk-Jan, and Wanders, Ronald J.A.
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- 2013
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18. Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene
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Ebberink, Merel S, Csanyi, Barbara, Chong, Wui K, Denis, Simone, Sharp, Peter, Mooijer, Petra A, Dekker, Conny J, Spooner, Claire, Ngu, Lock H, De Sousa, Carlos, Wanders, Ronald J, Fietz, Michael J, Clayton, Peter T, Waterham, Hans R, and Ferdinandusse, Sacha
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- 2010
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19. Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF‐16‐induced longevity.
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McIntyre, Rebecca L., Denis, Simone W., Kamble, Rashmi, Molenaars, Marte, Petr, Michael, Schomakers, Bauke V., Rahman, Mizanur, Gupta, Siddhartha, Toth, Marton L., Vanapalli, Siva A., Jongejan, Aldo, Scheibye‐Knudsen, Morten, Houtkooper, Riekelt H., and Janssens, Georges E.
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LONGEVITY , *GENETIC engineering , *GENETIC databases , *CAENORHABDITIS elegans , *SUGAMMADEX , *MYONEURAL junction , *CHOLINERGIC receptors - Abstract
Transcriptome‐based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age‐related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf‐16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA‐approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in Caenorhabditis elegans. This longevity is dependent on both daf‐16 signaling and inhibition of the neuromuscular acetylcholine receptor subunit unc‐38. We found unc‐38 RNAi to improve healthspan, lifespan, and stimulate DAF‐16 nuclear localization, similar to atracurium treatment. Finally, using RNA‐seq transcriptomics, we identify atracurium activation of DAF‐16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF‐16 longevity pathway. [ABSTRACT FROM AUTHOR]
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- 2021
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20. Quantification of Myocardial Creatine and Triglyceride Content in the Human Heart: Precision and Accuracy of in vivo Proton Magnetic Resonance Spectroscopy.
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Bakermans, Adrianus J., Boekholdt, S. Matthijs, Vries, Dylan K., Reckman, Yolan J., Farag, Emile S., Heer, Paul, Uthman, Laween, Denis, Simone W., Zuurbier, Coert J., Houtkooper, Riekelt H., Koolbergen, David R., Kluin, Jolanda, Planken, R. Nils, Lamb, Hildo J., Webb, Andrew G., Strijkers, Gustav J., Beard, Daniel A., Jeneson, Jeroen A.L., and Nederveen, Aart J.
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PROTON magnetic resonance spectroscopy ,CREATINE ,TRIGLYCERIDES ,AORTIC valve transplantation - Abstract
Background: Proton magnetic resonance spectroscopy (1H‐MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking. Purpose: To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized 1H‐MRS. Study type: Test–retest repeatability and measurement validation study. Subjects: Sixteen volunteers and 22 patients scheduled for open‐heart aortic valve replacement or septal myectomy. Field Strength/Sequence: Prospectively ECG‐triggered respiratory‐gated free‐breathing single‐voxel point‐resolved spectroscopy (PRESS) sequence at 3 T. Assessment: Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the 1H‐MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo 1H‐MRS measurements against biochemical assays in myocardial tissue from the same subjects. Statistical Tests: Intrasession and intersession repeatability was assessed using Bland–Altman analyses. Agreement between 1H‐MRS measurements and biochemical assay was tested with regression analyses. Results: The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% ± 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% ± 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with 1H‐MRS: n = 22, r = 0.44; P < 0.05. Likewise, ex vivo myocardial triglyceride concentrations correlated with the in vivo myocardial triglyceride content: n = 20, r = 0.50; P < 0.05. Data Conclusion: We validated the use of localized 1H‐MRS of the human heart at 3 T for quantitative assessments of in vivo myocardial tissue metabolite content by estimating the measurement precision and accuracy. Level of Evidence: 2 Technical Efficacy Stage: 2 [ABSTRACT FROM AUTHOR]
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- 2021
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21. Clinical, Biochemical, and Mutational Spectrum of Peroxisomal Acyl-Coenzyme A Oxidase Deficiency
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Ferdinandusse, Sacha, Denis, Simone, Hogenhout, Eveline M., Koster, Janet, van Roermund, Carlo W.T., IJlst, Lodewijk, Moser, Ann B., Wanders, Ronald J.A., and Waterham, Hans R.
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- 2007
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22. Peroxisomal Branched Chain Fatty Acid β-Oxidation Pathway Is Upregulated in Prostate Cancer
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Zha, Shan, Ferdinandusse, Sacha, Hicks, Jessica L., Denis, Simone, Dunn, Thomas A., Wanders, Ronald J., Luo, Jun, De Marzo, Angelo M., and Isaacs, William B.
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- 2005
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23. Increased cardiac fatty acid oxidation in a mouse model with decreased malonyl-CoA sensitivity of CPT1B.
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Weeghel, Michel van, Abdurrachim, Desiree, Nederlof, Rianne, Argmann, Carmen A, Houtkooper, Riekelt H, Hagen, Jacob, Nabben, Miranda, Denis, Simone, Ciapaite, Jolita, and Kolwicz, Stephen C
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FATTY acid oxidation ,CARNITINE palmitoyltransferase ,HEART metabolism ,MALONYL-coenzyme A ,HEART function tests - Abstract
Aims Mitochondrial fatty acid oxidation (FAO) is an important energy provider for cardiac work and changes in cardiac substrate preference are associated with different heart diseases. Carnitine palmitoyltransferase 1B (CPT1B) is thought to perform the rate limiting enzyme step in FAO and is inhibited by malonyl-CoA. The role of CPT1B in cardiac metabolism has been addressed by inhibiting or decreasing CPT1B protein or after modulation of tissue malonyl-CoA metabolism. We assessed the role of CPT1B malonyl-CoA sensitivity in cardiac metabolism. Methods and results We generated and characterized a knock in mouse model expressing the CPT1B
E3A mutant enzyme, which has reduced sensitivity to malonyl-CoA. In isolated perfused hearts, FAO was 1.9-fold higher in Cpt1bE3A/E3A hearts compared with Cpt1bWT/WT hearts. Metabolomic, proteomic and transcriptomic analysis showed increased levels of malonylcarnitine, decreased concentration of CPT1B protein and a small but coordinated downregulation of the mRNA expression of genes involved in FAO in Cpt1bE3A/E3A hearts, all of which aim to limit FAO. In vivo assessment of cardiac function revealed only minor changes, cardiac hypertrophy was absent and histological analysis did not reveal fibrosis. Conclusions Malonyl-CoA-dependent inhibition of CPT1B plays a crucial role in regulating FAO rate in the heart. Chronic elevation of FAO has a relatively subtle impact on cardiac function at least under baseline conditions. [ABSTRACT FROM AUTHOR]- Published
- 2018
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24. A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase.
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Ferdinandusse, Sacha, Denis, Simone, van Roermund, Carlo W.T., Preece, Mary Anne, Koster, Janet, Ebberink, Merel S., Waterham, Hans R., and Wanders, Ronald J.A.
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PEROXISOMAL disorders , *OXIDASES , *FATTY acids , *BILE acids , *BIOSYNTHESIS - Abstract
Peroxisomal acyl-CoA oxidases catalyze the first step of beta-oxidation of a variety of substrates broken down in the peroxisome. These include the CoA-esters of very long-chain fatty acids, branched-chain fatty acids and the C27-bile acid intermediates. In rat, three peroxisomal acyl-CoA oxidases with different substrate specificities are known, whereas in humans it is believed that only two peroxisomal acyl-CoA oxidases are expressed under normal circumstances. Only three patients with ACOX2 deficiency, including two siblings, have been identified so far, showing accumulation of the C27-bile acid intermediates. Here, we performed biochemical studies in material from a novel ACOX2-deficient patient with increased levels of C27-bile acids in plasma, a complete loss of ACOX2 protein expression on immunoblot, but normal pristanic acid oxidation activity in fibroblasts. Since pristanoyl-CoA is presumed to be handled by ACOX2 specifically, these findings prompted us to re-investigate the expression of the human peroxisomal acyl-CoA oxidases. We report for the first time expression of ACOX3 in normal human tissues at the mRNA and protein level. Substrate specificity studies were done for ACOX1, 2 and 3 which revealed that ACOX1 is responsible for the oxidation of straight-chain fatty acids with different chain lengths, ACOX2 is the only human acyl-CoA oxidase involved in bile acid biosynthesis, and both ACOX2 and ACOX3 are involved in the degradation of the branched-chain fatty acids. Our studies provide new insights both into ACOX2 deficiency and into the role of the different acyl-CoA oxidases in peroxisomal metabolism. [ABSTRACT FROM AUTHOR]
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- 2018
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25. Clinical heterogeneity of mitochondrial NAD kinase deficiency caused by a <italic>NADK2</italic> start loss variant.
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Pomerantz, Daniel J., Ferdinandusse, Sacha, Cogan, Joy, Cooper, David N., Reimschisel, Tyler, Robertson, Amy, Bican, Anna, McGregor, Tracy, Gauthier, Jackie, Millington, David S., Andrae, Jaime L. W., Tschannen, Michael R., Helbling, Daniel C., Demos, Wendy M., Denis, Simone, Wanders, Ronald J. A., Newman, John N., Hamid, Rizwan, Phillips, III, John A., and Collaborators of UDN
- Abstract
Mitochondrial NAD kinase deficiency (NADK2D, OMIM #615787) is a rare autosomal recessive disorder of NADPH biosynthesis that can cause hyperlysinemia and dienoyl‐CoA reductase deficiency (DECRD, OMIM #616034). NADK2 deficiency has been reported in only three unrelated patients. Two had severe, unremitting disease; one died at 4 months and the other at 5 years of age. The third was a 10 year old female with CNS anomalies, ataxia, and incoordination. In two cases mutations in NADK2 have been demonstrated. Here, we report the fourth known case, a 15 year old female with normal intelligence and a mild clinical and biochemical phenotype presumably without DECRD. Her clinical symptoms, which are now stable, became evident at the age of 9 with the onset of decreased visual acuity, bilateral optic atrophy, nystagmus, episodic lower extremity weakness, peripheral neuropathy, and gait abnormalities. Plasma amino acid levels were within normal limits except for mean lysine and proline levels that were 3.7 and 2.5 times the upper limits of normal. Whole exome sequencing (WES) revealed homozygosity for a g.36241900 A>G p. Met1Val start loss mutation in the primary NADK2 transcript (NM_001085411.1) encoding the 442 amino acid isoform. This presumed hypomorphic mutation has not been previously reported and is absent from the v1000GP, EVS, and ExAC databases. Our patient's normal intelligence and stable disease expands the clinical heterogeneity and the prognosis associated with NADK2 deficiency. Our findings also clarify the mechanism underlying NADK2 deficiency and suggest that this disease should be ruled out in cases of hyperlysinemia, especially those with visual loss, and neurological phenotypes. [ABSTRACT FROM AUTHOR]
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- 2018
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26. Alpha-methylacyl-CoA racemase as an androgen-independent growth modifier in prostate cancer
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Zha, Shan, Ferdinandusse, Sacha, Denis, Simone, Wanders, Ronald J., Ewing, Charles M., Luo, Jun, de Marzo, Angelo M., Isaacs, William B., Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, and Paediatric Metabolic Diseases
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urologic and male genital diseases - Abstract
Alpha-methylacyl-CoA racemase (AMACR) is an enzyme involved in beta-oxidation of branched-chain fatty acids and bile acid intermediates. Recent work has identified AMACR as a new diagnostic marker for prostate cancer (PCa). The data from the present study suggest that AMACR is also functionally important for the growth of PCa cells. Overexpressed AMACR from both clinical tissues and PCa cell lines is wild type by sequence analysis and functionally active by enzymatic assay. Correspondingly, enzyme activity of AMACR increases approximately 4-fold in PCa in comparison with adjacent normal prostate. Small interference RNA (siRNA) against AMACR, but not the control inverted siRNA, reduced the expression of AMACR and significantly impaired proliferation of the androgen-responsive PCa cell line LAPC-4. No effect was observed in HeLaS3 cells, which express AMACR at a low level. Cell cycle analyses revealed a G(2)-M cell cycle arrest in LAPC-4 cells treated with siRNA compared with mock treatment or control inverted siRNA. Expression of a siRNA-resistant form of AMACR in LAPC-4 cells protects the cells from growth arrest after AMACR-specific siRNA treatment. Data from Western blotting and luciferase-based reporter assays suggest that the function and expression of AMACR are independent of androgen receptor-mediated signaling. Moreover, simultaneous inhibition of both the AMACR pathway by siRNA and androgen signaling by means of androgen withdrawal or antiandrogen suppressed the growth of LAPC-4 cells to a greater extent than either treatment alone. Taken together, these data suggest that AMACR is essential for optimal growth of PCa cells in vitro and that this enzyme has the potential to be a complementary target with androgen ablation in PCa treatment
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- 2003
27. Genetic basis of hyperlysinemia.
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Houten, Sander M., Brinke, Heleen te, Denis, Simone, Ruiter, Jos P. N., Knegt, Alida C., de Klerk, Johannis B. C., Augoustides-Savvopoulou, Persephone, Häberle, Johannes, Baumgartner, Matthias R., Coskun, Turgay, Zschocke, Johannes, Sass, Jörn Oliver, Poll-The, Bwee Tien, Wanders, Ronald J. A., and Duran, Marinus
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METABOLIC disorders ,GENETIC disorders ,LYSINE ,MISSENSE mutation ,GENETIC mutation - Abstract
Background: Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the gene encoding a-aminoadipic semialdehyde synthase has been reported. We aimed to AASS better define the genetic basis of hyperlysinemia. Methods: We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features. Results: We found novel causal mutations in in all affected individuals, including 4 missense mutations, AASS 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting and AASS and PTPRZ1 Conclusions: Hyperlysinemia is caused by mutations in AASS and PTPRZ1 hyperlysinemia is generally considered a benign AASS metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PIPRZ1. Our findings illustrate the importance of detailed PTPRZ1 biochemical and genetic studies in any hyperlysinemia patient. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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28. Fasting-Induced Myocardial Lipid Accumulation in Long-Chain Acyl-CoA Dehydrogenase Knockout Mice Is Accompanied by Impaired Left Ventricular Function.
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Bakermans, Adrianus J., Geraedts, Tom R., van Weeghel, Michel, Denis, Simone, Ferraz, Maria João, Aerts, Johannes M. F. G., Aten, Jan, Nicolay, Klaas, Houten, Sander M., and Prompers, Jeanine J.
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- 2011
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29. Toxicity of peroxisomal C27-bile acid intermediates
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Ferdinandusse, Sacha, Denis, Simone, Dacremont, Georges, and Wanders, Ronald J.A.
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PEROXISOMAL disorders , *BILE acids , *POISONS , *BIOSYNTHESIS , *PHOSPHORYLATION , *OXYGEN in the body , *TOXICITY testing , *LIVER diseases - Abstract
Abstract: Peroxisomes play an important role in bile acid biosynthesis because the last steps of the synthesis pathway are performed by the β-oxidation system located inside peroxisomes. As a consequence, C27-bile acid intermediates accumulate in several peroxisomal disorders. It has been suggested that C27-bile acids are especially toxic and contribute to the liver disease associated with peroxisomal disorders. For this reason, we investigated the toxicity of C27-bile acids and the underlying mechanisms. We studied the effects of conjugated and unconjugated C27-bile acids on cell viability, mitochondrial respiratory chain function and production of oxygen radicals in the rat hepatoma cell line McA-RH7777. Cell viability decreased progressively after incubation with increasing concentrations of different bile acids with dihydroxycholestanoic acid (DHCA) being clearly the most cytotoxic bile acid. In addition, the different bile acids caused a dose-dependent decrease in ATP synthesis by isolated mitochondria oxidizing malate and glutamate. Finally, there was a dose-dependent stimulation of ROS generation in the presence of C27-bile acids. In conclusion, our studies showed that C27-bile acids are more cytotoxic than mature C24-bile acids. In addition, C27-bile acids are potent inhibitors of oxidative phosphorylation and enhance mitochondrial ROS production by inhibiting the respiratory chain. [Copyright &y& Elsevier]
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- 2009
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30. Developmental Changes of Bile Acid Composition and Conjugation in L- and D-Bifunctional Protein Single and Double Knockout Mice.
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Ferdinandusse, Sacha, Denis, Simone, Overmars, Henk, Van Eeckhoudt, Lisbeth, Van Veldhoven, Paul P., Duran, Marinus, Wanders, Ronald J. A., and Baes, Myriam
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BILE acids , *PROTEINS , *PHYSIOLOGICAL oxidation , *BIOSYNTHESIS , *ACETYLCOENZYME A , *ACYLTRANSFERASES , *NUCLEAR receptors (Biochemistry) , *BIOCHEMISTRY - Abstract
Peroxisomal β-oxidation is an essential step in bile acid synthesis, since it is required for shortening of C27-bile acid intermediates to produce mature C24-bile acids. D-Bifunctional protein (DBP) is responsible for the second and third step of this β-oxidation process. However, both patients and mice with a DBP deficiency still produce C24-bile acids, although C27-intermediates accumulate. An alternative pathway for bile acid biosynthesis involving the peroxisomal L-bifunctional protein (LBP) has been proposed. We investigated the role of LBP and DBP in bile acid synthesis by analyzing bile acids in bile, liver, and plasma from LBP, DBP, and LBP:DBP double knock-out mice. Bile acid biosynthesis, estimated by the ratio of C27/C24-bile acids, was more severely affected in double knock-out mice as compared with DBP-/- mice but was normal in LBP-/- mice. Unexpectedly, trihydroxycholestanoyl-CoA oxidase was inactive in double knock-out mice due to a peroxisomal import defect, preventing us from drawing any firm conclusion about the potential role of LBP in an alternative bile acid biosynthesis pathway. Interestingly, the immature C27-bile acids in DBP and double knock-out mice remained unconjugated in juvenile mice, whereas they occurred as taurine conjugates after weaning, probably contributing to the minimal weight gain of the mice during the lactation period. This correlated with a marked induction of bile acyl-CoA:amino acid N-acyltransferase expression and enzyme activity between postnatal days 10 and 21, whereas the bile acyl-CoA synthetases increased gradually with age. The nuclear receptors hepatocyte nuclear factor-4α farnesoid X receptor, and peroxisome proliferator receptor a did not appear to be involved in the up-regulation of the transferase. [ABSTRACT FROM AUTHOR]
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- 2005
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31. Mutations in the gene encoding peroxisomal α-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy.
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Ferdinandusse, Sacha, Denis, Simone, Clayton, Peter T., Graham, Andrew, Rees, John E., Allen, John T., McLean, Brendan N., Brown, Ann Y., Vreken, Peter, Waterham, Hans R., and Wanders, Ronald J.A.
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AFFERENT pathway diseases , *CHARCOT-Marie-Tooth disease - Abstract
Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease. In the latter two, the neuropathy is thought to result from the accumulation of specific fatty acids. We describe here three patients with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27-bile-acid intermediates. Two of the patients suffered from adult-onset sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting Refsum disease, whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy. The third patient was a child without neuropathy. In all three patients we discovered a deficiency of α-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only stereoisomers that can be degraded via peroxisomal β-oxidation. Sequence analysis of AMACR cDNA from the patients identified two different mutations that are likely to cause disease, based on analysis in Escherichia coli. Our findings have implications for the diagnosis of adult-onset neuropathies of unknown aetiology. [ABSTRACT FROM AUTHOR]
- Published
- 2000
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32. Reduced nicotinamide mononucleotide is a new and potent NAD+ precursor in mammalian cells and mice.
- Author
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Zapata-Pérez, Rubén, Tammaro, Alessandra, Schomakers, Bauke V., Scantlebery, Angelique M. L., Denis, Simone, Elfrink, Hyung L., Giroud-Gerbetant, Judith, Cantó, Carles, López-Leonardo, Carmen, McIntyre, Rebecca L., van Weeghel, Michel, Sánchez-Ferrer, Álvaro, and Houtkooper, Riekelt H.
- Published
- 2021
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33. A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia.
- Author
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Baardman, Jeroen, Verberk, Sanne G.S., Prange, Koen H.M., van Weeghel, Michel, van der Velden, Saskia, Ryan, Dylan G., Wüst, Rob C.I., Neele, Annette E., Speijer, Dave, Denis, Simone W., Witte, Maarten E., Houtkooper, Riekelt H., O'neill, Luke A., Knatko, Elena V., Dinkova-Kostova, Albena T., Lutgens, Esther, de Winther, Menno P.J., and Van den Bossche, Jan
- Abstract
Summary Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function. Graphical Abstract Highlights • Systemic metabolism affects immune cell metabolism • Hypercholesterolemia suppresses the PPP and Nrf2 pathway in macrophages • PPP inhibition and hypercholesterolemia deactivate inflammatory macrophage responses • The Nrf2 pathway regulates the PPP in an LXR-independent manner The link between systemic and cellular metabolism is a neglected aspect in immunometabolism. Baardman et al. show that hypercholesterolemia alters macrophage metabolism and phenotype. The suppressed pentose phosphate pathway (PPP) in those "foam cell" macrophages attenuates inflammatory responses, signifying that systemic and cellular metabolism together regulate macrophage function. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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34. Mitochondrial disruption in peroxisome deficient cells is hepatocyte selective but is not mediated by common hepatic peroxisomal metabolites.
- Author
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Shinde, Abhijit Babaji, Baboota, Ritesh Kumar, Denis, Simone, Loizides-Mangold, Ursula, Peeters, Annelies, Espeel, Marc, Malheiro, Ana Rita, Riezman, Howard, Vinckier, Stefan, Vaz, Frédéric M., Brites, Pedro, Ferdinandusse, Sacha, Van Veldhoven, Paul P., and Baes, Myriam
- Subjects
- *
PEROXISOMES , *LIVER cells , *METABOLITES , *MITOCHONDRIA , *FATTY acids - Abstract
The structural disruption of the mitochondrial inner membrane in hepatocytes lacking functional peroxisomes along with selective impairment of respiratory complexes and depletion of mitochondrial DNA was previously reported. In search for the molecular origin of these mitochondrial alterations, we here show that these are tissue selective as they do neither occur in peroxisome deficient brain nor in peroxisome deficient striated muscle. Given the hepatocyte selectivity, we investigated the potential involvement of metabolites that are primarily handled by hepatic peroxisomes. Levels of these metabolites were manipulated in L-Pex5 knockout mice and/or compared with levels in different mouse models with a peroxisomal β-oxidation deficiency. We show that neither the deficiency of docosahexaenoic acid nor the accumulation of branched chain fatty acids, dicarboxylic acids or C27 bile acid intermediates are solely responsible for the mitochondrial anomalies. In conclusion, we demonstrate that peroxisomal inactivity differentially impacts mitochondria depending on the cell type but the cause of the mitochondrial destruction needs to be further explored. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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35. Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy
- Author
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Kemp, Stephan, Valianpour, Fredoen, Denis, Simone, Ofman, Rob, Sanders, Robert-Jan, Mooyer, Petra, Barth, Peter G., and Wanders, Ronald J.A.
- Subjects
- *
FIBROBLASTS , *OXIDATION , *PERIPHERAL neuropathy , *X chromosome abnormalities - Abstract
Abstract: X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder characterized by the accumulation of saturated and mono-unsaturated very long-chain fatty acids (VLCFA) and reduced peroxisomal VLCFA β-oxidation activity. In this study, we investigated the role of VLCFA biosynthesis in X-ALD fibroblasts. Our data demonstrate that elongation of both saturated and mono-unsaturated VLCFAs is enhanced in fibroblasts from patients with peroxisomal β-oxidation defects including X-ALD, and peroxisome biogenesis disorders. These data indicate that enhanced VLCFA elongation is a general phenomenon associated with an impairment in peroxisomal β-oxidation, and not specific for X-ALD alone. Analysis of plasma samples from patients with X-ALD and different peroxisomal β-oxidation deficiencies revealed increased concentrations of VLCFAs up to 32 carbons. We infer that enhanced elongation does not result from impaired peroxisomal β-oxidation alone, but is due to the additional effect of unchecked chain elongation. We demonstrate that elongated VLCFAs are incorporated into complex lipids. The role of chain elongation was also studied retrospectively in samples from patients with X-ALD previously treated with “Lorenzo’s oil.” We found that the decrease in plasma C26:0 previously found is offset by the increase of mono-unsaturated VLCFAs, not measured previously during the trial. We conclude that evaluation of treatment protocols for disorders of peroxisomal β-oxidation making use of plasma samples should include the measurement of saturated and unsaturated VLCFAs of chain lengths above 26 carbon atoms. We also conclude that chain elongation offers an interesting target to be studied as a possible mode of treatment for X-ALD and other peroxisomal β-oxidation disorders. [Copyright &y& Elsevier]
- Published
- 2005
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36. Corrigendum to “Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy” [Mol. Genet. Metab. 84 (2005) 144–151]
- Author
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Kemp, Stephan, Valianpour, Fredoen, Denis, Simone, Ofman, Rob, Sanders, Robert-Jan, Mooyer, Petra, Barth, Peter G., and Wanders, Ronald J.A.
- Published
- 2008
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37. Evidence for increased oxidative stress in peroxisomal D-bifunctional protein deficiency
- Author
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Ferdinandusse, Sacha, Finckh, Barbara, de Hingh, Yvette C., Stroomer, Lida E.M., Denis, Simone, Kohlschütter, Alfried, and Wanders, Ronald J.A.
- Subjects
- *
PEROXISOMES , *PROTEINS , *ENZYMES , *NEUROLOGY - Abstract
Peroxisome biogenesis disorders (PBDs) and D-bifunctional protein (D-BP) deficiency are two types of inherited peroxisomal disorders. Patients with a PBD lack functional peroxisomes and patients with D-BP deficiency lack the enzyme, which is responsible for the second and third step of the peroxisomal β-oxidation. The clinical presentation of these peroxisomal disorders is severe and includes several neurological abnormalities. The pathological mechanisms underlying these disorders are not understood and no therapies are available. Because peroxisomes have been associated with oxidative stress, as oxygen radicals are both produced and scavenged in peroxisomes, we have investigated whether oxidative stress is involved in the pathogenesis of PBDs and D-BP deficiency. We found in D-BP-deficient patients increased levels of thiobarbituric acid-reactive substances (TBARS) and 8-hydroxydeoxyguanosine (8-OHdG), which are markers for lipid peroxidation and oxidative DNA damage, respectively, whereas the levels of the lipophilic antioxidants α-tocopherol and coenzyme Q10 were decreased. In addition, we found in skin fibroblasts from D-BP-deficient patients an imbalance between the activities of the peroxisomal H2O2-generating straight-chain acyl-CoA oxidase (SCOX) and the peroxisomal H2O2-degrading enzyme catalase. In conclusion, we have found clear evidence for the presence of increased oxidative stress in patients with D-BP deficiency, but not in patients with a PBD. [Copyright &y& Elsevier]
- Published
- 2003
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38. Upregulation of the AMPK-FOXO1-PDK4 pathway is a primary mechanism of pyruvate dehydrogenase activity reduction and leads to increased glucose uptake in tafazzin-deficient cells.
- Author
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Liang Z, Ralph-Epps T, Schmidtke MW, Lazcano P, Denis SW, Balážová M, Chakkour M, Hazime S, Ren M, Schlame M, Houtkooper RH, and Greenberg ML
- Abstract
Barth syndrome (BTHS) is a rare disorder caused by mutations in the TAFAZZIN gene. Previous studies from both patients and model systems have established metabolic dysregulation as a core component of BTHS pathology. In particular, features such as lactic acidosis, pyruvate dehydrogenase (PDH) deficiency, and aberrant fatty acid and glucose oxidation have been identified. However, the lack of a mechanistic understanding of what causes these conditions in the context of BTHS remains a significant knowledge gap, and this has hindered the development of effective therapeutic strategies for treating the associated metabolic problems. In the current study, we utilized tafazzin-knockout C2C12 mouse myoblasts (TAZ-KO) and cardiac and skeletal muscle tissue from tafazzin-knockout mice to identify an upstream mechanism underlying impaired PDH activity in BTHS. This mechanism centers around robust upregulation of pyruvate dehydrogenase kinase 4 (PDK4), resulting from hyperactivation of AMP-activated protein kinase (AMPK) and subsequent transcriptional upregulation by forkhead box protein O1 (FOXO1). Upregulation of PDK4 in tafazzin-deficient cells causes direct phospho-inhibition of PDH activity accompanied by increased glucose uptake and elevated intracellular glucose concentration. Collectively, our findings provide a novel mechanistic framework whereby impaired tafazzin function ultimately results in robust PDK4 upregulation, leading to impaired PDH activity and likely linked to dysregulated metabolic substrate utilization. This mechanism may underlie previously reported findings of BTHS-associated metabolic dysregulation.
- Published
- 2024
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39. Lower Metabolic Potential and Impaired Metabolic Flexibility in Human Lymph Node Stromal Cells from Patients with Rheumatoid Arthritis.
- Author
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de Jong TA, Semmelink JF, Denis SW, Bolt JW, Maas M, van de Sande MGH, Houtkooper RHL, and van Baarsen LGM
- Subjects
- Humans, Immune Tolerance, Immunity, Lymph Nodes pathology, Stromal Cells metabolism, Arthritis, Rheumatoid
- Abstract
Cellular metabolism is important for determining cell function and shaping immune responses. Studies have shown a crucial role for stromal cells in steering proper immune responses in the lymph node microenvironment. These lymph node stromal cells (LNSCs) tightly regulate immune tolerance. We hypothesize that malfunctioning LNSCs create a microenvironment in which normal immune responses are not properly controlled, possibly leading to the development of autoimmune diseases such as rheumatoid arthritis (RA). Therefore, we set out to determine their metabolic profile during health and systemic autoimmunity. We included autoantibody positive individuals at risk of developing RA (RA-risk individuals), RA patients and healthy volunteers. All study subjects underwent lymph node biopsy sampling. Mitochondrial function in cultured LNSCs was assessed by quantitative PCR, flow cytometry, Seahorse and oleate oxidation assays. Overall, mitochondrial respiration was lower in RA(-risk) LNSCs compared with healthy LNSCs, while metabolic potential was only lower in RA LNSCs. To maintain basal mitochondrial respiration, all LNSCs were mostly dependent on fatty acid oxidation. However, RA(-risk) LNSCs were also dependent on glutamine oxidation. Finally, we showed that RA LNSCs have impaired metabolic flexibility. Our results show that the metabolic landscape of LNSCs is not only altered during established disease, but partly already in individuals at risk of developing RA. Future studies are needed to investigate the impact of restoring metabolic capacity in LNSC-mediated immunomodulation and disease progression., Competing Interests: The authors declare no conflict of interest.
- Published
- 2022
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40. Neonatal Long-Chain 3-Ketoacyl-CoA Thiolase deficiency: Clinical-biochemical phenotype, sodium-D,L-3-hydroxybutyrate treatment experience and cardiac evaluation using speckle echocardiography.
- Author
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Veenvliet ARJ, Garrelfs MR, Udink Ten Cate FEA, Ferdinandusse S, Denis S, Fuchs SA, Schwantje M, Geurtzen R, van Wegberg AMJ, Huigen MCDG, Kluijtmans LAJ, Wanders RJA, Derks TGJ, de Boer L, Houtkooper RH, de Vries MC, and van Karnebeek CDM
- Abstract
Isolated long-chain 3-keto-acyl CoA thiolase (LCKAT) deficiency is a rare long-chain fatty acid oxidation disorder caused by mutations in HADHB. LCKAT is part of a multi-enzyme complex called the mitochondrial trifunctional protein (MTP) which catalyzes the last three steps in the long-chain fatty acid oxidation. Until now, only three cases of isolated LCKAT deficiency have been described. All patients developed a severe cardiomyopathy and died before the age of 7 weeks. Here, we describe a newborn with isolated LCKAT deficiency, presenting with neonatal-onset cardiomyopathy, rhabdomyolysis, hypoglycemia and lactic acidosis. Bi-allelic 185G > A (p.Arg62His) and c1292T > C (p.Phe431Ser) mutations were found in HADHB . Enzymatic analysis in both lymphocytes and cultured fibroblasts revealed LCKAT deficiency with a normal long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD, also part of MTP) enzyme activity. Clinically, the patient showed recurrent cardiomyopathy, which was monitored by speckle tracking echocardiography. Subsequent treatment with special low-fat formula, low in long chain triglycerides (LCT) and supplemented with medium chain triglycerides (MCT) and ketone body therapy in (sodium-D,L-3-hydroxybutyrate) was well tolerated and resulted in improved carnitine profiles and cardiac function. Resveratrol, a natural polyphenol that has been shown to increase fatty acid oxidation, was also considered as a potential treatment option but showed no in vitro benefits in the patient's fibroblasts. Even though our patient deceased at the age of 13 months, early diagnosis and prompt initiation of dietary management with addition of sodium-D,L-3-hydroxybutyrate may have contributed to improved cardiac function and a much longer survival when compared to the previously reported cases of isolated LCKAT-deficiency., Competing Interests: We have no conflicts of interest to report., (© 2022 The Authors.)
- Published
- 2022
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41. Reduced nicotinamide mononucleotide is a new and potent NAD + precursor in mammalian cells and mice.
- Author
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Zapata-Pérez R, Tammaro A, Schomakers BV, Scantlebery AML, Denis S, Elfrink HL, Giroud-Gerbetant J, Cantó C, López-Leonardo C, McIntyre RL, van Weeghel M, Sánchez-Ferrer Á, and Houtkooper RH
- Subjects
- Animals, Cell Line, Cell Survival, Epithelial Cells drug effects, Homeostasis, Humans, Kidney Tubules, Male, Mice, Mice, Inbred C57BL, Molecular Structure, NAD genetics, Nicotinamide Mononucleotide chemistry, Reperfusion Injury, NAD metabolism, Nicotinamide Mononucleotide metabolism
- Abstract
Nicotinamide adenine dinucleotide (NAD
+ ) homeostasis is constantly compromised due to degradation by NAD+ -dependent enzymes. NAD+ replenishment by supplementation with the NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) can alleviate this imbalance. However, NMN and NR are limited by their mild effect on the cellular NAD+ pool and the need of high doses. Here, we report a synthesis method of a reduced form of NMN (NMNH), and identify this molecule as a new NAD+ precursor for the first time. We show that NMNH increases NAD+ levels to a much higher extent and faster than NMN or NR, and that it is metabolized through a different, NRK and NAMPT-independent, pathway. We also demonstrate that NMNH reduces damage and accelerates repair in renal tubular epithelial cells upon hypoxia/reoxygenation injury. Finally, we find that NMNH administration in mice causes a rapid and sustained NAD+ surge in whole blood, which is accompanied by increased NAD+ levels in liver, kidney, muscle, brain, brown adipose tissue, and heart, but not in white adipose tissue. Together, our data highlight NMNH as a new NAD+ precursor with therapeutic potential for acute kidney injury, confirm the existence of a novel pathway for the recycling of reduced NAD+ precursors and establish NMNH as a member of the new family of reduced NAD+ precursors., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)- Published
- 2021
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- View/download PDF
42. Cardiolipin-induced activation of pyruvate dehydrogenase links mitochondrial lipid biosynthesis to TCA cycle function.
- Author
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Li Y, Lou W, Raja V, Denis S, Yu W, Schmidtke MW, Reynolds CA, Schlame M, Houtkooper RH, and Greenberg ML
- Subjects
- Acetyl Coenzyme A biosynthesis, Acyltransferases, Animals, Carbon metabolism, Cell Line, Energy Metabolism, Enzyme Activation, Mice, Mice, Knockout, Pyruvate Carboxylase metabolism, Transcription Factors genetics, Cardiolipins physiology, Citric Acid Cycle, Lipids biosynthesis, Mitochondria metabolism, Pyruvate Dehydrogenase Complex metabolism
- Abstract
Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes. Although it has long been known that CL plays an important role in mitochondrial bioenergetics, recent evidence in the yeast model indicates that CL is also essential for intermediary metabolism. To gain insight into the function of CL in energy metabolism in mammalian cells, here we analyzed the metabolic flux of [U-
13 C]glucose in a mouse C2C12 myoblast cell line, TAZ-KO, which is CL-deficient because of CRISPR/Cas9-mediated knockout of the CL-remodeling enzyme tafazzin (TAZ). TAZ-KO cells exhibited decreased flux of [U-13 C]glucose to [13 C]acetyl-CoA and M2 and M4 isotopomers of tricarboxylic acid (TCA) cycle intermediates. The activity of pyruvate carboxylase, the predominant enzyme for anaplerotic replenishing of the TCA cycle, was elevated in TAZ-KO cells, which also exhibited increased sensitivity to the pyruvate carboxylase inhibitor phenylacetate. We attributed a decreased carbon flux from glucose to acetyl-CoA in the TAZ-KO cells to a ∼50% decrease in pyruvate dehydrogenase (PDH) activity, which was observed in both TAZ-KO cells and cardiac tissue from TAZ-KO mice. Protein-lipid overlay experiments revealed that PDH binds to CL, and supplementing digitonin-solubilized TAZ-KO mitochondria with CL restored PDH activity to WT levels. Mitochondria from TAZ-KO cells exhibited an increase in phosphorylated PDH, levels of which were reduced in the presence of supplemented CL. These findings indicate that CL is required for optimal PDH activation, generation of acetyl-CoA, and TCA cycle function, findings that link the key mitochondrial lipid CL to TCA cycle function and energy metabolism., (© 2019 Li et al.)- Published
- 2019
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43. Increased cardiac fatty acid oxidation in a mouse model with decreased malonyl-CoA sensitivity of CPT1B.
- Author
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van Weeghel M, Abdurrachim D, Nederlof R, Argmann CA, Houtkooper RH, Hagen J, Nabben M, Denis S, Ciapaite J, Kolwicz SC Jr, Lopaschuk GD, Auwerx J, Nicolay K, Des Rosiers C, Wanders RJ, Zuurbier CJ, Prompers JJ, and Houten SM
- Subjects
- Animals, Carnitine O-Palmitoyltransferase genetics, Genotype, Glucose metabolism, Glycolysis, Isolated Heart Preparation, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Oxidation-Reduction, Phenotype, Ventricular Function, Left, Carnitine O-Palmitoyltransferase metabolism, Energy Metabolism, Fatty Acids metabolism, Malonyl Coenzyme A metabolism, Mitochondria, Heart enzymology, Myocardium enzymology
- Abstract
Aims: Mitochondrial fatty acid oxidation (FAO) is an important energy provider for cardiac work and changes in cardiac substrate preference are associated with different heart diseases. Carnitine palmitoyltransferase 1B (CPT1B) is thought to perform the rate limiting enzyme step in FAO and is inhibited by malonyl-CoA. The role of CPT1B in cardiac metabolism has been addressed by inhibiting or decreasing CPT1B protein or after modulation of tissue malonyl-CoA metabolism. We assessed the role of CPT1B malonyl-CoA sensitivity in cardiac metabolism., Methods and Results: We generated and characterized a knock in mouse model expressing the CPT1BE3A mutant enzyme, which has reduced sensitivity to malonyl-CoA. In isolated perfused hearts, FAO was 1.9-fold higher in Cpt1bE3A/E3A hearts compared with Cpt1bWT/WT hearts. Metabolomic, proteomic and transcriptomic analysis showed increased levels of malonylcarnitine, decreased concentration of CPT1B protein and a small but coordinated downregulation of the mRNA expression of genes involved in FAO in Cpt1bE3A/E3A hearts, all of which aim to limit FAO. In vivo assessment of cardiac function revealed only minor changes, cardiac hypertrophy was absent and histological analysis did not reveal fibrosis., Conclusions: Malonyl-CoA-dependent inhibition of CPT1B plays a crucial role in regulating FAO rate in the heart. Chronic elevation of FAO has a relatively subtle impact on cardiac function at least under baseline conditions.
- Published
- 2018
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- View/download PDF
44. Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids.
- Author
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Houten SM, Denis S, Argmann CA, Jia Y, Ferdinandusse S, Reddy JK, and Wanders RJ
- Subjects
- 3-Hydroxyacyl CoA Dehydrogenases deficiency, 3-Hydroxyacyl CoA Dehydrogenases genetics, Animals, Computational Biology, Enoyl-CoA Hydratase deficiency, Enoyl-CoA Hydratase genetics, Fasting, Isomerases deficiency, Isomerases genetics, Mice, Mice, Knockout, Mitochondria metabolism, Multienzyme Complexes deficiency, Multienzyme Complexes genetics, Multienzyme Complexes metabolism, Peroxisomal Bifunctional Enzyme, Peroxisomes metabolism, 3-Hydroxyacyl CoA Dehydrogenases metabolism, Dicarboxylic Acids metabolism, Enoyl-CoA Hydratase metabolism, Isomerases metabolism
- Abstract
L-bifunctional enzyme (Ehhadh) is part of the classical peroxisomal fatty acid β-oxidation pathway. This pathway is highly inducible via peroxisome proliferator-activated receptor α (PPARα) activation. However, no specific substrates or functions for Ehhadh are known, and Ehhadh knockout (KO) mice display no appreciable changes in lipid metabolism. To investigate Ehhadh functions, we used a bioinformatics approach and found that Ehhadh expression covaries with genes involved in the tricarboxylic acid cycle and in mitochondrial and peroxisomal fatty acid oxidation. Based on these findings and the regulation of Ehhadh's expression by PPARα, we hypothesized that the phenotype of Ehhadh KO mice would become apparent after fasting. Ehhadh mice tolerated fasting well but displayed a marked deficiency in the fasting-induced production of the medium-chain dicarboxylic acids adipic and suberic acid and of the carnitine esters thereof. The decreased levels of adipic and suberic acid were not due to a deficient induction of ω-oxidation upon fasting, as Cyp4a10 protein levels increased in wild-type and Ehhadh KO mice.We conclude that Ehhadh is indispensable for the production of medium-chain dicarboxylic acids, providing an explanation for the coordinated induction of mitochondrial and peroxisomal oxidative pathways during fasting.
- Published
- 2012
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- View/download PDF
45. Bile acids: the role of peroxisomes.
- Author
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Ferdinandusse S, Denis S, Faust PL, and Wanders RJ
- Subjects
- Animals, Biosynthetic Pathways, Humans, Peroxisomal Disorders physiopathology, Peroxisomes physiology, Bile Acids and Salts biosynthesis, Peroxisomal Disorders metabolism, Peroxisomes metabolism
- Abstract
It is well established that peroxisomes play a crucial role in de novo bile acid synthesis. Studies in patients with a peroxisomal disorder have been indispensable for the elucidation of the precise role of peroxisomes. Several peroxisomal disorders are associated with distinct bile acid abnormalities and each disorder has a characteristic pattern of abnormal bile acids that accumulate, which is often used for diagnostic purposes. The patients have also been important for determining the pathophysiological consequences of defects in bile acid biosynthesis. In this review, we will discuss all the peroxisomal steps involved in bile acid synthesis and the bile acid abnormalities in patients with peroxisomal disorders. We will show the results of bile acid measurements in several tissues from patients, including brain, and we will discuss the toxicity and the pathological effects of the abnormal bile acids.
- Published
- 2009
- Full Text
- View/download PDF
46. Toxicity of peroxisomal C27-bile acid intermediates.
- Author
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Ferdinandusse S, Denis S, Dacremont G, and Wanders RJ
- Subjects
- Adenosine Triphosphate metabolism, Animals, Bile Acids and Salts chemistry, Bile Acids and Salts metabolism, Cell Line, Tumor, Cell Survival, Humans, Mitochondria metabolism, Rats, Reactive Oxygen Species metabolism, Bile Acids and Salts toxicity, Peroxisomal Disorders metabolism, Peroxisomes metabolism
- Abstract
Peroxisomes play an important role in bile acid biosynthesis because the last steps of the synthesis pathway are performed by the beta-oxidation system located inside peroxisomes. As a consequence, C(27)-bile acid intermediates accumulate in several peroxisomal disorders. It has been suggested that C(27)-bile acids are especially toxic and contribute to the liver disease associated with peroxisomal disorders. For this reason, we investigated the toxicity of C(27)-bile acids and the underlying mechanisms. We studied the effects of conjugated and unconjugated C(27)-bile acids on cell viability, mitochondrial respiratory chain function and production of oxygen radicals in the rat hepatoma cell line McA-RH7777. Cell viability decreased progressively after incubation with increasing concentrations of different bile acids with dihydroxycholestanoic acid (DHCA) being clearly the most cytotoxic bile acid. In addition, the different bile acids caused a dose-dependent decrease in ATP synthesis by isolated mitochondria oxidizing malate and glutamate. Finally, there was a dose-dependent stimulation of ROS generation in the presence of C(27)-bile acids. In conclusion, our studies showed that C(27)-bile acids are more cytotoxic than mature C(24)-bile acids. In addition, C(27)-bile acids are potent inhibitors of oxidative phosphorylation and enhance mitochondrial ROS production by inhibiting the respiratory chain.
- Published
- 2009
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- View/download PDF
47. Design, synthesis, and in vitro testing of alpha-methylacyl-CoA racemase inhibitors.
- Author
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Carnell AJ, Hale I, Denis S, Wanders RJ, Isaacs WB, Wilson BA, and Ferdinandusse S
- Subjects
- Acyl Coenzyme A chemistry, Acyl Coenzyme A pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Binding Sites, Cell Proliferation drug effects, Crystallography, X-Ray, Drug Design, Drug Screening Assays, Antitumor, Humans, Male, Myristates chemistry, Myristates pharmacology, Prostatic Neoplasms, Racemases and Epimerases chemistry, Stereoisomerism, Acyl Coenzyme A chemical synthesis, Antineoplastic Agents chemical synthesis, Myristates chemical synthesis, Racemases and Epimerases antagonists & inhibitors
- Abstract
The enzyme alpha-methylacyl-CoA racemase (AMACR) is overexpressed in prostate, colon, and other cancers and has been partially validated as a potential therapeutic target by siRNA knockdown of the AMACR gene. Analogs of the natural substrate branched chain alpha-methylacyl coenzyme A esters, possessing one or more beta-fluorine atoms, have been synthesized using Wittig, conjugate addition, and asymmetric aldol reactions and found to be reversible competitive inhibitors. Each diastereomer of the previously reported inhibitor ibuprofenoyl-CoA was also tested. The compounds had Ki values of 0.9-20 microM and are the most potent inhibitors yet known. The presence of beta-fluorine on the alpha-methyl group or the acyl chain results in a significant lowering of the Ki value compared with nonfluorinated analogs, and this is attributed to a lowering of the pKa of the alpha-proton, facilitating enolization and binding. Several of the CoA ester inhibitors were formed by incubating the free carboxylic acid precursors with cell free extracts and CoA. alpha-Trifluoromethyltetradecanoic acid, the precursor to the most potent inhibitor, was shown to inhibit growth of cancer cell lines PC3, CWR22 Rv1, and Du145 in a dose-dependent manner and could be related to the expression level of AMACR.
- Published
- 2007
- Full Text
- View/download PDF
48. Clinical and biochemical spectrum of D-bifunctional protein deficiency.
- Author
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Ferdinandusse S, Denis S, Mooyer PA, Dekker C, Duran M, Soorani-Lunsing RJ, Boltshauser E, Macaya A, Gärtner J, Majoie CB, Barth PG, Wanders RJ, and Poll-The BT
- Subjects
- Blood Chemical Analysis, Bone and Bones anatomy & histology, Bone and Bones pathology, Brain anatomy & histology, Brain pathology, Child, Child, Preschool, Cohort Studies, Fibroblasts cytology, Fibroblasts metabolism, Humans, Infant, Kidney anatomy & histology, Kidney pathology, Life Expectancy, Liver anatomy & histology, Liver pathology, Magnetic Resonance Imaging, Peroxisomal Bifunctional Enzyme, Surveys and Questionnaires, 3-Hydroxyacyl CoA Dehydrogenases deficiency, Enoyl-CoA Hydratase deficiency, Isomerases deficiency, Lipid Metabolism, Inborn Errors, Multienzyme Complexes deficiency, Peroxisomal Disorders classification, Peroxisomal Disorders pathology, Peroxisomal Disorders physiopathology
- Abstract
Objective: D-bifunctional protein deficiency is an autosomal recessive inborn error of peroxisomal fatty acid oxidation. Although case reports and small series of patients have been published, these do not give a complete and balanced picture of the clinical and biochemical spectrum associated with this disorder., Methods: To improve early recognition, diagnosis, prognosis, and management of this disorder and to provide markers for life expectancy, we performed extensive biochemical studies in a large cohort of D-bifunctional protein-deficient patients and sent out questionnaires about clinical signs and symptoms to the responsible physicians., Results: Virtually all children presented with neonatal hypotonia and seizures and died within the first 2 years of life without achieving any developmental milestones. However, within our cohort, 12 patients survived beyond the age of 2 years, and detailed information on 5 patients with prolonged survival (> or =7.5 years) is provided., Interpretation: Biochemical analyses showed that there is a clear correlation between several biochemical parameters and survival of the patient, with C26:0 beta-oxidation activity in cultured skin fibroblasts being the best predictive marker for life expectancy. Remarkably, three patients were identified without biochemical abnormalities in plasma, stressing that D-bifunctional protein deficiency cannot be excluded when all peroxisomal parameters in plasma are normal.
- Published
- 2006
- Full Text
- View/download PDF
49. Peroxisomal branched chain fatty acid beta-oxidation pathway is upregulated in prostate cancer.
- Author
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Zha S, Ferdinandusse S, Hicks JL, Denis S, Dunn TA, Wanders RJ, Luo J, De Marzo AM, and Isaacs WB
- Subjects
- 17-Hydroxysteroid Dehydrogenases genetics, 17-Hydroxysteroid Dehydrogenases metabolism, Acyl-CoA Oxidase genetics, Acyl-CoA Oxidase metabolism, Carcinoma, Hepatocellular, Cell Line, Tumor, Enoyl-CoA Hydratase genetics, Enoyl-CoA Hydratase metabolism, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Hydro-Lyases, Immunohistochemistry, Liver Neoplasms, Male, Multienzyme Complexes genetics, Multienzyme Complexes metabolism, Oxidation-Reduction, Oxidoreductases metabolism, Peroxisomal Multifunctional Protein-2, Prostate enzymology, Prostatic Neoplasms genetics, RNA, Messenger analysis, Up-Regulation, Fatty Acids metabolism, Oxidoreductases genetics, Peroxisomes enzymology, Prostatic Neoplasms metabolism
- Abstract
Overexpression of alpha-methylacyl-CoA racemase (AMACR), an enzyme involved in branched chain fatty acid beta-oxidation, in prostate cancer has been reported. Here, we report that an enzyme downstream from AMACR in the peroxisomal branched chain fatty acid beta-oxidation pathway-D-bifunctional protein (DBP)-is also upregulated in prostate cancer at both mRNA and protein levels, accompanied by increased enzymatic activity. Furthermore, our data suggest that pristanoyl-CoA oxidase (ACOX3), which is expressed at extremely low level in other human organs studied including the liver, might contribute significantly to peroxisomal branched chain fatty acid beta-oxidation in human prostate tissue and some prostate cancer cell lines. In contrast to these results for peroxisomal enzymes, no significant expression changes of mitochondrial fatty acid beta-oxidation enzymes were observed in prostate cancer tissues through comprehensive quantitative RT-PCR screening. These data for the first time provide evidence for the selective over-activation of peroxisomal branched chain fatty acid beta-oxidation in prostate cancer, emphasizing a new metabolic change during prostate oncogenesis., (Copyright 2004 Wiley-Liss, Inc.)
- Published
- 2005
- Full Text
- View/download PDF
50. Identification of the peroxisomal beta-oxidation enzymes involved in the degradation of long-chain dicarboxylic acids.
- Author
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Ferdinandusse S, Denis S, Van Roermund CW, Wanders RJ, and Dacremont G
- Subjects
- Carbon Radioisotopes chemistry, Catalysis, Cells, Cultured, Fibroblasts, Humans, Kinetics, Molecular Structure, Oxidation-Reduction, Peroxisomes chemistry, Recombinant Proteins metabolism, Skin cytology, Skin metabolism, Dicarboxylic Acids chemistry, Dicarboxylic Acids metabolism, Peroxisomes enzymology
- Abstract
Dicarboxylic acids (DCAs) are omega-oxidation products of monocarboxylic acids. After activation by a dicarboxylyl-CoA synthetase, the dicarboxylyl-CoA esters are shortened via beta-oxidation. Although it has been studied extensively where this beta-oxidation process takes place, the intracellular site of DCA oxidation has remained controversial. Making use of fibroblasts from patients with defined mitochondrial and peroxisomal fatty acid oxidation defects, we show in this paper that peroxisomes, and not mitochondria, are involved in the beta-oxidation of C16DCA. Additional studies in fibroblasts from patients with X-linked adrenoleukodystrophy, straight-chain acyl-CoA oxidase (SCOX) deficiency, d-bifunctional protein (DBP) deficiency, and rhizomelic chondrodysplasia punctata type 1, together with direct enzyme measurements with human recombinant l-bifunctional protein (LBP) and DBP expressed in a fox2 deletion mutant of Saccharomyces cerevisiae, show that the main enzymes involved in beta-oxidation of C16DCA are SCOX, both LBP and DBP, and sterol carrier protein X, possibly together with the classic 3-ketoacyl-CoA thiolase. This is the first indication of a specific function for LBP, which has remained elusive until now.
- Published
- 2004
- Full Text
- View/download PDF
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