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Chen X, Cheng Q, Zhang GF. Elevated propionate and its association with neurological dysfunctions in propionic acidemia. Front Mol Neurosci 2025; 18:1499376. [PMID: 40177291 PMCID: PMC11962025 DOI: 10.3389/fnmol.2025.1499376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 03/03/2025] [Indexed: 04/05/2025] Open
Abstract
Propionate, a short-chain fatty acid (SCFA), has recently attracted attention for its various health benefits. However, elevated levels of propionate in certain pathological conditions can have adverse effects. Propionic acidemia (PA) is a rare metabolic disorder caused by mutations in the propionyl-CoA carboxylase (PCC) gene (PCCA or PCCB), leading to reduced PCC activity and impaired propionyl-CoA metabolism. This metabolic block at the PCC-mediated step results in the accumulation of propionyl-CoA and its metabolites, including propionate, contributing to various complications, such as neurological dysfunction, in patients with PA. This review examines propionate synthesis, its physiological role, its metabolism in healthy individuals and those with PA, and the pathological link between elevated propionate levels and neurological dysfunctions in PA patients. A deeper understanding of propionate metabolism under both normal and pathological conditions will help clarify the full spectrum of its metabolic effects.
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Affiliation(s)
- Xiaoxin Chen
- Surgical Research Lab, Department of Surgery, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ, United States
- Coriell Institute for Medical Research, Camden, NJ, United States
- MD Anderson Cancer Center at Cooper, Camden, NJ, United States
| | - Qing Cheng
- Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC, United States
| | - Guo-Fang Zhang
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University, Durham, NC, United States
- Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, United States
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2
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El-Kurjieh A, Al-Arab R, Hachem QA, Ibrahim JN, Kobeissy PH. ACSS2 and metabolic diseases: from lipid metabolism to therapeutic target. Lipids Health Dis 2025; 24:74. [PMID: 40001058 PMCID: PMC11853604 DOI: 10.1186/s12944-025-02491-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 02/16/2025] [Indexed: 02/27/2025] Open
Abstract
Elevated incidence of metabolic disorders has been reported worldwide in the recent decade, highlighting the need for developing efficient therapies. These diseases result from a complex interplay of various factors that contribute to disease progression, complications, and resistance to current treatment options. Acetyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) is a nucleo-cytosolic enzyme with both lipogenic and metabolic regulatory roles. Studies on ACSS2 have shown that it is involved in pathways commonly dysregulated in metabolic disorders, leading to fat deposition and disrupted cellular signaling. Although multiple studies have suggested a role of ACSS2 in the metabolic rewiring during tumorigenesis, few studies have examined its involvement in the pathophysiology of metabolic diseases. Recent evidence indicates that ACSS2 may contribute to the pathogenesis of various metabolic disorders making its examination of great interest and potentially aiding in the development of new therapeutic strategies. The objective of this review is to summarize the current understanding of ACSS2's role in metabolic disorders and its potential as a therapeutic target.
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Affiliation(s)
- Alaa El-Kurjieh
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - Reem Al-Arab
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - Qamar Abou Hachem
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - José-Noel Ibrahim
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon.
| | - Philippe Hussein Kobeissy
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon.
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3
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Yoshimura Y, Matsui T, Kaneko N, Kobayashi I. Digestion and absorption of triacetin, a short-chain triacylglycerol. Lipids 2025. [PMID: 39891375 DOI: 10.1002/lipd.12433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 01/19/2025] [Accepted: 01/21/2025] [Indexed: 02/03/2025]
Abstract
Triacylglycerol (TG) is categorized into long-, medium-, and short-chain TG (SCTG). While the digestion of long- and medium-chain TG is well established, the process for SCTG remains unclear. This study investigated SCTG digestion by administering 2 mmol of triacetin to rats and analyzing acetin, acetic acid, and glycerol levels in the portal blood and small intestine. Triacetin was fully degraded in the upper gastrointestinal tract and absorbed as acetic acid and glycerol. Glycerol influx into the liver promoted gluconeogenesis, while acetate activated AMPK, resulting in the suppression of fatty acid synthesis-related genes and the upregulation of fatty acid β-oxidation-related genes. These findings demonstrate that triacetin not only serves as a substrate for energy metabolism but also regulates hepatic gene expression, highlighting its dual role as both a metabolic substrate and signaling molecule. Triacetin thus shows potential as a dietary modulator for improving metabolic health.
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Affiliation(s)
| | - Tomoka Matsui
- Department of Nutrition, Kobe Gakuin University, Kobe City, Japan
| | - Nagisa Kaneko
- Department of Nutrition, Kobe Gakuin University, Kobe City, Japan
| | - Ikuha Kobayashi
- Department of Nutrition, Kobe Gakuin University, Kobe City, Japan
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4
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Martá-Ariza M, Leitner DF, Kanshin E, Suazo J, Giusti Pedrosa A, Thierry M, Lee EB, Devinsky O, Drummond E, Fortea J, Lleó A, Ueberheide B, Wisniewski T. Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease. Acta Neuropathol 2025; 149:9. [PMID: 39825890 PMCID: PMC11742868 DOI: 10.1007/s00401-025-02844-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/02/2025] [Accepted: 01/04/2025] [Indexed: 01/20/2025]
Abstract
Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R2 = .77), DS and LOAD (R2 = .73), and EOAD and LOAD (R2 = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 × 10-5) for DS, immune system regulation (p = 4.33 × 10-5) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R2 = .59) and LOAD (R2 = .33) compared to the correlation between EOAD and LOAD (R2 = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein-DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.
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Affiliation(s)
- Mitchell Martá-Ariza
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Dominique F Leitner
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Health and Grossman School of Medicine, New York, NY, USA
| | - Evgeny Kanshin
- Proteomics Laboratory, Division of Advanced Research Technologies, NYU Grossman School of Medicine, New York, NY, USA
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Jianina Suazo
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA
| | | | - Manon Thierry
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA
| | - Edward B Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Orrin Devinsky
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Health and Grossman School of Medicine, New York, NY, USA
| | - Eleanor Drummond
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Brain and Mind Centre and School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia
| | - Juan Fortea
- Memory Unit, Department of Neurology, Institut de Recerca Sant Pau, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain
| | - Alberto Lleó
- Memory Unit, Department of Neurology, Institut de Recerca Sant Pau, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Beatrix Ueberheide
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Proteomics Laboratory, Division of Advanced Research Technologies, NYU Grossman School of Medicine, New York, NY, USA
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Thomas Wisniewski
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA.
- Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
- Department of Psychiatry, NYU Grossman School of Medicine, New York, NY, USA.
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5
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Wang Y, Zhu S, He W, Marchuk H, Richard E, Desviat LR, Young SP, Koeberl D, Kasumov T, Chen X, Zhang GF. The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia. Basic Res Cardiol 2024; 119:1045-1062. [PMID: 38992300 PMCID: PMC11702364 DOI: 10.1007/s00395-024-01066-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 06/29/2024] [Accepted: 06/30/2024] [Indexed: 07/13/2024]
Abstract
Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca-/-(A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice. Additionally, Pcca-/-(A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.
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Affiliation(s)
- You Wang
- School of Basic Medicine, Jining Medical University, Shandong, 272067, China
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Carmichael Building 48-203, 300 North Duke Street, Durham, NC, 27701, USA
| | - Suhong Zhu
- School of Basic Medicine, Jining Medical University, Shandong, 272067, China
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Carmichael Building 48-203, 300 North Duke Street, Durham, NC, 27701, USA
| | - Wentao He
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Carmichael Building 48-203, 300 North Duke Street, Durham, NC, 27701, USA
| | - Hannah Marchuk
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Carmichael Building 48-203, 300 North Duke Street, Durham, NC, 27701, USA
| | - Eva Richard
- Centro de Biología Molecular Severo Ochoa UAM-CSIC, CIBERER, IdiPaz, IUBM, Universidad Autónoma de Madrid, Madrid, Spain
| | - Lourdes R Desviat
- Centro de Biología Molecular Severo Ochoa UAM-CSIC, CIBERER, IdiPaz, IUBM, Universidad Autónoma de Madrid, Madrid, Spain
| | - Sarah P Young
- Biochemical Genetics Laboratory, Duke University Health System, Durham, NC, USA
- Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Duke University Medical Center, Durham, NC, 27710, USA
| | - Dwight Koeberl
- Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Duke University Medical Center, Durham, NC, 27710, USA
| | - Takhar Kasumov
- Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Xiaoxin Chen
- Surgical Research Lab, Department of Surgery, Cooper University Hospital and Cooper Medical School of Rowan University, Camden, NJ, 08103, USA
- Coriell Institute for Medical Research, Camden, NJ, 08103, USA
- MD Anderson Cancer Center at Cooper, Camden, NJ, 08103, USA
| | - Guo-Fang Zhang
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Carmichael Building 48-203, 300 North Duke Street, Durham, NC, 27701, USA.
- Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Duke University Medical Center, Durham, NC, 27701, USA.
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6
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Zhang B, Guo P, Sun X, Shang Y, Luo Y, Wu H. Enhancement of lactate fraction in poly(lactate-co-3-hydroxybutyrate) biosynthesized by metabolically engineered E. coli. BIORESOUR BIOPROCESS 2024; 11:88. [PMID: 39297980 PMCID: PMC11413402 DOI: 10.1186/s40643-024-00803-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 09/05/2024] [Indexed: 09/21/2024] Open
Abstract
Poly(lactate-co-3-hydroxybutyrate) [P(LA-co-3HB)] is a high-molecular-weight biomaterial with excellent biocompatibility and biodegradability. In this study, the properties of P(LA-co-3HB) were examined and found to be affected by its lactate fraction. The efficiency of lactyl-CoA biosynthesis from intracellular lactate significantly affected the microbial synthesis of P(LA-co-3HB). Two CoA transferases from Anaerotignum lactatifermentans and Bacillota bacterium were selected for use in copolymer biosynthesis from 11 candidates. We found that cotAl enhanced the lactate fraction by 31.56% compared to that of the frequently used modified form of propionyl-CoA transferase from Anaerotignum propionicum. In addition, utilizing xylose as a favorable carbon source and blocking the lactate degradation pathway further enhanced the lactate fraction to 30.42 mol% and 52.84 mol%, respectively. Furthermore, when a 5 L bioreactor was used for fermentation utilizing xylose as a carbon source, the engineered strain produced 60.60 wt% P(46.40 mol% LA-co-3HB), which was similar to the results of our flask experiments. Our results indicate that the application of new CoA transferases has great potential for the biosynthesis of other lactate-based copolymers.
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Affiliation(s)
- Binghao Zhang
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Biotechnology, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China
| | - Pengye Guo
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Biotechnology, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China
| | - Xinye Sun
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Biotechnology, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China
| | - Yanzhe Shang
- MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian, China
| | - Yuanchan Luo
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Biotechnology, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China
| | - Hui Wu
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Biotechnology, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
- MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian, China.
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai, 200237, China.
- Key Laboratory of Bio-based Material Engineering of China, National Light Industry Council, 130 Meilong Road, Shanghai, 200237, China.
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7
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Goetzman ES, Zhang BB, Zhang Y, Bharathi SS, Bons J, Rose J, Shah S, Solo KJ, Schmidt AV, Richert AC, Mullett SJ, Gelhaus SL, Rao KS, Shiva SS, Pfister KE, Silva Barbosa A, Sims-Lucas S, Dobrowolski SF, Schilling B. Dietary dicarboxylic acids provide a nonstorable alternative fat source that protects mice against obesity. J Clin Invest 2024; 134:e174186. [PMID: 38687608 PMCID: PMC11178532 DOI: 10.1172/jci174186] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 04/23/2024] [Indexed: 05/02/2024] Open
Abstract
Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for 9 weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized by many tissues. In tissues expressing the "a" isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.
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Affiliation(s)
- Eric S. Goetzman
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Bob B. Zhang
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yuxun Zhang
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Sivakama S. Bharathi
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Joanna Bons
- The Buck Institute for Research on Aging, Novato, California, USA
| | - Jacob Rose
- The Buck Institute for Research on Aging, Novato, California, USA
| | - Samah Shah
- The Buck Institute for Research on Aging, Novato, California, USA
| | - Keaton J. Solo
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Alexandra V. Schmidt
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Adam C. Richert
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Steven J. Mullett
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Stacy L. Gelhaus
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Krithika S. Rao
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Vascular Medicine Institute and
| | - Sruti S. Shiva
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Vascular Medicine Institute and
| | - Katherine E. Pfister
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Anne Silva Barbosa
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Sunder Sims-Lucas
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Steven F. Dobrowolski
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Birgit Schilling
- The Buck Institute for Research on Aging, Novato, California, USA
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8
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Zlatic SA, Werner E, Surapaneni V, Lee CE, Gokhale A, Singleton K, Duong D, Crocker A, Gentile K, Middleton F, Dalloul JM, Liu WLY, Patgiri A, Tarquinio D, Carpenter R, Faundez V. Systemic Proteome Phenotypes Reveal Defective Metabolic Flexibility in Mecp2 Mutants. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.03.535431. [PMID: 37066332 PMCID: PMC10103972 DOI: 10.1101/2023.04.03.535431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/24/2023]
Abstract
Genes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2. Transcriptomes and proteomes of organs and brain regions from Mecp2-null mice as well as diverse MECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2- and MECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2/MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.
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Affiliation(s)
| | - Erica Werner
- Department of Cell Biology, Emory University, Atlanta, GA, USA, 30322
| | - Veda Surapaneni
- Department of Cell Biology, Emory University, Atlanta, GA, USA, 30322
| | - Chelsea E. Lee
- Department of Cell Biology, Emory University, Atlanta, GA, USA, 30322
| | - Avanti Gokhale
- Department of Cell Biology, Emory University, Atlanta, GA, USA, 30322
| | - Kaela Singleton
- Department of Cell Biology, Emory University, Atlanta, GA, USA, 30322
| | - Duc Duong
- Department of Biochemistry, Emory University, Atlanta, GA, USA, 30322
| | - Amanda Crocker
- Program in Neuroscience, Middlebury College, Middlebury, Vermont 05753
| | - Karen Gentile
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Frank Middleton
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Joseph Martin Dalloul
- Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA, USA, 30322
| | - William Li-Yun Liu
- Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA, USA, 30322
| | - Anupam Patgiri
- Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA, USA, 30322
| | | | | | - Victor Faundez
- Department of Cell Biology, Emory University, Atlanta, GA, USA, 30322
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9
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Allen SP, Al Sultan A, Kabucho Kibirige E, Tonkiss E, Hamer KJ, Castelli LM, Lin YH, Roscoe S, Stefanidis N, Mead RJ, Highley JR, Cooper-Knock J, Hautbergue GM, Heath PR, Kirby J, Shaw PJ. A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations. Front Aging Neurosci 2023; 15:1151848. [PMID: 37251807 PMCID: PMC10213779 DOI: 10.3389/fnagi.2023.1151848] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 04/18/2023] [Indexed: 05/31/2023] Open
Abstract
A p.Y374X truncation in TARDBP was recently shown to reduce expression of TDP43 in fibroblasts isolated from ALS cases. In this follow up study focused on assessing the downstream phenotypic consequences of loss of TDP43 in the context of the truncation, we have shown a striking effect on the fibroblast metabolic profile. Phenotypic metabolic screening uncovered a distinct metabolic profile in TDP43-Y374X fibroblasts compared to controls, which was driven by alterations in key metabolic checkpoint intermediates including pyruvate, alpha-ketoglutarate and succinate. These metabolic alterations were confirmed using transcriptomics and bioenergetic flux analysis. These data suggest that TDP43 truncation directly compromises glycolytic and mitochondrial function, identifying potential therapeutic targets for mitigating the effects of TDP43-Y374X truncation.
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Affiliation(s)
- Scott P. Allen
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
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10
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Xiong W, Ge H, Shen C, Li C, Zhang X, Tang L, Shen Y, Lu S, Zhang H, Wang Z. PRSS37 deficiency leads to impaired energy metabolism in testis and sperm revealed by DIA-based quantitative proteomic analysis. Reprod Sci 2023; 30:145-168. [PMID: 35471551 DOI: 10.1007/s43032-022-00918-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 03/12/2022] [Indexed: 01/11/2023]
Abstract
Our previous studies have reported that a putative trypsin-like serine protease, PRSS37, is exclusively expressed in testicular germ cells during late spermatogenesis and essential for sperm migration from the uterus into the oviduct and sperm-egg recognition via mediating the interaction between PDILT and ADAM3. In the present study, the global proteome profiles of wild-type (wt) and Prss37-/- mice in testis and sperm were compared employing data independent acquisition (DIA) technology. Overall, 2506 and 459 differentially expressed proteins (DEPs) were identified in Prss37-null testis and sperm, respectively, when compared to control groups. Bioinformatic analyses revealed that most of DEPs were related to energy metabolism. Of note, the DEPs associated with pathways for the catabolism such as glucose via glycolysis, fatty acids via β-oxidation, and amino acids via oxidative deamination were significantly down-regulated. Meanwhile, the DEPs involved in the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation (OXPHOS) were remarkably decreased. The DIA data were further confirmed by a markedly reduction of intermediate metabolites (citrate and fumarate) in TCA cycle and terminal metabolite (ATP) in OXPHOS system after disruption of PRSS37. These outcomes not only provide a more comprehensive understanding of the male fertility of energy metabolism modulated by PRSS37 but also furnish a dynamic proteomic resource for further reproductive biology studies.
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Affiliation(s)
- Wenfeng Xiong
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Haoyang Ge
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Chunling Shen
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China.
| | - Chaojie Li
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Xiaohong Zhang
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Lingyun Tang
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Yan Shen
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Shunyuan Lu
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Hongxin Zhang
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Zhugang Wang
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China.
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11
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Methanol fixed feeder layers altered the pluripotency and metabolism of bovine pluripotent stem cells. Sci Rep 2022; 12:9177. [PMID: 35654935 PMCID: PMC9163156 DOI: 10.1038/s41598-022-13249-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 05/23/2022] [Indexed: 11/22/2022] Open
Abstract
The pluripotency maintenance of pluripotent stem cells (PSCs) requires the suitable microenvironment, which commonly provided by feeder layers. However, the preparation of feeder layers is time consuming and labor exhaustive, and the feeder cells treated with mitomycin C or γ-ray irradiation bring heterologous contamination. In this study, mouse embryonic fibroblasts (MEFs) were treated by methanol to generate chemical fixed feeder cells, and bovine embryonic stem cells F7 (bESC-F7) cultured on this feeder layer. Then the pluripotency and metabolism of bESC-F7 cultured on methanol-fixed MEFs (MT-MEFs) named MT-F7 was compared with mitomycin C treated MEFs (MC-MEFs). The results showed that bESC-F7 formed alkaline phosphatase positive colonies on MT-MEFs, the relative expression of pluripotent markers of these cells was different from the bESCs cultured on the MC-MEFs (MC-F7). The long-term cultured MT-F7 formed embryoid bodies, showed the ability to differentiate into three germ layers similar to MC-F7. The analyses of RNA-seq data showed that MT-MEFs lead bESCs to novel steady expression patterns of genes regulating pluripotency and metabolism. Furthermore, the bovine expanded pluripotent stem cells (bEPSCs) cultured on MT-MEFs formed classical colonies, maintained pluripotency, and elevated metabolism. In conclusion, MT-MEFs were efficient feeder layer that maintain the distinctive pluripotency and metabolism of PSCs.
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12
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Kim SQ, Mohallem R, Franco J, Buhman KK, Kim KH, Aryal UK. Multi-Omics Approach Reveals Dysregulation of Protein Phosphorylation Correlated with Lipid Metabolism in Mouse Non-Alcoholic Fatty Liver. Cells 2022; 11:cells11071172. [PMID: 35406736 PMCID: PMC8997945 DOI: 10.3390/cells11071172] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/24/2022] [Accepted: 03/26/2022] [Indexed: 02/04/2023] Open
Abstract
Obesity caused by overnutrition is a major risk factor for non-alcoholic fatty liver disease (NAFLD). Several lipid intermediates such as fatty acids, glycerophospholipids and sphingolipids are implicated in NAFLD, but detailed characterization of lipids and their functional links to proteome and phosphoproteome remain to be elucidated. To characterize this complex molecular relationship, we used a multi-omics approach by conducting comparative proteomic, phoshoproteomic and lipidomic analyses of high fat (HFD) and low fat (LFD) diet fed mice livers. We quantified 2447 proteins and 1339 phosphoproteins containing 1650 class I phosphosites, of which 669 phosphosites were significantly different between HFD and LFD mice livers. We detected alterations of proteins associated with cellular metabolic processes such as small molecule catabolic process, monocarboxylic acid, long- and medium-chain fatty acid, and ketone body metabolic processes, and peroxisome organization. We observed a significant downregulation of protein phosphorylation in HFD fed mice liver in general. Untargeted lipidomics identified upregulation of triacylglycerols, glycerolipids and ether glycerophosphocholines and downregulation of glycerophospholipids, such as lysoglycerophospholipids, as well as ceramides and acylcarnitines. Analysis of differentially regulated phosphosites revealed phosphorylation dependent deregulation of insulin signaling as well as lipogenic and lipolytic pathways during HFD induced obesity. Thus, this study reveals a molecular connection between decreased protein phosphorylation and lipolysis, as well as lipid-mediated signaling in diet-induced obesity.
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Affiliation(s)
- Sora Q. Kim
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA; (S.Q.K.); (K.K.B.)
| | - Rodrigo Mohallem
- Bindley Bioscience Center, Purdue Proteomics Facility, Purdue University, West Lafayette, IN 47907, USA; (R.M.); (J.F.)
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA
| | - Jackeline Franco
- Bindley Bioscience Center, Purdue Proteomics Facility, Purdue University, West Lafayette, IN 47907, USA; (R.M.); (J.F.)
| | - Kimberly K. Buhman
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA; (S.Q.K.); (K.K.B.)
| | - Kee-Hong Kim
- Department of Food Science, Purdue University, West Lafayette, IN 47907, USA;
| | - Uma K. Aryal
- Bindley Bioscience Center, Purdue Proteomics Facility, Purdue University, West Lafayette, IN 47907, USA; (R.M.); (J.F.)
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA
- Correspondence: ; Tel.: +1-765-494-4960
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13
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Ma Y, Nenkov M, Chen Y, Press AT, Kaemmerer E, Gassler N. Fatty acid metabolism and acyl-CoA synthetases in the liver-gut axis. World J Hepatol 2021; 13:1512-1533. [PMID: 34904027 PMCID: PMC8637682 DOI: 10.4254/wjh.v13.i11.1512] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/28/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
Fatty acids are energy substrates and cell components which participate in regulating signal transduction, transcription factor activity and secretion of bioactive lipid mediators. The acyl-CoA synthetases (ACSs) family containing 26 family members exhibits tissue-specific distribution, distinct fatty acid substrate preferences and diverse biological functions. Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis, designated as the bidirectional relationship between the gut, microbiome and liver, is closely associated with a range of human diseases including metabolic disorders, inflammatory disease and carcinoma in the gastrointestinal tract and liver. In this review, we depict the role of ACSs in fatty acid metabolism, possible molecular mechanisms through which they exert functions, and their involvement in hepatocellular and colorectal carcinoma, with particular attention paid to long-chain fatty acids and small-chain fatty acids. Additionally, the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed. Moreover, the development of potentially therapeutic small molecules, proteins and compounds targeting ACSs in cancer treatment is summarized.
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Affiliation(s)
- Yunxia Ma
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Miljana Nenkov
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Adrian T Press
- Department of Anesthesiology and Intensive Care Medicine and Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Elke Kaemmerer
- Department of Pediatrics, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany.
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14
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Weitkunat K, Bishop CA, Wittmüss M, Machate T, Schifelbein T, Schulze MB, Klaus S. Effect of Microbial Status on Hepatic Odd-Chain Fatty Acids Is Diet-Dependent. Nutrients 2021; 13:nu13051546. [PMID: 34064336 PMCID: PMC8147859 DOI: 10.3390/nu13051546] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 11/16/2022] Open
Abstract
Odd-chain fatty acids (OCFA) are inversely associated with type-2-diabetes in epidemiological studies. They are considered as a biomarker for dairy intake because fermentation in ruminants yields high amounts of propionate, which is used as the primer for lipogenesis. Recently, we demonstrated endogenous OCFA synthesis from propionate in humans and mice, but how this is affected by microbial colonization is still unexplored. Here, we investigated the effect of increasing microbiota complexity on hepatic lipid metabolism and OCFA levels in different dietary settings. Germ-free (GF), gnotobiotic (SIH, simplified human microbiota) or conventional (CONV) C3H/HeOuJ-mice were fed a CHOW or high-fat diet with inulin (HFI) to induce microbial fermentation. We found that hepatic lipogenesis was increased with increasing microbiota complexity, independently of diet. In contrast, OCFA formation was affected by diet as well as microbiota. On CHOW, hepatic OCFA and intestinal gluconeogenesis decreased with increasing microbiota complexity (GF > SIH > CONV), while cecal propionate showed a negative correlation with hepatic OCFA. On HFI, OCFA levels were highest in SIH and positively correlated with cecal propionate. The propionate content in the CHOW diet was 10 times higher than that of HFI. We conclude that bacterial propionate production affects hepatic OCFA formation, unless this effect is masked by dietary propionate intake.
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Affiliation(s)
- Karolin Weitkunat
- Department Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (C.A.B.); (M.W.); (T.M.); (S.K.)
- Correspondence:
| | - Christopher A. Bishop
- Department Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (C.A.B.); (M.W.); (T.M.); (S.K.)
| | - Maria Wittmüss
- Department Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (C.A.B.); (M.W.); (T.M.); (S.K.)
| | - Tina Machate
- Department Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (C.A.B.); (M.W.); (T.M.); (S.K.)
| | - Tina Schifelbein
- Research Group Intestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany;
| | - Matthias B. Schulze
- Department Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany;
- Institute of Nutritional Science, University of Potsdam, 14469 Potsdam, Germany
| | - Susanne Klaus
- Department Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (C.A.B.); (M.W.); (T.M.); (S.K.)
- Institute of Nutritional Science, University of Potsdam, 14469 Potsdam, Germany
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15
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Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan. Antioxidants (Basel) 2021; 10:antiox10040572. [PMID: 33917812 PMCID: PMC8068152 DOI: 10.3390/antiox10040572] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/16/2022] Open
Abstract
Acetyl-CoA is a metabolite at the crossroads of central metabolism and the substrate of histone acetyltransferases regulating gene expression. In many tissues fasting or lifespan extending calorie restriction (CR) decreases glucose-derived metabolic flux through ATP-citrate lyase (ACLY) to reduce cytoplasmic acetyl-CoA levels to decrease activity of the p300 histone acetyltransferase (HAT) stimulating pro-longevity autophagy. Because of this, compounds that decrease cytoplasmic acetyl-CoA have been described as CR mimetics. But few authors have highlighted the potential longevity promoting roles of nuclear acetyl-CoA. For example, increasing nuclear acetyl-CoA levels increases histone acetylation and administration of class I histone deacetylase (HDAC) inhibitors increases longevity through increased histone acetylation. Therefore, increased nuclear acetyl-CoA likely plays an important role in promoting longevity. Although cytoplasmic acetyl-CoA synthetase 2 (ACSS2) promotes aging by decreasing autophagy in some peripheral tissues, increased glial AMPK activity or neuronal differentiation can stimulate ACSS2 nuclear translocation and chromatin association. ACSS2 nuclear translocation can result in increased activity of CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and other HATs to increase histone acetylation on the promoter of neuroprotective genes including transcription factor EB (TFEB) target genes resulting in increased lysosomal biogenesis and autophagy. Much of what is known regarding acetyl-CoA metabolism and aging has come from pioneering studies with yeast, fruit flies, and nematodes. These studies have identified evolutionary conserved roles for histone acetylation in promoting longevity. Future studies should focus on the role of nuclear acetyl-CoA and histone acetylation in the control of hypothalamic inflammation, an important driver of organismal aging.
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16
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Lagerwaard B, Pougovkina O, Bekebrede AF, te Brinke H, Wanders RJ, Nieuwenhuizen AG, Keijer J, de Boer VCJ. Increased protein propionylation contributes to mitochondrial dysfunction in liver cells and fibroblasts, but not in myotubes. J Inherit Metab Dis 2021; 44:438-449. [PMID: 32740932 PMCID: PMC8049071 DOI: 10.1002/jimd.12296] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/14/2020] [Accepted: 07/30/2020] [Indexed: 12/22/2022]
Abstract
Post-translational protein modifications derived from metabolic intermediates, such as acyl-CoAs, have been shown to regulate mitochondrial function. Patients with a genetic defect in the propionyl-CoA carboxylase (PCC) gene clinically present symptoms related to mitochondrial disorders and are characterised by decreased mitochondrial respiration. Since propionyl-CoA accumulates in PCC deficient patients and protein propionylation can be driven by the level of propionyl-CoA, we hypothesised that protein propionylation could play a role in the pathology of the disease. Indeed, we identified increased protein propionylation due to pathologic propionyl-CoA accumulation in patient-derived fibroblasts and this was accompanied by defective mitochondrial respiration, as was shown by a decrease in complex I-driven respiration. To mimic pathological protein propionylation levels, we exposed cultured fibroblasts, Fao liver cells and C2C12 muscle myotubes to propionate levels that are typically found in these patients. This induced a global increase in protein propionylation and histone protein propionylation and was also accompanied by a decrease in mitochondrial respiration in liver and fibroblasts. However, in C2C12 myotubes propionate exposure did not decrease mitochondrial respiration, possibly due to differences in propionyl-CoA metabolism as compared to the liver. Therefore, protein propionylation could contribute to the pathology in these patients, especially in the liver, and could therefore be an interesting target to pursue in the treatment of this metabolic disease.
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Affiliation(s)
- Bart Lagerwaard
- Human and Animal Physiology, Wageningen University and ResearchWageningenNetherlands
- TI Food and NutritionWageningenNetherlands
| | - Olga Pougovkina
- Laboratory Genetic Metabolic Diseases, Department of Clinical ChemistryAcademic Medical Center, University of AmsterdamAmsterdamNetherlands
| | - Anna F. Bekebrede
- Human and Animal Physiology, Wageningen University and ResearchWageningenNetherlands
| | - Heleen te Brinke
- Laboratory Genetic Metabolic Diseases, Department of Clinical ChemistryAcademic Medical Center, University of AmsterdamAmsterdamNetherlands
| | - Ronald J.A. Wanders
- Laboratory Genetic Metabolic Diseases, Department of Clinical ChemistryAcademic Medical Center, University of AmsterdamAmsterdamNetherlands
- Department of PediatricsEmma Children's Hospital, Academic Medical Center, University of AmsterdamAmsterdamNetherlands
| | - Arie G. Nieuwenhuizen
- Human and Animal Physiology, Wageningen University and ResearchWageningenNetherlands
| | - Jaap Keijer
- Human and Animal Physiology, Wageningen University and ResearchWageningenNetherlands
| | - Vincent C. J. de Boer
- Human and Animal Physiology, Wageningen University and ResearchWageningenNetherlands
- Laboratory Genetic Metabolic Diseases, Department of Clinical ChemistryAcademic Medical Center, University of AmsterdamAmsterdamNetherlands
- Department of PediatricsEmma Children's Hospital, Academic Medical Center, University of AmsterdamAmsterdamNetherlands
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17
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Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling. Cancers (Basel) 2021; 13:cancers13040706. [PMID: 33572349 PMCID: PMC7916108 DOI: 10.3390/cancers13040706] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Melanotic neuroectodermal tumor of infancy (MNTI) is a rare tumor of uncertain origin, morphologically overlapping other rare neoplasms such as pineal anlage tumor (PAT) and a subset of medulloblastomas (i.e., melanotic medulloblastoma). Despite the similarities with MNTI, their possible histogenetic relationship has been traditionally disregarded based on their aggressive behavior and dismal prognosis. The aim of this study was to further characterize the molecular features of MNTI and PAT based on DNA-methylation and copy number variation profiling analysis. We found that MNTI shares a methylation profile with group 3 high-risk medulloblastoma, and potentially with PAT, suggesting a common histogenesis. Most MNTIs in our series lacked copy number variation alterations, whereas their presence in the one PAT deserves further study in larger cohorts to better determine their impact in prognosis and biologic behavior. Abstract MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients’ mean age was 8 months (range: 4–48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation.
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18
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Moffett JR, Puthillathu N, Vengilote R, Jaworski DM, Namboodiri AM. Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics and Oncogenesis-Part 1: Acetyl-CoA, Acetogenesis and Acyl-CoA Short-Chain Synthetases. Front Physiol 2020; 11:580167. [PMID: 33281616 PMCID: PMC7689297 DOI: 10.3389/fphys.2020.580167] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 09/23/2020] [Indexed: 12/19/2022] Open
Abstract
Acetate is a major end product of bacterial fermentation of fiber in the gut. Acetate, whether derived from the diet or from fermentation in the colon, has been implicated in a range of health benefits. Acetate is also generated in and released from various tissues including the intestine and liver, and is generated within all cells by deacetylation reactions. To be utilized, all acetate, regardless of the source, must be converted to acetyl coenzyme A (acetyl-CoA), which is carried out by enzymes known as acyl-CoA short-chain synthetases. Acyl-CoA short-chain synthetase-2 (ACSS2) is present in the cytosol and nuclei of many cell types, whereas ACSS1 is mitochondrial, with greatest expression in heart, skeletal muscle, and brown adipose tissue. In addition to acting to redistribute carbon systemically like a ketone body, acetate is becoming recognized as a cellular regulatory molecule with diverse functions beyond the formation of acetyl-CoA for energy derivation and lipogenesis. Acetate acts, in part, as a metabolic sensor linking nutrient balance and cellular stress responses with gene transcription and the regulation of protein function. ACSS2 is an important task-switching component of this sensory system wherein nutrient deprivation, hypoxia and other stressors shift ACSS2 from a lipogenic role in the cytoplasm to a regulatory role in the cell nucleus. Protein acetylation is a critical post-translational modification involved in regulating cell behavior, and alterations in protein acetylation status have been linked to multiple disease states, including cancer. Improving our fundamental understanding of the "acetylome" and how acetate is generated and utilized at the subcellular level in different cell types will provide much needed insight into normal and neoplastic cellular metabolism and the epigenetic regulation of phenotypic expression under different physiological stressors. This article is Part 1 of 2 - for Part 2 see doi: 10.3389/fphys.2020.580171.
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Affiliation(s)
- John R. Moffett
- Department of Anatomy, Physiology and Genetics, and Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Narayanan Puthillathu
- Department of Anatomy, Physiology and Genetics, and Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Ranjini Vengilote
- Department of Anatomy, Physiology and Genetics, and Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Diane M. Jaworski
- Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, United States
| | - Aryan M. Namboodiri
- Department of Anatomy, Physiology and Genetics, and Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
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19
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Moffett JR, Puthillathu N, Vengilote R, Jaworski DM, Namboodiri AM. Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics, and Oncogenesis - Part 2: Acetate and ACSS2 in Health and Disease. Front Physiol 2020; 11:580171. [PMID: 33304273 PMCID: PMC7693462 DOI: 10.3389/fphys.2020.580171] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 10/19/2020] [Indexed: 12/19/2022] Open
Abstract
Acetate, the shortest chain fatty acid, has been implicated in providing health benefits whether it is derived from the diet or is generated from microbial fermentation of fiber in the gut. These health benefits range widely from improved cardiac function to enhanced red blood cell generation and memory formation. Understanding how acetate could influence so many disparate biological functions is now an area of intensive research. Protein acetylation is one of the most common post-translational modifications and increased systemic acetate strongly drives protein acetylation. By virtue of acetylation impacting the activity of virtually every class of protein, acetate driven alterations in signaling and gene transcription have been associated with several common human diseases, including cancer. In part 2 of this review, we will focus on some of the roles that acetate plays in health and human disease. The acetate-activating enzyme acyl-CoA short-chain synthetase family member 2 (ACSS2) will be a major part of that focus due to its role in targeted protein acetylation reactions that can regulate central metabolism and stress responses. ACSS2 is the only known enzyme that can recycle acetate derived from deacetylation reactions in the cytoplasm and nucleus of cells, including both protein and metabolite deacetylation reactions. As such, ACSS2 can recycle acetate derived from histone deacetylase reactions as well as protein deacetylation reactions mediated by sirtuins, among many others. Notably, ACSS2 can activate acetate released from acetylated metabolites including N-acetylaspartate (NAA), the most concentrated acetylated metabolite in the human brain. NAA has been associated with the metabolic reprograming of cancer cells, where ACSS2 also plays a role. Here, we discuss the context-specific roles that acetate can play in health and disease.
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Affiliation(s)
- John R. Moffett
- Department of Anatomy, Physiology and Genetics, and Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Narayanan Puthillathu
- Department of Anatomy, Physiology and Genetics, and Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Ranjini Vengilote
- Department of Anatomy, Physiology and Genetics, and Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Diane M. Jaworski
- Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, United States
| | - Aryan M. Namboodiri
- Department of Anatomy, Physiology and Genetics, and Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
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20
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Odera JO, Xiong Z, Huang C, Gu N, Yang W, Githang’a J, Odera E, Paiboonrungruang C, Chen X. NRF2/ACSS2 axis mediates the metabolic effect of alcohol drinking on esophageal squamous cell carcinoma. Biochem J 2020; 477:3075-3089. [PMID: 32776152 PMCID: PMC7590234 DOI: 10.1042/bcj20200452] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/01/2020] [Accepted: 08/07/2020] [Indexed: 12/24/2022]
Abstract
Alcohol drinking is a leading risk factor for the development of esophageal squamous cell carcinoma (ESCC). However, the molecular mechanisms of alcohol-associated ESCC remain poorly understood. One of the most commonly mutated genes in ESCC is nuclear factor erythroid 2 like 2 (NFE2L2 or NRF2), which is a critical transcription factor regulating oxidative stress response and drug detoxification. When NRF2 is hyperactive in cancer cells, however, it leads to metabolic reprogramming, cell proliferation, chemoradioresistance, and poor prognosis. In this study, hyperactive NRF2 was found to up-regulate acetyl-CoA synthetase short-chain family members 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in ESCC cells and mouse esophagus. We also showed that knockdown of NRF2 or ACSS2 led to decreased ACSS2 expression, which in turn reduced the levels of acetyl-CoA and ATP with or without ethanol exposure. In addition, ethanol exposure enhanced lipid synthesis in ESCC cells. Moreover, we observed a change in the metabolic profile of ESCC cells exposed to ethanol as a result of their NRF2 or ACSS2 status. We further showed that ACSS2 contributed to the invasive capability of NRF2high ESCC cells exposed to ethanol. In conclusion, the NRF2/ACSS2 axis mediates the metabolic effect of alcohol drinking on ESCC.
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Affiliation(s)
- Joab Otieno Odera
- Cancer Research Program, Julius L Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
- Integrated Biosciences PhD Program, North Carolina Central University, Durham, NC 27707, USA
| | - Zhaohui Xiong
- Cancer Research Program, Julius L Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Caizhi Huang
- Cancer Research Program, Julius L Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Ning Gu
- Cancer Research Program, Julius L Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Wenjun Yang
- Key Laboratory of Fertility Preservation and Maintenance, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, China
| | - Jessie Githang’a
- Department of Human Pathology, University of Nairobi, Nairobi, Kenya
| | - Elizabeth Odera
- Department of Human Pathology, University of Nairobi, Nairobi, Kenya
| | - Chorlada Paiboonrungruang
- Cancer Research Program, Julius L Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Xiaoxin Chen
- Cancer Research Program, Julius L Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
- Center for Esophageal Disease and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27519, USA
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21
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Trefely S, Lovell CD, Snyder NW, Wellen KE. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation. Mol Metab 2020; 38:100941. [PMID: 32199817 PMCID: PMC7300382 DOI: 10.1016/j.molmet.2020.01.005] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/03/2020] [Accepted: 01/07/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Many metabolites serve as important signalling molecules to adjust cellular activities and functions based on nutrient availability. Links between acetyl-CoA metabolism, histone lysine acetylation, and gene expression have been documented and studied over the past decade. In recent years, several additional acyl modifications to histone lysine residues have been identified, which depend on acyl-coenzyme A thioesters (acyl-CoAs) as acyl donors. Acyl-CoAs are intermediates of multiple distinct metabolic pathways, and substantial evidence has emerged that histone acylation is metabolically sensitive. Nevertheless, the metabolic sources of acyl-CoAs used for chromatin modification in most cases remain poorly understood. Elucidating how these diverse chemical modifications are coupled to and regulated by cellular metabolism is important in deciphering their functional significance. SCOPE OF REVIEW In this article, we review the metabolic pathways that produce acyl-CoAs, as well as emerging evidence for functional roles of diverse acyl-CoAs in chromatin regulation. Because acetyl-CoA has been extensively reviewed elsewhere, we will focus on four other acyl-CoA metabolites integral to major metabolic pathways that are also known to modify histones: succinyl-CoA, propionyl-CoA, crotonoyl-CoA, and butyryl-CoA. We also briefly mention several other acyl-CoA species, which present opportunities for further research; malonyl-CoA, glutaryl-CoA, 3-hydroxybutyryl-CoA, 2-hydroxyisobutyryl-CoA, and lactyl-CoA. Each acyl-CoA species has distinct roles in metabolism, indicating the potential to report shifts in the metabolic status of the cell. For each metabolite, we consider the metabolic pathways in which it participates and the nutrient sources from which it is derived, the compartmentalisation of its metabolism, and the factors reported to influence its abundance and potential nuclear availability. We also highlight reported biological functions of these metabolically-linked acylation marks. Finally, we aim to illuminate key questions in acyl-CoA metabolism as they relate to the control of chromatin modification. MAJOR CONCLUSIONS A majority of acyl-CoA species are annotated to mitochondrial metabolic processes. Since acyl-CoAs are not known to be directly transported across mitochondrial membranes, they must be synthesized outside of mitochondria and potentially within the nucleus to participate in chromatin regulation. Thus, subcellular metabolic compartmentalisation likely plays a key role in the regulation of histone acylation. Metabolite tracing in combination with targeting of relevant enzymes and transporters will help to map the metabolic pathways that connect acyl-CoA metabolism to chromatin modification. The specific function of each acyl-CoA may be determined in part by biochemical properties that affect its propensity for enzymatic versus non-enzymatic protein modification, as well as the various enzymes that can add, remove and bind each modification. Further, competitive and inhibitory effects of different acyl-CoA species on these enzymes make determining the relative abundance of acyl-CoA species in specific contexts important to understand the regulation of chromatin acylation. An improved and more nuanced understanding of metabolic regulation of chromatin and its roles in physiological and disease-related processes will emerge as these questions are answered.
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Affiliation(s)
- Sophie Trefely
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Metabolic Disease Research, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Claudia D Lovell
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nathaniel W Snyder
- Center for Metabolic Disease Research, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
| | - Kathryn E Wellen
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
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22
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Gene co-expression networks are associated with obesity-related traits in kidney transplant recipients. BMC Med Genomics 2020; 13:37. [PMID: 32151267 PMCID: PMC7063809 DOI: 10.1186/s12920-020-0702-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 02/27/2020] [Indexed: 12/02/2022] Open
Abstract
Background Obesity is common among kidney transplant recipients; However biological mediators of obesity are not well understood in this population. Because subcutaneous adipose tissue can be easily obtained during kidney transplant surgery, it provides a unique avenue for studying the mechanisms of obesity for this group. Although differential gene expression patterns were previously profiled for kidney transplant patients, gene co-expression patterns can shed light on gene modules not yet explored on the coordinative behaviors of gene transcription in biological and disease processes from a systems perspective. Methods In this study, we collected 29 demographic and clinical variables and matching microarray expression data for 26 kidney transplant patients. We conducted Weighted Gene Correlation Network Analysis (WGCNA) for 5758 genes with the highest average expression levels and related gene co-expression to clinical traits. Results A total of 35 co-expression modules were detected, two of which showed associations with obesity-related traits, mainly at baseline. Gene Ontology (GO) enrichment was found for these two clinical trait-associated modules. One module consisting of 129 genes was enriched for a variety of processes, including cellular homeostasis and immune responses. The other module consisting of 36 genes was enriched for tissue development processes. Conclusions Our study generated gene co-expression modules associated with obesity-related traits in kidney transplant patients and provided new insights regarding the cellular biological processes underlying obesity in this population.
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23
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RNA-Seq Study of Hepatic Response of Yellow-Feather Chickens to Acute Heat Stress. ANNALS OF ANIMAL SCIENCE 2020. [DOI: 10.2478/aoas-2019-0060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Abstract
The yellow-feather broiler is a popular poultry breed in Asia, particularly in China. In this study, we performed RNA-seq analysis to identify differentially expressed genes (deGs) in the liver of yellow-feather broilers that had been subjected to acute heat stress treatment (38±1°C for 4 h, recovery 2 h) and determine the response of the liver to high temperature and its effects on yellow-feather broiler physiology. We found that the cloacal temperature and respiratory rate of yellow-feather chickens were significantly increased immediately after the initiation of acute heat stress (38°c) treatment. And after recovery for 2 h, there was no difference in the cloacal temperature and respiratory rate between the acute heat stress and control groups. A total of 834 DEGs were observed in response to heat stress by RNA-seq. Almost half of the DEGs were involved in the lipid and energy metabolism, including fatty acid metabolism (ACOX1, ACACA, ACSL1, ACSL6, ACAA1, ACAA2, HADHB, and FASN) and propanoate metabolism (ACSS2, ALDH2, ACACA, DLAT, ALDH7A1, MDH1, ME1, ABAT, SUCLG2, and ACSS3). Our findings provide the context for RNA-seq studies in the liver of yellow-feather chickens and suggest that the liver of yellow-feather broilers has the lipid and energy metabolism physiological mechanisms activated in response to heat stress.
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24
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Arpón A, Milagro FI, Ramos-Lopez O, Mansego ML, Riezu-Boj JI, Martínez JA. Methylome-Wide Association Study in Peripheral White Blood Cells Focusing on Central Obesity and Inflammation. Genes (Basel) 2019; 10:444. [PMID: 31212707 PMCID: PMC6627499 DOI: 10.3390/genes10060444] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 06/03/2019] [Accepted: 06/07/2019] [Indexed: 12/13/2022] Open
Abstract
Epigenetic signatures such as DNA methylation may be associated with specific obesity traits in different tissues. The onset and development of some obesity-related complications are often linked to visceral fat accumulation. The aim of this study was to explore DNA methylation levels in peripheral white blood cells to identify epigenetic methylation marks associated with waist circumference (WC). DNA methylation levels were assessed using Infinium Human Methylation 450K and MethylationEPIC beadchip (Illumina) to search for putative associations with WC values of 473 participants from the Methyl Epigenome Network Association (MENA) project. Statistical analysis and Ingenuity Pathway Analysis (IPA) were employed for assessing the relationship between methylation and WC. A total of 669 CpGs were statistically associated with WC (FDR < 0.05, slope ≥ |0.1|). From these CpGs, 375 CpGs evidenced a differential methylation pattern between females with WC ≤ 88 and > 88 cm, and 95 CpGs between males with WC ≤ 102 and > 102 cm. These differentially methylated CpGs are located in genes related to inflammation and obesity according to IPA. Receiver operating characteristic (ROC) curves of the top four significant differentially methylated CpGs separated by sex discriminated individuals with presence or absence of abdominal fat. ROC curves of all the CpGs from females and one CpG from males were validated in an independent sample (n = 161). These methylation results add further insights about the relationships between obesity, adiposity-associated comorbidities, and DNA methylation where inflammation processes may be involved.
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Affiliation(s)
- Ana Arpón
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, Irunlarrea 1,31008 Pamplona, Spain.
- Centre for Nutrition Research, University of Navarra, Irunlarrea 1, 31008, Pamplona, Spain.
| | - Fermín I Milagro
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, Irunlarrea 1,31008 Pamplona, Spain.
- Centre for Nutrition Research, University of Navarra, Irunlarrea 1, 31008, Pamplona, Spain.
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain.
- Navarra Institute for Health Research (IdiSNa), 31008, Pamplona, Spain.
| | - Omar Ramos-Lopez
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, Irunlarrea 1,31008 Pamplona, Spain.
- Centre for Nutrition Research, University of Navarra, Irunlarrea 1, 31008, Pamplona, Spain.
| | - Maria L Mansego
- Department of Bioinformatics, Making Genetics S.L., 31002, Pamplona, Spain.
| | - José-Ignacio Riezu-Boj
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, Irunlarrea 1,31008 Pamplona, Spain.
- Centre for Nutrition Research, University of Navarra, Irunlarrea 1, 31008, Pamplona, Spain.
- Navarra Institute for Health Research (IdiSNa), 31008, Pamplona, Spain.
| | - J Alfredo Martínez
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, Irunlarrea 1,31008 Pamplona, Spain.
- Centre for Nutrition Research, University of Navarra, Irunlarrea 1, 31008, Pamplona, Spain.
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain.
- Navarra Institute for Health Research (IdiSNa), 31008, Pamplona, Spain.
- Precision Nutrition and Cardiometabolic Health Program, Madrid Institute for Advanced Studies (IMDEA), IMDEA Food, 28049, Madrid, Spain.
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25
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Chambers ES, Byrne CS, Rugyendo A, Morrison DJ, Preston T, Tedford C, Bell JD, Thomas L, Akbar AN, Riddell NE, Sharma R, Thursz MR, Manousou P, Frost G. The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease. Diabetes Obes Metab 2019; 21:372-376. [PMID: 30098126 PMCID: PMC6667894 DOI: 10.1111/dom.13500] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/30/2018] [Accepted: 08/07/2018] [Indexed: 12/19/2022]
Abstract
The short chain fatty acid (SCFA) propionate, produced through fermentation of dietary fibre by the gut microbiota, has been shown to alter hepatic metabolic processes that reduce lipid storage. We aimed to investigate the impact of raising colonic propionate production on hepatic steatosis in adults with non-alcoholic fatty liver disease (NAFLD). Eighteen adults were randomized to receive 20 g/d of an inulin-propionate ester (IPE), designed to deliver propionate to the colon, or an inulin control for 42 days in a parallel design. The change in intrahepatocellular lipid (IHCL) following the supplementation period was not different between the groups (P = 0.082), however, IHCL significantly increased within the inulin-control group (20.9% ± 2.9% to 26.8% ± 3.9%; P = 0.012; n = 9), which was not observed within the IPE group (22.6% ± 6.9% to 23.5% ± 6.8%; P = 0.635; n = 9). The predominant SCFA from colonic fermentation of inulin is acetate, which, in a background of NAFLD and a hepatic metabolic profile that promotes fat accretion, may provide surplus lipogenic substrate to the liver. The increased colonic delivery of propionate from IPE appears to attenuate this acetate-mediated increase in IHCL.
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Affiliation(s)
- Edward S. Chambers
- Section for Nutrition Research, Faculty of MedicineImperial College London, Hammersmith HospitalLondonUK
| | - Claire S. Byrne
- Section for Nutrition Research, Faculty of MedicineImperial College London, Hammersmith HospitalLondonUK
| | - Annette Rugyendo
- Section for Nutrition Research, Faculty of MedicineImperial College London, Hammersmith HospitalLondonUK
| | - Douglas J. Morrison
- Stable Isotope Biochemistry LaboratoryScottish Universities Environmental Research Centre, University of GlasgowGlasgowUK
| | - Tom Preston
- Stable Isotope Biochemistry LaboratoryScottish Universities Environmental Research Centre, University of GlasgowGlasgowUK
| | | | - Jimmy D. Bell
- Department of Life Sciences, Faculty of Science and Technology, Research Centre for Optimal HealthUniversity of WestminsterLondonUK
| | - Louise Thomas
- Department of Life Sciences, Faculty of Science and Technology, Research Centre for Optimal HealthUniversity of WestminsterLondonUK
| | - Arne N. Akbar
- Division of Infection and ImmunityUniversity College LondonLondonUK
| | | | - Rohini Sharma
- Department of Surgery and CancerImperial College LondonLondonUK
| | - Mark R. Thursz
- Department of Surgery and CancerImperial College LondonLondonUK
| | | | - Gary Frost
- Section for Nutrition Research, Faculty of MedicineImperial College London, Hammersmith HospitalLondonUK
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26
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Appu AP, Moffett JR, Arun P, Moran S, Nambiar V, Krishnan JKS, Puthillathu N, Namboodiri AMA. Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease. Front Mol Neurosci 2017; 10:161. [PMID: 28626388 PMCID: PMC5454052 DOI: 10.3389/fnmol.2017.00161] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 05/09/2017] [Indexed: 01/03/2023] Open
Abstract
Canavan disease is caused by mutations in the gene encoding aspartoacylase (ASPA), a deacetylase that catabolizes N-acetylaspartate (NAA). The precise involvement of elevated NAA in the pathogenesis of Canavan disease is an ongoing debate. In the present study, we tested the effects of elevated NAA in the brain during postnatal development. Mice were administered high doses of the hydrophobic methyl ester of NAA (M-NAA) twice daily starting on day 7 after birth. This treatment increased NAA levels in the brain to those observed in the brains of Nur7 mice, an established model of Canavan disease. We evaluated various serological parameters, oxidative stress, inflammatory and neurodegeneration markers and the results showed that there were no pathological alterations in any measure with increased brain NAA levels. We examined oxidative stress markers, malondialdehyde content (indicator of lipid peroxidation), expression of NADPH oxidase and nuclear translocation of the stress-responsive transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF-2) in brain. We also examined additional pathological markers by immunohistochemistry and the expression of activated caspase-3 and interleukin-6 by Western blot. None of the markers were increased in the brains of M-NAA treated mice, and no vacuoles were observed in any brain region. These results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination. We hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive NAA related signaling processes in oligodendrocytes that have not been fully determined and we discuss some of the potential mechanisms.
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Affiliation(s)
- Abhilash P. Appu
- Department of Anatomy, Physiology and Genetics and Neuroscience Program, Uniformed Services University of the Health SciencesBethesda, MD, United States
| | - John R. Moffett
- Department of Anatomy, Physiology and Genetics and Neuroscience Program, Uniformed Services University of the Health SciencesBethesda, MD, United States
| | - Peethambaran Arun
- Department of Anatomy, Physiology and Genetics and Neuroscience Program, Uniformed Services University of the Health SciencesBethesda, MD, United States
| | - Sean Moran
- Department of Anatomy, Physiology and Genetics and Neuroscience Program, Uniformed Services University of the Health SciencesBethesda, MD, United States
| | - Vikram Nambiar
- Department of Anatomy, Physiology and Genetics and Neuroscience Program, Uniformed Services University of the Health SciencesBethesda, MD, United States
| | - Jishnu K. S. Krishnan
- Department of Anatomy, Physiology and Genetics and Neuroscience Program, Uniformed Services University of the Health SciencesBethesda, MD, United States
| | - Narayanan Puthillathu
- Department of Anatomy, Physiology and Genetics and Neuroscience Program, Uniformed Services University of the Health SciencesBethesda, MD, United States
| | - Aryan M. A. Namboodiri
- Department of Anatomy, Physiology and Genetics and Neuroscience Program, Uniformed Services University of the Health SciencesBethesda, MD, United States
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