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1
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Fowle-Grider R, Rowles JL, Shen I, Wang Y, Schwaiger-Haber M, Dunham AJ, Jayachandran K, Inkman M, Zahner M, Naser FJ, Jackstadt MM, Spalding JL, Chiang S, McCommis KS, Dolle RE, Kramer ET, Zimmerman SM, Souroullas GP, Finck BN, Shriver LP, Kaufman CK, Schwarz JK, Zhang J, Patti GJ. Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer. Nature 2024; 636:737-744. [PMID: 39633044 DOI: 10.1038/s41586-024-08258-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 10/21/2024] [Indexed: 12/07/2024]
Abstract
Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener1. It has been proposed that fructose promotes the growth of some tumours directly by serving as a fuel2,3. Here we show that fructose supplementation enhances tumour growth in animal models of melanoma, breast cancer and cervical cancer without causing weight gain or insulin resistance. The cancer cells themselves were unable to use fructose readily as a nutrient because they did not express ketohexokinase-C (KHK-C). Primary hepatocytes did express KHK-C, resulting in fructolysis and the excretion of a variety of lipid species, including lysophosphatidylcholines (LPCs). In co-culture experiments, hepatocyte-derived LPCs were consumed by cancer cells and used to generate phosphatidylcholines, the major phospholipid of cell membranes. In vivo, supplementation with high-fructose corn syrup increased several LPC species by more than sevenfold in the serum. Administration of LPCs to mice was sufficient to increase tumour growth. Pharmacological inhibition of ketohexokinase had no direct effect on cancer cells, but it decreased circulating LPC levels and prevented fructose-mediated tumour growth in vivo. These findings reveal that fructose supplementation increases circulating nutrients such as LPCs, which can enhance tumour growth through a cell non-autonomous mechanism.
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Affiliation(s)
- Ronald Fowle-Grider
- Department of Chemistry, Washington University, St Louis, MO, USA
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
| | - Joe L Rowles
- Department of Chemistry, Washington University, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
| | - Isabel Shen
- Department of Chemistry, Washington University, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
| | - Yahui Wang
- Department of Chemistry, Washington University, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
| | - Michaela Schwaiger-Haber
- Department of Chemistry, Washington University, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
| | - Alden J Dunham
- Department of Chemistry, Washington University, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
| | - Kay Jayachandran
- Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA
| | - Matthew Inkman
- Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA
| | - Michael Zahner
- Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA
- Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA
| | - Fuad J Naser
- Department of Chemistry, Washington University, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
| | - Madelyn M Jackstadt
- Department of Chemistry, Washington University, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
| | - Jonathan L Spalding
- Department of Chemistry, Washington University, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
- Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA
| | - Sarah Chiang
- Department of Chemistry, Washington University, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
| | - Kyle S McCommis
- Department of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USA
| | - Roland E Dolle
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA
| | - Eva T Kramer
- Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA
- Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA
| | - Sarah M Zimmerman
- Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA
| | - George P Souroullas
- Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA
| | - Brian N Finck
- Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St Louis, MO, USA
| | - Leah P Shriver
- Department of Chemistry, Washington University, St Louis, MO, USA
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA
| | - Charles K Kaufman
- Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA
- Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA
| | - Julie K Schwarz
- Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA
- Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA
| | - Jin Zhang
- Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA
- Institute for Informatics, Data Science & Biostatistics (I2DB), Washington University School of Medicine, St Louis, MO, USA
| | - Gary J Patti
- Department of Chemistry, Washington University, St Louis, MO, USA.
- Center for Mass Spectrometry and Metabolic Tracing, Washington University, St Louis, MO, USA.
- Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA.
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
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2
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Yu PC, Hou D, Chang B, Liu N, Xu CH, Chen X, Hu CL, Liu T, Wang X, Zhang Q, Liu P, Jiang Y, Fei MY, Zong LJ, Zhang JY, Liu H, Chen BY, Chen SB, Wang Y, Li ZJ, Li X, Deng CH, Ren YY, Zhao M, Jiang S, Wang R, Jin J, Yang S, Xue K, Shi J, Chang CK, Shen S, Wang Z, He PC, Chen Z, Chen SJ, Sun XJ, Wang L. SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis. Dev Cell 2024; 59:1954-1971.e7. [PMID: 38776924 DOI: 10.1016/j.devcel.2024.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/13/2024] [Accepted: 04/30/2024] [Indexed: 05/25/2024]
Abstract
A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.
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Affiliation(s)
- Peng-Cheng Yu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Dan Hou
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Binhe Chang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Na Liu
- Department of Hematology, Institute of Hematology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Chun-Hui Xu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xinchi Chen
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Cheng-Long Hu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Ting Liu
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Xiaoning Wang
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Qunling Zhang
- Department of Medical Oncology, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ping Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yilun Jiang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Ming-Yue Fei
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Li-Juan Zong
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jia-Ying Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Hui Liu
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Bing-Yi Chen
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Shu-Bei Chen
- School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yong Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zi-Juan Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiya Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Chu-Han Deng
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yi-Yi Ren
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Muying Zhao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Shiyu Jiang
- Department of Medical Oncology, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Roujia Wang
- Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Jiacheng Jin
- Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Shaoxin Yang
- Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Kai Xue
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jun Shi
- Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Chun-Kang Chang
- Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Shuhong Shen
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zhikai Wang
- MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China
| | - Peng-Cheng He
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Zhu Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Sai-Juan Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiao-Jian Sun
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Lan Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
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Ferreira JC, Villanueva AJ, Fadl S, Al Adem K, Cinviz ZN, Nedyalkova L, Cardoso THS, Andrade ME, Saksena NK, Sensoy O, Rabeh WM. Residues in the fructose-binding pocket are required for ketohexokinase-A activity. J Biol Chem 2024; 300:107538. [PMID: 38971308 PMCID: PMC11332825 DOI: 10.1016/j.jbc.2024.107538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/08/2024] Open
Abstract
Excessive fructose consumption is a primary contributor to the global surges in obesity, cancer, and metabolic syndrome. Fructolysis is not robustly regulated and is initiated by ketohexokinase (KHK). In this study, we determined the crystal structure of KHK-A, one of two human isozymes of KHK, in the apo-state at 1.85 Å resolution, and we investigated the roles of residues in the fructose-binding pocket by mutational analysis. Introducing alanine at D15, N42, or N45 inactivated KHK-A, whereas mutating R141 or K174 reduced activity and thermodynamic stability. Kinetic studies revealed that the R141A and K174A mutations reduced fructose affinity by 2- to 4-fold compared to WT KHK-A, without affecting ATP affinity. Molecular dynamics simulations provided mechanistic insights into the potential roles of the mutated residues in ligand coordination and the maintenance of an open state in one monomer and a closed state in the other. Protein-protein interactome analysis indicated distinct expression patterns and downregulation of partner proteins in different tumor tissues, warranting a reevaluation of KHK's role in cancer development and progression. The connections between different cancer genes and the KHK signaling pathway suggest that KHK is a potential target for preventing cancer metastasis. This study enhances our understanding of KHK-A's structure and function and offers valuable insights into potential targets for developing treatments for obesity, cancer, and metabolic syndrome.
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Affiliation(s)
- Juliana C Ferreira
- Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Adrian J Villanueva
- Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Samar Fadl
- Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Kenana Al Adem
- Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Zeynep Nur Cinviz
- Graduate School of Engineering and Natural Sciences, Istanbul Medipol University, Istanbul, Turkey
| | - Lyudmila Nedyalkova
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada
| | | | - Mario Edson Andrade
- Horticultural Sciences Department, University of Florida, Gainesville, Florida, USA
| | - Nitin K Saksena
- Institute for Health and Sport, Victoria University, Melbourne, Victoria, Australia
| | - Ozge Sensoy
- Graduate School of Engineering and Natural Sciences, Istanbul Medipol University, Istanbul, Turkey; Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
| | - Wael M Rabeh
- Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
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4
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Moses RM, Stenhouse C, Halloran KM, Sah N, Hoskins EC, Washburn SE, Johnson GA, Wu G, Bazer FW. Metabolic pathways for glucose and fructose: I synthesis and metabolism of fructose by ovine conceptuses†. Biol Reprod 2024; 111:148-158. [PMID: 38501845 DOI: 10.1093/biolre/ioae043] [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: 12/06/2023] [Revised: 01/23/2024] [Accepted: 02/24/2024] [Indexed: 03/20/2024] Open
Abstract
Fructose, the most abundant hexose sugar in fetal fluids and the blood of sheep and other ungulates and cetaceans, is synthesized from glucose via the polyol pathway in trophectoderm and chorion. However, the cell-specific and temporal expression of enzymes for the synthesis and metabolism of fructose in sheep conceptuses (embryo and placental membranes) and placentomes has not been characterized. This study characterized key enzymes involved in fructose synthesis and metabolism by ovine conceptuses throughout pregnancy. Day 17 conceptuses expressed mRNAs for the polyol pathway (SORD and AKR1B1) and glucose and fructose metabolism (HK1, HK2, G6PD, OGT, and FBP), but not those required for gluconeogenesis (G6Pase or PCK). Ovine placentomes also expressed mRNAs for SORD, AKR1B1, HK1, and OGT. Fructose can be metabolized via the ketohexokinase (KHK) pathway, and isoforms, KHK-A and KHK-C, were expressed in ovine conceptuses from Day 16 of pregnancy and placentomes during pregnancy in a cell-specific manner. The KHK-A protein was more abundant in the trophectoderm and cotyledons of placentomes, while KHK-C protein was more abundant in the endoderm of Day 16 conceptuses and the chorionic epithelium in placentomes. Expression of KHK mRNAs in placentomes was greatest at Day 30 of pregnancy (P < 0.05), but not different among days later in gestation. These results provide novel insights into the synthesis and metabolism of fructose via the uninhibited KHK pathway in ovine conceptuses to generate ATP via the tricarboxylic cycle, as well as substrates for the pentose cycle, hexosamine biosynthesis pathway, and one-carbon metabolism required for conceptus development throughout pregnancy.
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Affiliation(s)
- Robyn M Moses
- Department of Animal Science, Texas A&M University, College Station, Texas, USA
| | - Claire Stenhouse
- Department of Animal Science, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Katherine M Halloran
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Nirvay Sah
- Department of Pathology, University of California-San Diego, San Diego, California, USA
| | - Emily C Hoskins
- Department of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, Tennessee, USA
| | - Shannon E Washburn
- Department of Veterinary Physiology and Pathology, Texas A&M University, College Station Texas, USA
| | - Gregory A Johnson
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA
| | - Guoyao Wu
- Department of Animal Science, Texas A&M University, College Station, Texas, USA
| | - Fuller W Bazer
- Department of Animal Science, Texas A&M University, College Station, Texas, USA
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Baugh ME, Ahrens ML, Hutelin Z, Stylianos C, Wohlers-Kariesch E, Oster ME, Dotson J, Moon J, Hanlon AL, DiFeliceantonio AG. Validity and reliability of a new whole room indirect calorimeter to assess metabolic response to small calorie loads. PLoS One 2024; 19:e0304030. [PMID: 38900814 PMCID: PMC11189231 DOI: 10.1371/journal.pone.0304030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 05/05/2024] [Indexed: 06/22/2024] Open
Abstract
We overview of our whole room indirect calorimeter (WRIC), demonstrate validity and reliability of our WRIC, and explore a novel application of Bayesian hierarchical modeling to assess responses to small carbohydrate loads. To assess WRIC validity seven gas infusion studies were performed using a gas blender and profiles designed to mimic resting and postprandial metabolic events. Sixteen participants underwent fasting and postprandial measurements, during which they consumed a 75-kcal drink containing sucrose, dextrose, or fructose in a crossover design. Linear mixed effects models were used to compare resting and postprandial metabolic rate (MR) and carbohydrate oxidation. Postprandial carbohydrate oxidation trajectories for each participant and condition were modeled using Bayesian Hierarchical Modeling. Mean total error in infusions were 1.27 ± 0.67% and 0.42 ± 0.70% for VO2 and VCO2 respectively, indicating a high level of validity. Mean resting MR was similar across conditions ([Formula: see text] = 1.05 ± 0.03 kcal/min, p = 0.82, ICC: 0.91). While MR increased similarly among all conditions (~13%, p = 0.29), postprandial carbohydrate oxidation parameters were significantly lower for dextrose compared with sucrose or fructose. We provide evidence validating our WRIC and a novel application of statistical methods useful for research using WRIC.
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Affiliation(s)
- Mary Elizabeth Baugh
- Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States of America
- Center for Health Behaviors Research at Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States of America
| | - Monica L. Ahrens
- Center for Biostatistics and Health Data Science, Department of Statistics, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Zach Hutelin
- Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States of America
- Center for Health Behaviors Research at Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States of America
- Translational Biology, Medicine, and Health, Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States of America
| | - Charlie Stylianos
- Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States of America
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia, United States of America
| | | | - Mary E. Oster
- Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States of America
- Center for Health Behaviors Research at Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States of America
| | - Jon Dotson
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Jon Moon
- MEI Research, Ltd, Edina, Minnesota, United States of America
| | - Alexandra L. Hanlon
- Center for Biostatistics and Health Data Science, Department of Statistics, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Alexandra G. DiFeliceantonio
- Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States of America
- Center for Health Behaviors Research at Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States of America
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia, United States of America
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6
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Gasper WC, Gardner S, Ross A, Oppelt SA, Allen KN, Tolan DR. Michaelis-like complex of mouse ketohexokinase isoform C. Acta Crystallogr D Struct Biol 2024; 80:377-385. [PMID: 38805243 DOI: 10.1107/s2059798324003723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 04/23/2024] [Indexed: 05/29/2024] Open
Abstract
Over the past forty years there has been a drastic increase in fructose-related diseases, including obesity, heart disease and diabetes. Ketohexokinase (KHK), the first enzyme in the liver fructolysis pathway, catalyzes the ATP-dependent phosphorylation of fructose to fructose 1-phosphate. Understanding the role of KHK in disease-related processes is crucial for the management and prevention of this growing epidemic. Molecular insight into the structure-function relationship in ligand binding and catalysis by KHK is needed for the design of therapeutic inhibitory ligands. Ketohexokinase has two isoforms: ketohexokinase A (KHK-A) is produced ubiquitously at low levels, whereas ketohexokinase C (KHK-C) is found at much higher levels, specifically in the liver, kidneys and intestines. Structures of the unliganded and liganded human isoforms KHK-A and KHK-C are known, as well as structures of unliganded and inhibitor-bound mouse KHK-C (mKHK-C), which shares 90% sequence identity with human KHK-C. Here, a high-resolution X-ray crystal structure of mKHK-C refined to 1.79 Å resolution is presented. The structure was determined in a complex with both the substrate fructose and the product of catalysis, ADP, providing a view of the Michaelis-like complex of the mouse ortholog. Comparison to unliganded structures suggests that KHK undergoes a conformational change upon binding of substrates that places the enzyme in a catalytically competent form in which the β-sheet domain from one subunit rotates by 16.2°, acting as a lid for the opposing active site. Similar kinetic parameters were calculated for the mouse and human enzymes and indicate that mice may be a suitable animal model for the study of fructose-related diseases. Knowledge of the similarity between the mouse and human enzymes is important for understanding preclinical efforts towards targeting this enzyme, and this ground-state, Michaelis-like complex suggests that a conformational change plays a role in the catalytic function of KHK-C.
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Affiliation(s)
- William C Gasper
- Program in Biochemistry and Molecular Biology, Boston University, Boston, MA 02215, USA
| | - Sarah Gardner
- Department of Chemistry, Boston University, Boston, MA 02215, USA
| | - Adam Ross
- Department of Chemistry, Boston University, Boston, MA 02215, USA
| | - Sarah A Oppelt
- Program in Biochemistry and Molecular Biology, Boston University, Boston, MA 02215, USA
| | - Karen N Allen
- Program in Biochemistry and Molecular Biology, Boston University, Boston, MA 02215, USA
| | - Dean R Tolan
- Program in Biochemistry and Molecular Biology, Boston University, Boston, MA 02215, USA
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7
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Ortjohann M, Schönheit P. Identification and characterization of a novel type of ketohexokinase from the haloarchaeon Haloferax volcanii. FEMS Microbiol Lett 2024; 371:fnae026. [PMID: 38587824 DOI: 10.1093/femsle/fnae026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/18/2024] [Accepted: 04/05/2024] [Indexed: 04/09/2024] Open
Abstract
Ketohexokinase (KHK) catalyzes the ATP-dependent phosphorylation of fructose, forming fructose-1-phosphate and ADP. The enzyme is well studied in Eukarya, in particular in humans and other vertebrates, but homologs have not been identified in Bacteria and Archaea. Here we report the identification of a novel type of KHK from the haloarchaeon Haloferax volcanii (HvKHK). The encoding gene khk was identified as HVO_1812. The gene was expressed as a 90-kDa homodimeric protein, catalyzing the phosphorylation of fructose with a Vmax value of 59 U/mg and apparent KM values for ATP and fructose of 0.47 and 1.29 mM, respectively. Homologs of HvKHK were only identified in a few haloarchaea and halophilic Bacteria. The protein showed low sequence identity to characterized KHKs from Eukarya and phylogenetic analyses indicate that haloarchaeal KHKs are largely separated from eukaryal KHKs. This is the first report of the identification of KHKs in prokaryotes that form a novel cluster of sugar kinases within the ribokinase/pfkB superfamily.
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Affiliation(s)
- Marius Ortjohann
- Institut für Allgemeine Mikrobiologie, Christian-Albrechts-Universität Kiel, Am Botanischen Garten 1-9, D-24118 Kiel, Germany
| | - Peter Schönheit
- Institut für Allgemeine Mikrobiologie, Christian-Albrechts-Universität Kiel, Am Botanischen Garten 1-9, D-24118 Kiel, Germany
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8
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Durham TB, Hao J, Spinazze P, Stack DR, Toth JL, Massey S, Mbofana CT, Johnston RD, Lineswala JP, Wrobleski A, Mínguez JM, Perez C, Smith DL, Lamar J, Leon R, Corkins C, Durbin J, Tung F, Guo S, Linder RJ, Yumibe N, Wang W, MacKrell J, Antonellis M, Mascaro B. Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor. J Med Chem 2023; 66:15960-15976. [PMID: 37992274 DOI: 10.1021/acs.jmedchem.3c01410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2023]
Abstract
The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.
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Affiliation(s)
- Timothy B Durham
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Junliang Hao
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Patrick Spinazze
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Douglas R Stack
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - James L Toth
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Steven Massey
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Curren T Mbofana
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Richard D Johnston
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Jayana P Lineswala
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Aaron Wrobleski
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Jose Miguel Mínguez
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly SA, Avenida de la Industria 30, 28108 Alcobendas, Madrid, Spain
| | - Carlos Perez
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly SA, Avenida de la Industria 30, 28108 Alcobendas, Madrid, Spain
| | - Daryl L Smith
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Jason Lamar
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Rebecca Leon
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Molecular Pharmacology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Christopher Corkins
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Molecular Pharmacology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Jim Durbin
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Structural Biology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Frances Tung
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Structural Biology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Sherry Guo
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Structural Biology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Ryan J Linder
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Molecular Innovation Hub, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Nathan Yumibe
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- ADME, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Wei Wang
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Toxicology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - James MacKrell
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Diabetes and Metabolic Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Meghan Antonellis
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Diabetes and Metabolic Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
| | - Bethany Mascaro
- Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
- Diabetes and Metabolic Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
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9
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Kjer-Hansen P, Weatheritt RJ. The function of alternative splicing in the proteome: rewiring protein interactomes to put old functions into new contexts. Nat Struct Mol Biol 2023; 30:1844-1856. [PMID: 38036695 DOI: 10.1038/s41594-023-01155-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 10/17/2023] [Indexed: 12/02/2023]
Abstract
Alternative splicing affects more than 95% of multi-exon genes in the human genome. These changes affect the proteome in a myriad of ways. Here, we review our understanding of the breadth of these changes from their effect on protein structure to their influence on interactions. These changes encompass effects on nucleic acid binding in the nucleus to protein-carbohydrate interactions in the extracellular milieu, altering interactions involving all major classes of biological molecules. Protein isoforms have profound influences on cellular and tissue physiology, for example, by shaping neuronal connections, enhancing insulin secretion by pancreatic beta cells and allowing for alternative viral defense strategies in stem cells. More broadly, alternative splicing enables repurposing proteins from one context to another and thereby contributes to both the evolution of new traits as well as the creation of disease-specific interactomes that drive pathological phenotypes. In this Review, we highlight this universal character of alternative splicing as a central regulator of protein function with implications for almost every biological process.
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Affiliation(s)
- Peter Kjer-Hansen
- EMBL Australia, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
- St. Vincent Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.
| | - Robert J Weatheritt
- EMBL Australia, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
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10
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Temaj G, Chichiarelli S, Saha S, Telkoparan-Akillilar P, Nuhii N, Hadziselimovic R, Saso L. An intricate rewiring of cancer metabolism via alternative splicing. Biochem Pharmacol 2023; 217:115848. [PMID: 37813165 DOI: 10.1016/j.bcp.2023.115848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/05/2023] [Accepted: 10/05/2023] [Indexed: 10/11/2023]
Abstract
All human genes undergo alternative splicing leading to the diversity of the proteins. However, in some cases, abnormal regulation of alternative splicing can result in diseases that trigger defects in metabolism, reduced apoptosis, increased proliferation, and progression in almost all tumor types. Metabolic dysregulations and immune dysfunctions are crucial factors in cancer. In this respect, alternative splicing in tumors could be a potential target for therapeutic cancer strategies. Dysregulation of alternative splicing during mRNA maturation promotes carcinogenesis and drug resistance in many cancer types. Alternative splicing (changing the target mRNA 3'UTR binding site) can result in a protein with altered drug affinity, ultimately leading to drug resistance.. Here, we will highlight the function of various alternative splicing factors, how it regulates the reprogramming of cancer cell metabolism, and their contribution to tumor initiation and proliferation. Also, we will discuss emerging therapeutics for treating tumors via abnormal alternative splicing. Finally, we will discuss the challenges associated with these therapeutic strategies for clinical applications.
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Affiliation(s)
- Gazmend Temaj
- Faculty of Pharmacy, College UBT, 10000 Prishtina, Kosovo
| | - Silvia Chichiarelli
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, 00185 Rome, Italy.
| | - Sarmistha Saha
- Department of Biotechnology, GLA University, Mathura 00185, Uttar Pradesh, India
| | | | - Nexhibe Nuhii
- Department of Pharmacy, Faculty of Medical Sciences, State University of Tetovo, 1200 Tetovo, Macedonia
| | - Rifat Hadziselimovic
- Faculty of Science, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", La Sapienza University, 00185 Rome, Italy.
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11
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Song A, Mao Y, Wei H. GLUT5: structure, functions, diseases and potential applications. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1519-1538. [PMID: 37674366 PMCID: PMC10582729 DOI: 10.3724/abbs.2023158] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 05/19/2023] [Indexed: 09/08/2023] Open
Abstract
Glucose transporter 5 (GLUT5) is a membrane transporter that specifically transports fructose and plays a key role in dietary fructose uptake and metabolism. In recent years, a high fructose diet has occupied an important position in the daily intake of human beings, resulting in a significant increase in the incidence of obesity and metabolic diseases worldwide. Over the past few decades, GLUT5 has been well understood to play a significant role in the pathogenesis of human digestive diseases. Recently, the role of GLUT5 in human cancer has received widespread attention, and a large number of studies have focused on exploring the effects of changes in GLUT5 expression levels on cancer cell survival, metabolism and metastasis. However, due to various difficulties and shortcomings, the molecular structure and mechanism of GLUT5 have not been fully elucidated, which to some extent prevents us from revealing the relationship between GLUT5 expression and cell carcinogenesis at the protein molecular level. In this review, we summarize the current understanding of the structure and function of mammalian GLUT5 and its relationship to intestinal diseases and cancer and suggest that GLUT5 may be an important target for cancer therapy.
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Affiliation(s)
- Aqian Song
- Department of GastroenterologyBeijing Ditan HospitalCapital Medical UniversityBeijing100015China
| | - Yuanpeng Mao
- Department of GastroenterologyPeking University Ditan Teaching HospitalBeijing100015China
| | - Hongshan Wei
- Department of GastroenterologyBeijing Ditan HospitalCapital Medical UniversityBeijing100015China
- Department of GastroenterologyPeking University Ditan Teaching HospitalBeijing100015China
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12
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Zhu G, Li J, Lin X, Zhang Z, Hu T, Huo S, Li Y. Discovery of a Novel Ketohexokinase Inhibitor with Improved Drug Distribution in Target Tissue for the Treatment of Fructose Metabolic Disease. J Med Chem 2023; 66:13501-13515. [PMID: 37766386 DOI: 10.1021/acs.jmedchem.3c00715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/29/2023]
Abstract
Excessive fructose absorption and its subsequent metabolisms are implicated in nonalcoholic fatty liver disease, obesity, and insulin resistance in humans. Ketohexokinase (KHK) is a primary enzyme involved in fructose metabolism via the conversion of fructose to fructose-1-phosphate. KHK inhibition might be a potential approach for the treatment of metabolic disorders. Herein, a series of novel KHK inhibitors were designed, synthesized, and evaluated. Among them, compound 14 exhibited more potent activity than PF-06835919 based on the rat KHK inhibition assay in vivo, and higher drug distribution concentration in the liver. Its good absorption, distribution, metabolism, and excretion and pharmacokinetic properties make it a promising clinical candidate.
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Affiliation(s)
- Guodong Zhu
- TuoJie Biotech (Shanghai) Co., Ltd., Shanghai 201206, P. R. China
| | - Jiao Li
- TuoJie Biotech (Shanghai) Co., Ltd., Shanghai 201206, P. R. China
| | - Xiaoyan Lin
- TuoJie Biotech (Shanghai) Co., Ltd., Shanghai 201206, P. R. China
| | - Zhen Zhang
- TuoJie Biotech (Shanghai) Co., Ltd., Shanghai 201206, P. R. China
| | - Tao Hu
- TuoJie Biotech (Shanghai) Co., Ltd., Shanghai 201206, P. R. China
| | - Shuhua Huo
- TuoJie Biotech (Shanghai) Co., Ltd., Shanghai 201206, P. R. China
| | - Yunfei Li
- TuoJie Biotech (Shanghai) Co., Ltd., Shanghai 201206, P. R. China
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13
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Baugh ME, Ahrens ML, Hutelin Z, Stylianos C, Wohlers-Kariesch E, Oster ME, Dotson J, Moon J, Hanlon AL, DiFeliceantonio AG. Validity and reliability of a new whole room indirect calorimeter to assess metabolic response to small-calorie loads. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.21.558672. [PMID: 37790401 PMCID: PMC10542547 DOI: 10.1101/2023.09.21.558672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
Objective To provide an overview of our whole room indirect calorimeter (WRIC), demonstrate validity and reliability of our WRIC, and explore a novel application of Bayesian hierarchical modeling to assess responses to small carbohydrate loads. Methods Seven gas infusion studies were performed using a gas blender and profiles designed to mimic resting and postprandial metabolic events to assess WRIC validity. In a crossover design, 16 participants underwent fasting and postprandial measurements, during which they consumed a 75-kcal drink containing sucrose, dextrose, or fructose. Linear mixed effects models were used to compare resting and postprandial metabolic rate (MR) and CO (CO). Bayesian Hierarchical Modeling was also used to model postprandial CO trajectories for each participant and condition. Results Mean total error in infusions were 1.27 ± 1.16% and 0.42 ± 1.21% for VO2 and VCO2 respectively, indicating a high level of validity. Mean resting MR was similar across conditions (x ¯ = 1.05 ± 0.03 kcal / min , p=0.82, ICC: 0.91). While MR increased similarly among all conditions (~13%, p=0.29), postprandial CO parameters were significantly lower for dextrose compared with sucrose or fructose. Conclusions Our WRIC validation and novel application of statistical methods presented here provide important foundations for new research directions using WRIC.
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Affiliation(s)
- Mary Elizabeth Baugh
- Fralin Biomedical Research Institute at VTC, Roanoke, VA
- Center for Health Behaviors Research at Fralin Biomedical Research Institute at VTC, Roanoke, VA
| | - Monica L. Ahrens
- Center for Biostatistics and Health Data Science, Department of Statistics, Blacksburg, VA
| | - Zach Hutelin
- Fralin Biomedical Research Institute at VTC, Roanoke, VA
- Center for Health Behaviors Research at Fralin Biomedical Research Institute at VTC, Roanoke, VA
- Translational Biology, Medicine, and Health, Fralin Biomedical Research Institute at VTC, Roanoke, VA
| | - Charlie Stylianos
- Fralin Biomedical Research Institute at VTC, Roanoke, VA
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA
| | | | - Mary E. Oster
- Fralin Biomedical Research Institute at VTC, Roanoke, VA
- Center for Health Behaviors Research at Fralin Biomedical Research Institute at VTC, Roanoke, VA
| | - Jon Dotson
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA
| | | | - Alexandra L. Hanlon
- Center for Biostatistics and Health Data Science, Department of Statistics, Blacksburg, VA
| | - Alexandra G. DiFeliceantonio
- Fralin Biomedical Research Institute at VTC, Roanoke, VA
- Center for Health Behaviors Research at Fralin Biomedical Research Institute at VTC, Roanoke, VA
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA
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14
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Xu HL, Zhou X, Chen S, Xu S, Li Z, Nakanishi H, Gao XD. Rare sugar L-sorbose exerts antitumor activity by impairing glucose metabolism. Commun Biol 2023; 6:259. [PMID: 36906698 PMCID: PMC10008635 DOI: 10.1038/s42003-023-04638-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 02/28/2023] [Indexed: 03/13/2023] Open
Abstract
Rare sugars are monosaccharides with low natural abundance. They are structural isomers of dietary sugars, but hardly be metabolized. Here, we report that rare sugar L-sorbose induces apoptosis in various cancer cells. As a C-3 epimer of D-fructose, L-sorbose is internalized via the transporter GLUT5 and phosphorylated by ketohexokinase (KHK) to produce L-sorbose-1-phosphate (S-1-P). Cellular S-1-P inactivates the glycolytic enzyme hexokinase resulting in attenuated glycolysis. Consequently, mitochondrial function is impaired and reactive oxygen species are produced. Moreover, L-sorbose downregulates the transcription of KHK-A, a splicing variant of KHK. Since KHK-A is a positive inducer of antioxidation genes, the antioxidant defense mechanism in cancer cells can be attenuated by L-sorbose-treatment. Thus, L-sorbose performs multiple anticancer activities to induce cell apoptosis. In mouse xenograft models, L-sorbose enhances the effect of tumor chemotherapy in combination with other anticancer drugs. These results demonstrate L-sorbose as an attractive therapeutic reagent for cancer treatment.
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Affiliation(s)
- Hui-Lin Xu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, China
| | - Xiaoman Zhou
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, China
| | - Shuai Chen
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, China
| | - Si Xu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, China
| | - Zijie Li
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, China.
| | - Hideki Nakanishi
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, China.
| | - Xiao-Dong Gao
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, China.
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China.
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15
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Wang K, Zhao Y, Xu L, Liao X, Xu Z. Health outcomes of 100% orange juice and orange flavored beverage: A comparative analysis of gut microbiota and metabolomics in rats. Curr Res Food Sci 2023; 6:100454. [PMID: 36815996 PMCID: PMC9932342 DOI: 10.1016/j.crfs.2023.100454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/08/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
A high intake of sugar-sweetened fruity beverage (FB) is associated with a higher risk of metabolic syndromes, but the health outcome of 100% fruit juice (FJ) intake remains unclear. We aim to reveal health outcomes of diet intervention (FJ or FB) with system profiling via interaction of gut microbiota and metabolomics in a rat (Rattus norvegicus) model. Firstly, the glucose, sucrose, fructose, and bioactive metabolites of FJ and FB were analyzed, and FJ possessed higher sucrose and flavonoids, while FB showed higher glucose and fructose. Secondly, C0 was set as the control group on Day 0, and a 4-week diet invention was performed to control, FJ-intake, and FB-intake groups with normal saline, FJ, and FB, respectively. The results showed that FJ improved alpha diversity and decreased the Firmicutes/Bacteroidota ratio (F/B ratio) of gut microbiota and prevented insulin resistance. However, FB possessed unchanged microbial diversity and enhanced F/B ratio, causing insulin resistance with renal triglyceride accumulation. In summary, FJ, although naturally containing similar amounts of total free sugars as FB, could be a healthier drink choice.
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Affiliation(s)
- Kewen Wang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
- Institute of Quality Standard & Testing Technology for Agro-Products, Key Laboratory of Agro-food Safety and Quality, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Yang Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
| | - Lei Xu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
- Institute of Quality Standard & Testing Technology for Agro-Products, Key Laboratory of Agro-food Safety and Quality, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Xiaojun Liao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
- Corresponding author.
| | - Zhenzhen Xu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
- Institute of Quality Standard & Testing Technology for Agro-Products, Key Laboratory of Agro-food Safety and Quality, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
- Corresponding author. College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China.
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16
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Fukushi A, Kim HD, Chang YC, Kim CH. Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells. Int J Mol Sci 2022; 23:10037. [PMID: 36077431 PMCID: PMC9456516 DOI: 10.3390/ijms231710037] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/22/2022] [Accepted: 08/29/2022] [Indexed: 12/22/2022] Open
Abstract
Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the "Warburg effect". Energy-metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the "Warburg effect", tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.
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Affiliation(s)
- Abekura Fukushi
- Department of Biological Sciences, College of Science, Sungkyunkwan University, Seoburo 2066, Suwon 16419, Korea
| | - Hee-Do Kim
- Department of Biological Sciences, College of Science, Sungkyunkwan University, Seoburo 2066, Suwon 16419, Korea
| | - Yu-Chan Chang
- Department of Biomedicine Imaging and Radiological Science, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Cheorl-Ho Kim
- Department of Biological Sciences, College of Science, Sungkyunkwan University, Seoburo 2066, Suwon 16419, Korea
- Samsung Advanced Institute of Health Science and Technology (SAIHST), Sungkyunkwan University, Seoul 06351, Korea
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17
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Tee SS, Kim N, Cullen Q, Eskandari R, Mamakhanyan A, Srouji RM, Chirayil R, Jeong S, Shakiba M, Kastenhuber ER, Chen S, Sigel C, Lowe SW, Jarnagin WR, Thompson CB, Schietinger A, Keshari KR. Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging. SCIENCE ADVANCES 2022; 8:eabm7985. [PMID: 35385296 PMCID: PMC8985914 DOI: 10.1126/sciadv.abm7985] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 02/15/2022] [Indexed: 06/14/2023]
Abstract
The ability to break down fructose is dependent on ketohexokinase (KHK) that phosphorylates fructose to fructose-1-phosphate (F1P). We show that KHK expression is tightly controlled and limited to a small number of organs and is down-regulated in liver and intestinal cancer cells. Loss of fructose metabolism is also apparent in hepatocellular adenoma and carcinoma (HCC) patient samples. KHK overexpression in liver cancer cells results in decreased fructose flux through glycolysis. We then developed a strategy to detect this metabolic switch in vivo using hyperpolarized magnetic resonance spectroscopy. Uniformly deuterating [2-13C]-fructose and dissolving in D2O increased its spin-lattice relaxation time (T1) fivefold, enabling detection of F1P and its loss in models of HCC. In summary, we posit that in the liver, fructolysis to F1P is lost in the development of cancer and can be used as a biomarker of tissue function in the clinic using metabolic imaging.
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Affiliation(s)
- Sui Seng Tee
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nathaniel Kim
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Quinlan Cullen
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Roozbeh Eskandari
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Arsen Mamakhanyan
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rami M. Srouji
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rachel Chirayil
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sangmoo Jeong
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mojdeh Shakiba
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Edward R. Kastenhuber
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Shuibing Chen
- Weill Cornell Medical College, New York, NY, USA
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Carlie Sigel
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Scott W. Lowe
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - William R. Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Craig B. Thompson
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andrea Schietinger
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kayvan R. Keshari
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
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18
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Benegas G, Fischer J, Song YS. Robust and annotation-free analysis of alternative splicing across diverse cell types in mice. eLife 2022; 11:73520. [PMID: 35229721 PMCID: PMC8975553 DOI: 10.7554/elife.73520] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 02/27/2022] [Indexed: 11/13/2022] Open
Abstract
Although alternative splicing is a fundamental and pervasive aspect of gene expression in higher eukaryotes, it is often omitted from single-cell studies due to quantification challenges inherent to commonly used short-read sequencing technologies. Here, we undertake the analysis of alternative splicing across numerous diverse murine cell types from two large-scale single-cell datasets-the Tabula Muris and BRAIN Initiative Cell Census Network-while accounting for understudied technical artifacts and unannotated events. We find strong and general cell-type-specific alternative splicing, complementary to total gene expression but of similar discriminatory value, and identify a large volume of novel splicing events. We specifically highlight splicing variation across different cell types in primary motor cortex neurons, bone marrow B cells, and various epithelial cells, and we show that the implicated transcripts include many genes which do not display total expression differences. To elucidate the regulation of alternative splicing, we build a custom predictive model based on splicing factor activity, recovering several known interactions while generating new hypotheses, including potential regulatory roles for novel alternative splicing events in critical genes like Khdrbs3 and Rbfox1. We make our results available using public interactive browsers to spur further exploration by the community.
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Affiliation(s)
- Gonzalo Benegas
- Graduate Group in Computational Biology, University of California, Berkeley, Berkeley, United States
| | - Jonathan Fischer
- Department of Biostatistics, University of Florida, Gainesville, United States
| | - Yun S Song
- Computer Science Division, University of California, Berkeley, Berkeley, United States
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19
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Vallon V, Nakagawa T. Renal Tubular Handling of Glucose and Fructose in Health and Disease. Compr Physiol 2021; 12:2995-3044. [PMID: 34964123 PMCID: PMC9832976 DOI: 10.1002/cphy.c210030] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The proximal tubule of the kidney is programmed to reabsorb all filtered glucose and fructose. Glucose is taken up by apical sodium-glucose cotransporters SGLT2 and SGLT1 whereas SGLT5 and potentially SGLT4 and GLUT5 have been implicated in apical fructose uptake. The glucose taken up by the proximal tubule is typically not metabolized but leaves via the basolateral facilitative glucose transporter GLUT2 and is returned to the systemic circulation or used as an energy source by distal tubular segments after basolateral uptake via GLUT1. The proximal tubule generates new glucose in metabolic acidosis and the postabsorptive phase, and fructose serves as an important substrate. In fact, under physiological conditions and intake, fructose taken up by proximal tubules is primarily utilized for gluconeogenesis. In the diabetic kidney, glucose is retained and gluconeogenesis enhanced, the latter in part driven by fructose. This is maladaptive as it sustains hyperglycemia. Moreover, renal glucose retention is coupled to sodium retention through SGLT2 and SGLT1, which induces secondary deleterious effects. SGLT2 inhibitors are new anti-hyperglycemic drugs that can protect the kidneys and heart from failing independent of kidney function and diabetes. Dietary excess of fructose also induces tubular injury. This can be magnified by kidney formation of fructose under pathological conditions. Fructose metabolism is linked to urate formation, which partially accounts for fructose-induced tubular injury, inflammation, and hemodynamic alterations. Fructose metabolism favors glycolysis over mitochondrial respiration as urate suppresses aconitase in the tricarboxylic acid cycle, and has been linked to potentially detrimental aerobic glycolysis (Warburg effect). © 2022 American Physiological Society. Compr Physiol 12:2995-3044, 2022.
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Affiliation(s)
- Volker Vallon
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, La Jolla, California, USA,Department of Pharmacology, University of California San Diego, La Jolla, California, USA,VA San Diego Healthcare System, San Diego, California, USA,Correspondence to and
| | - Takahiko Nakagawa
- Division of Nephrology, Rakuwakai-Otowa Hospital, Kyoto, Japan,Correspondence to and
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20
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Herman MA, Birnbaum MJ. Molecular aspects of fructose metabolism and metabolic disease. Cell Metab 2021; 33:2329-2354. [PMID: 34619074 PMCID: PMC8665132 DOI: 10.1016/j.cmet.2021.09.010] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/02/2021] [Accepted: 09/13/2021] [Indexed: 02/06/2023]
Abstract
Excessive sugar consumption is increasingly considered as a contributor to the emerging epidemics of obesity and the associated cardiometabolic disease. Sugar is added to the diet in the form of sucrose or high-fructose corn syrup, both of which comprise nearly equal amounts of glucose and fructose. The unique aspects of fructose metabolism and properties of fructose-derived metabolites allow for fructose to serve as a physiological signal of normal dietary sugar consumption. However, when fructose is consumed in excess, these unique properties may contribute to the pathogenesis of cardiometabolic disease. Here, we review the biochemistry, genetics, and physiology of fructose metabolism and consider mechanisms by which excessive fructose consumption may contribute to metabolic disease. Lastly, we consider new therapeutic options for the treatment of metabolic disease based upon this knowledge.
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Affiliation(s)
- Mark A Herman
- Division of Endocrinology, Metabolism, and Nutrition, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
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21
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Nakagawa T, Kang DH. Fructose in the kidney: from physiology to pathology. Kidney Res Clin Pract 2021; 40:527-541. [PMID: 34781638 PMCID: PMC8685370 DOI: 10.23876/j.krcp.21.138] [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: 07/06/2021] [Accepted: 08/13/2021] [Indexed: 11/30/2022] Open
Abstract
The Warburg effect is a unique property of cancer cells, in which glycolysis is activated instead of mitochondrial respiration despite oxygen availability. However, recent studies found that the Warburg effect also mediates non-cancer disorders, including kidney disease. Currently, diabetes or glucose has been postulated to mediate the Warburg effect in the kidney, but it is of importance that the Warburg effect can be induced under nondiabetic conditions. Fructose is endogenously produced in several organs, including the kidney, under both physiological and pathological conditions. In the kidney, fructose is predominantly metabolized in the proximal tubules; under normal physiologic conditions, fructose is utilized as a substrate for gluconeogenesis and contributes to maintain systemic glucose concentration under starvation conditions. However, when present in excess, fructose likely becomes deleterious, possibly due in part to excessive uric acid, which is a by-product of fructose metabolism. A potential mechanism is that uric acid suppresses aconitase in the Krebs cycle and therefore reduces mitochondrial oxidation. Consequently, fructose favors glycolysis over mitochondrial respiration, a process that is similar to the Warburg effect in cancer cells. Activation of glycolysis also links to several side pathways, including the pentose phosphate pathway, hexosamine pathway, and lipid synthesis, to provide biosynthetic precursors as fuel for renal inflammation and fibrosis. We now hypothesize that fructose could be the mediator for the Warburg effect in the kidney and a potential mechanism for chronic kidney disease.
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Affiliation(s)
| | - Duk-Hee Kang
- Division of Nephrology, Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University College of Medicine, Seoul, Republic of Korea
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22
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Fructose and Mannose in Inborn Errors of Metabolism and Cancer. Metabolites 2021; 11:metabo11080479. [PMID: 34436420 PMCID: PMC8397987 DOI: 10.3390/metabo11080479] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/21/2021] [Accepted: 07/21/2021] [Indexed: 12/19/2022] Open
Abstract
History suggests that tasteful properties of sugar have been domesticated as far back as 8000 BCE. With origins in New Guinea, the cultivation of sugar quickly spread over centuries of conquest and trade. The product, which quickly integrated into common foods and onto kitchen tables, is sucrose, which is made up of glucose and fructose dimers. While sugar is commonly associated with flavor, there is a myriad of biochemical properties that explain how sugars as biological molecules function in physiological contexts. Substantial research and reviews have been done on the role of glucose in disease. This review aims to describe the role of its isomers, fructose and mannose, in the context of inborn errors of metabolism and other metabolic diseases, such as cancer. While structurally similar, fructose and mannose give rise to very differing biochemical properties and understanding these differences will guide the development of more effective therapies for metabolic disease. We will discuss pathophysiology linked to perturbations in fructose and mannose metabolism, diagnostic tools, and treatment options of the diseases.
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23
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Yin J, Lu J, Lei P, He M, Huang S, Lv J, Zhu Y, Liu Z, Jiang M. Danggui-Shaoyao-San Improves Gut Microbia Dysbiosis and Hepatic Lipid Homeostasis in Fructose-Fed Rats. Front Pharmacol 2021; 12:671708. [PMID: 34326769 PMCID: PMC8313808 DOI: 10.3389/fphar.2021.671708] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 06/28/2021] [Indexed: 01/02/2023] Open
Abstract
Metabolic syndrome (MetS) is a pathological state of many abnormal metabolic sections. These abnormalities are closely related to diabetes, heart pathologies and other vascular diseases. Danggui-Shaoyao-San (DSS) is a traditional Chinese medicine formula that has been used as a therapy for Alzheimer’s disease. DSS has rarely been reported in the application of MetS and its mechanism of how it improves gut microbia dysbiosis and hepatic lipid homeostasis. In this study, three extracts of DSS were obtained using water, 50% methanol in water and methanol as extracting solvents. Their chemical substances were analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass (UPLC-Q/TOF-MS). Pharmacodynamic effect of the extracts were evaluated by comparison of biochemical factors, 16S rRNA sequencing test for gut microbiota analysis, as well as metabonomic and transcriptomic assessments on liver tissues from fructose-fed rats. This study aimed at investigating DSS’s mechanism of regulating blood lipid, anti-inflammation and reducing blood glucose. The results showed that the 50% methanol extract (HME) was more effective. It was worth noting that hydroxysteroid 17β-dehydrogenase 13 (HSD17β13) as a critical element of increasing blood lipid biomarker-triglyceride (TG), was decreased markedly by DSS. The influence from upgraded hydroxysteroid 17β-dehydrogenase 7 (HSD17β7) may be stronger than that from downgraded Lactobacillus in the aspect of regulating back blood lipid biomarker-total cholesterol (TC). The differential down-regulation of tumornecrosis factor alpha (TNF-α) and the significant up-regulation of Akkermansia showed the effective effect of anti-inflammation by DSS. The declining glycine and alanine induced the lowering glucose and lactate. It demonstrated that DSS slowed down the reaction of gluconeogenesis to reduce the blood glucose. The results demonstrated that DSS improved pathological symptoms of MetS and some special biochemical factors in three aspects by better regulating intestinal floras and improving hepatic gene expressions and metabolites.
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Affiliation(s)
- Jing Yin
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jiaxi Lu
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Peng Lei
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mingshuai He
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shengjie Huang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jialin Lv
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yan Zhu
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhidong Liu
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Miaomiao Jiang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Department of Pharmacy, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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24
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Park G, Jung S, Wellen KE, Jang C. The interaction between the gut microbiota and dietary carbohydrates in nonalcoholic fatty liver disease. Exp Mol Med 2021; 53:809-822. [PMID: 34017059 PMCID: PMC8178320 DOI: 10.1038/s12276-021-00614-x] [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] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/24/2021] [Indexed: 02/04/2023] Open
Abstract
Imbalance between fat production and consumption causes various metabolic disorders. Nonalcoholic fatty liver disease (NAFLD), one such pathology, is characterized by abnormally increased fat synthesis and subsequent fat accumulation in hepatocytes1,2. While often comorbid with obesity and insulin resistance, this disease can also be found in lean individuals, suggesting specific metabolic dysfunction2. NAFLD has become one of the most prevalent liver diseases in adults worldwide, but its incidence in both children and adolescents has also markedly increased in developed nations3,4. Progression of this disease into nonalcoholic steatohepatitis (NASH), cirrhosis, liver failure, and hepatocellular carcinoma in combination with its widespread incidence thus makes NAFLD and its related pathologies a significant public health concern. Here, we review our understanding of the roles of dietary carbohydrates (glucose, fructose, and fibers) and the gut microbiota, which provides essential carbon sources for hepatic fat synthesis during the development of NAFLD.
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Affiliation(s)
- Grace Park
- Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Sunhee Jung
- Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Kathryn E Wellen
- Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Cholsoon Jang
- Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
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25
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Federico A, Rosato V, Masarone M, Torre P, Dallio M, Romeo M, Persico M. The Role of Fructose in Non-Alcoholic Steatohepatitis: Old Relationship and New Insights. Nutrients 2021; 13:1314. [PMID: 33923525 PMCID: PMC8074203 DOI: 10.3390/nu13041314] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/12/2021] [Accepted: 04/14/2021] [Indexed: 12/22/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the result of hepatic fat overload not due to alcohol consumption and potentially evolving to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Fructose is a naturally occurring simple sugar widely used in food industry linked to glucose to form sucrose, largely contained in hypercaloric food and beverages. An increasing amount of evidence in scientific literature highlighted a detrimental effect of dietary fructose consumption on metabolic disorders such as insulin resistance, obesity, hepatic steatosis, and NAFLD-related fibrosis as well. An excessive fructose consumption has been associated with NAFLD development and progression to more clinically severe phenotypes by exerting various toxic effects, including increased fatty acid production, oxidative stress, and worsening insulin resistance. Furthermore, some studies in this context demonstrated even a crucial role in liver cancer progression. Despite this compelling evidence, the molecular mechanisms by which fructose elicits those effects on liver metabolism remain unclear. Emerging data suggest that dietary fructose may directly alter the expression of genes involved in lipid metabolism, including those that increase hepatic fat accumulation or reduce hepatic fat removal. This review aimed to summarize the current understanding of fructose metabolism on NAFLD pathogenesis and progression.
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Affiliation(s)
- Alessandro Federico
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.D.); (M.R.)
| | - Valerio Rosato
- Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, “Scuola Medica Salernitana”, University of Salerno, 84084 Salerno, Italy; (V.R.); (M.M.); (P.T.); (M.P.)
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, “Scuola Medica Salernitana”, University of Salerno, 84084 Salerno, Italy; (V.R.); (M.M.); (P.T.); (M.P.)
| | - Pietro Torre
- Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, “Scuola Medica Salernitana”, University of Salerno, 84084 Salerno, Italy; (V.R.); (M.M.); (P.T.); (M.P.)
| | - Marcello Dallio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.D.); (M.R.)
| | - Mario Romeo
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.D.); (M.R.)
| | - Marcello Persico
- Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, “Scuola Medica Salernitana”, University of Salerno, 84084 Salerno, Italy; (V.R.); (M.M.); (P.T.); (M.P.)
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26
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Johnston JA, Nelson DR, Bhatnagar P, Curtis SE, Chen Y, MacKrell JG. Prevalence and cardiometabolic correlates of ketohexokinase gene variants among UK Biobank participants. PLoS One 2021; 16:e0247683. [PMID: 33621267 PMCID: PMC7901775 DOI: 10.1371/journal.pone.0247683] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 02/11/2021] [Indexed: 11/18/2022] Open
Abstract
Essential fructosuria (EF) is a benign, asymptomatic, autosomal recessive condition caused by loss-of-function variants in the ketohexokinase gene and characterized by intermittent appearance of fructose in the urine. Despite a basic understanding of the genetic and molecular basis of EF, relatively little is known about the long-term clinical consequences of ketohexokinase gene variants. We examined the frequency of ketohexokinase variants in the UK Biobank sample and compared the cardiometabolic profiles of groups of individuals with and without these variants alone or in combination. Study cohorts consisted of groups of participants defined based on the presence of one or more of the five ketohexokinase gene variants tested for in the Affymetrix assays used by the UK Biobank. The rs2304681:G>A (p.Val49Ile) variant was present on more than one-third (36.8%) of chromosomes; other variant alleles were rare (<1%). No participants with the compound heterozygous genotype present in subjects exhibiting the EF phenotype in the literature (Gly40Arg/Ala43Thr) were identified. The rs2304681:G>A (p.Val49Ile), rs41288797 (p.Val188Met), and rs114353144 (p.Val264Ile) variants were more common in white versus non-white participants. Otherwise, few statistically or clinically significant differences were observed after adjustment for multiple comparisons. These findings reinforce the current understanding of EF as a rare, benign, autosomal recessive condition.
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Affiliation(s)
- Joseph A. Johnston
- Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Indianapolis, Indiana, United States of America
- * E-mail:
| | - David R. Nelson
- Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Pallav Bhatnagar
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Sarah E. Curtis
- Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Yu Chen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - James G. MacKrell
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
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27
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Skenderian S, Park G, Jang C. Organismal Fructose Metabolism in Health and Non-Alcoholic Fatty Liver Disease. BIOLOGY 2020; 9:E405. [PMID: 33218081 PMCID: PMC7698815 DOI: 10.3390/biology9110405] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/16/2020] [Accepted: 11/17/2020] [Indexed: 02/07/2023]
Abstract
NAFLD has alarmingly increased, yet FDA-approved drugs are still lacking. An excessive intake of fructose, especially in liquid form, is a dietary risk factor of NAFLD. While fructose metabolism has been studied for decades, it is still controversial how fructose intake can cause NAFLD. It has long been believed that fructose metabolism solely happens in the liver and accordingly, numerous studies have investigated liver fructose metabolism using primary hepatocytes or liver cell lines in culture. While cultured cells are useful for studying detailed signaling pathways and metabolism in a cell-autonomous manner, it is equally important to understand fructose metabolism at the whole-body level in live organisms. In this regard, recent in vivo studies using genetically modified mice and stable isotope tracing have tremendously expanded our understanding of the complex interaction between fructose-catabolizing organs and gut microbiota. Here, we discuss how the aberrant distribution of fructose metabolism between organs and gut microbiota can contribute to NAFLD. We also address potential therapeutic interventions of fructose-elicited NAFLD.
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Affiliation(s)
- Shea Skenderian
- Department of Molecular & Cell Biology, University of California Berkeley, Berkeley, CA 94720, USA;
- Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA;
| | - Grace Park
- Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA;
| | - Cholsoon Jang
- Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA;
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28
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Ketohexokinase-A acts as a nuclear protein kinase that mediates fructose-induced metastasis in breast cancer. Nat Commun 2020; 11:5436. [PMID: 33116123 PMCID: PMC7595112 DOI: 10.1038/s41467-020-19263-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 09/29/2020] [Indexed: 02/06/2023] Open
Abstract
Harmful effects of high fructose intake on health have been widely reported. Although fructose is known to promote cancer, little is known about the underlying mechanisms. Here, we found that fructose triggers breast cancer metastasis through the ketohexokinase-A signaling pathway. Molecular experiments showed that ketohexokinase-A, rather than ketohexokinase-C, is necessary and sufficient for fructose-induced cell invasion. Ketohexokinase-A-overexpressing breast cancer was found to be highly metastatic in fructose-fed mice. Mechanistically, cytoplasmic ketohexokinase-A enters into the nucleus during fructose stimulation, which is mediated by LRRC59 and KPNB1. In the nucleus, ketohexokinase-A phosphorylates YWHAH at Ser25 and the YWHAH recruits SLUG to the CDH1 promoter, which triggers cell migration. This study provides the effect of nutrition on breast cancer metastasis. High intake of fructose should be restricted in cancer patients to reduce the risk of metastasis. From a therapeutic perspective, the ketohexokinase-A signaling pathway could be a potential target to prevent cancer metastasis.
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29
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Helsley RN, Moreau F, Gupta MK, Radulescu A, DeBosch B, Softic S. Tissue-Specific Fructose Metabolism in Obesity and Diabetes. Curr Diab Rep 2020; 20:64. [PMID: 33057854 DOI: 10.1007/s11892-020-01342-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/10/2020] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW The objective of this review is to provide up-to-date and comprehensive discussion of tissue-specific fructose metabolism in the context of diabetes, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS Increased intake of dietary fructose is a risk factor for a myriad of metabolic complications. Tissue-specific fructose metabolism has not been well delineated in terms of its contribution to detrimental health effects associated with fructose intake. Since inhibitors targeting fructose metabolism are being developed for the management of NAFLD and diabetes, it is essential to recognize how inability of one tissue to metabolize fructose may affect metabolism in the other tissues. The primary sites of fructose metabolism are the liver, intestine, and kidney. Skeletal muscle and adipose tissue can also metabolize a large portion of fructose load, especially in the setting of ketohexokinase deficiency, the rate-limiting enzyme of fructose metabolism. Fructose can also be sensed by the pancreas and the brain, where it can influence essential functions involved in energy homeostasis. Lastly, fructose is metabolized by the testes, red blood cells, and lens of the eye where it may contribute to infertility, advanced glycation end products, and cataracts, respectively. An increase in sugar intake, particularly fructose, has been associated with the development of obesity and its complications. Inhibition of fructose utilization in tissues primary responsible for its metabolism alters consumption in other tissues, which have not been traditionally regarded as important depots of fructose metabolism.
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Affiliation(s)
- Robert N Helsley
- Division of Pediatric Gastroenterology, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, 40506, USA
| | - Francois Moreau
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Manoj K Gupta
- Islet Cell and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA
| | - Aurelia Radulescu
- Department of Pediatrics, University of Kentucky College of Medicine and Kentucky Children's Hospital, Lexington, KY, 40536, USA
| | - Brian DeBosch
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63131, USA
| | - Samir Softic
- Division of Pediatric Gastroenterology, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, 138 Leader Ave, Lexington, KY, 40506, USA.
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30
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Triose Kinase Controls the Lipogenic Potential of Fructose and Dietary Tolerance. Cell Metab 2020; 32:605-618.e7. [PMID: 32818435 DOI: 10.1016/j.cmet.2020.07.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 04/16/2020] [Accepted: 07/28/2020] [Indexed: 01/01/2023]
Abstract
The surge in fructose consumption is a major factor behind the rapid rise of nonalcoholic fatty liver disease in modern society. Through flux and genetic analyses, we demonstrate that fructose is catabolized at a much higher rate than glucose, and triose kinase (TK) couples fructolysis with lipogenesis metabolically and transcriptionally. In the absence of TK, fructose oxidation is accelerated through the activation of aldehyde dehydrogenase (ALDH) and serine biosynthesis, accompanied by increased oxidative stress and fructose aversion. TK is also required by the endogenous fructolysis pathway to drive lipogenesis and hepatic triglyceride accumulation under high-fat diet and leptin-deficient conditions. Intriguingly, a nonsynonymous TK allele (rs2260655_A) segregated during human migration out of Africa behaves as TK null for its inability to rescue fructose toxicity and increase hepatic triglyceride accumulation. Therefore, we posit TK as a metabolic switch controlling the lipogenic potential of fructose and its dietary tolerance.
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31
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Yang J, Yang S, Wang Q, Pang J, Wang Y, Wang H, Fu X. KHK-A promotes the proliferation of oesophageal squamous cell carcinoma through the up-regulation of PRPS1. Arab J Gastroenterol 2020; 22:40-46. [PMID: 32928708 DOI: 10.1016/j.ajg.2020.08.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 08/11/2020] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND STUDY AIMS The metabolism of dietary fructose by ketohexokinase (KHK) is an important step in glucose metabolism in various tumour types. However, the expression, function and underlying mechanisms of KHK in oesophageal squamous cell carcinoma (ESCC) remain largely unclear. The objective of this study was to investigate the effects of KHK-A, a peripheral isoform of KHK, on the proliferation of ESCC cell lines. MATERIAL AND METHODS The function and mechanism of KHK-A in ESCC cells were investigated by constructing stable KHK-A-knockdown and -overexpressing ESCC cell lines (KYSE410 and KYSE150, respectively). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry and colony formation assays were used to analyse the effects of KHK-A on cell proliferation, cell cycle and colony formation, respectively. KHK-A and phosphoribosyl pyrophosphate synthetase isoform 1 (PRPS1) mRNA and protein expressions in several ESCC cell lines were determined using routine reverse transcription-polymerase chain reaction and immunoblotting, respectively. KHK and PRPS1 expressions in ESCC tumour tissues and corresponding adjacent non-tumour tissues were evaluated according to the gene expression omnibus (GEO) database (GSE20347). RESULTS In vitro experiments showed that KHK-A significantly promoted cell proliferation by modulating the G1/S phase transition in the cell cycle, which was probably regulated by PRPS1 expression. GEO database-based analysis showed that KHK levels were significantly higher in the ESCC tissues than in the corresponding adjacent non-tumour tissues. Pearson's correlation coefficient analysis showed that KHK expression in ESCC cell lines and tissues was significantly positively associated with the up-regulation of PRPS1, suggesting that KHK-A levels regulate PRPS1 expression in ESCC. CONCLUSION KHK-A may serve as a driving gene in ESCC for the activation of PRPS1, resulting in the up-regulation of PRPS1. This could lead to enhanced nucleic acid synthesis for tumourigenesis. Our study showed that KHK-A is a potential target for ESCC diagnosis and therapy.
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Affiliation(s)
- Jie Yang
- Department of Gastroenterology, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China.
| | - Senlin Yang
- Department of Gastroenterology, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
| | - Qi Wang
- Department of Gastroenterology, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
| | - Jing Pang
- Endoscopy Center, Affiliated Tumor Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
| | - Yuan Wang
- Department of Gastroenterology, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
| | - Huimin Wang
- Department of Gastroenterology, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
| | - Xiaohong Fu
- Department of Gastroenterology, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
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Eberhart T, Schönenberger MJ, Walter KM, Charles KN, Faust PL, Kovacs WJ. Peroxisome-Deficiency and HIF-2α Signaling Are Negative Regulators of Ketohexokinase Expression. Front Cell Dev Biol 2020; 8:566. [PMID: 32733884 PMCID: PMC7360681 DOI: 10.3389/fcell.2020.00566] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/15/2020] [Indexed: 12/28/2022] Open
Abstract
Ketohexokinase (KHK) is the first and rate-limiting enzyme of fructose metabolism. Expression of the two alternatively spliced KHK isoforms, KHK-A and KHK-C, is tissue-specific and KHK-C is predominantly expressed in liver, kidney and intestine and responsible for the fructose-catabolizing function. While KHK isoform choice has been linked to the development of disorders such as obesity, diabetes, cardiovascular disease and cancer, little is known about the regulation of total KHK expression. In the present study, we investigated how hypoxic signaling influences fructose metabolism in the liver. Hypoxia or von Hippel-Lindau (VHL) tumor suppressor loss leads to the stabilization of hypoxia-inducible factors alpha (HIF-1α and HIF-2α) and the activation of their signaling to mediate adaptive responses. By studying liver-specific Vhl, Vhl/Hif1a, and Vhl/Epas1 knockout mice, we found that KHK expression is suppressed by HIF-2α (encoded by Epas1) but not by HIF-1α signaling on mRNA and protein levels. Reduced KHK levels were accompanied by downregulation of aldolase B (ALDOB) in the livers of Vhl and Vhl/Hif1a knockout mice, further indicating inhibited fructose metabolism. HIF-1α and HIF-2α have both overlapping and distinct target genes but are differentially regulated depending on the cell type and physiologic or pathologic conditions. HIF-2α activation augments peroxisome degradation in mammalian cells by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We further demonstrated that fructose metabolism is negatively regulated by peroxisome-deficiency in a Pex2 knockout Zellweger mouse model, which lacks functional peroxisomes and is characterized by widespread metabolic dysfunction. Repression of fructolytic genes in Pex2 knockout mice appeared to be independent of PPARα signaling and nutritional status. Interestingly, our results demonstrate that both HIF-2α and peroxisome-deficiency result in downregulation of Khk independent of splicing as both isoforms, Khka as well as Khkc, are significantly downregulated. Hence, our study offers new and unexpected insights into the general regulation of KHK, and therefore fructolysis. We revealed a novel regulatory function of HIF-2α, suggesting that HIF-1α and HIF-2α have tissue-specific opposing roles in the regulation of Khk expression, isoform choice and fructolysis. In addition, we discovered a previously unknown function of peroxisomes in the regulation of fructose metabolism.
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Affiliation(s)
- Tanja Eberhart
- Institute of Molecular Health Sciences, ETH Zürich, Zurich, Switzerland
| | | | | | - Khanichi N. Charles
- Department of Biology, San Diego State University, San Diego, CA, United States
| | - Phyllis L. Faust
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
| | - Werner J. Kovacs
- Institute of Molecular Health Sciences, ETH Zürich, Zurich, Switzerland
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33
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Williams EAJ, Douard V, Sugimoto K, Inui H, Devime F, Zhang X, Kishida K, Ferraris RP, Fritton JC. Bone Growth is Influenced by Fructose in Adolescent Male Mice Lacking Ketohexokinase (KHK). Calcif Tissue Int 2020; 106:541-552. [PMID: 31996963 PMCID: PMC9466006 DOI: 10.1007/s00223-020-00663-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 01/20/2020] [Indexed: 01/01/2023]
Abstract
Fructose is metabolized in the cytoplasm by the enzyme ketohexokinase (KHK), and excessive consumption may affect bone health. Previous work in calcium-restricted, growing mice demonstrated that fructose disrupted intestinal calcium transport. Thus, we hypothesized that the observed effects on bone were dependent on fructose metabolism and took advantage of a KHK knockout (KO) model to assess direct effects of high plasma fructose on the long bones of growing mice. Four groups (n = 12) of 4-week-old, male, C57Bl/6 background, congenic mice with intact KHK (wild-type, WT) or global knockout of both isoforms of KHK-A/C (KHK-KO), were fed 20% glucose (control diet) or fructose for 8 weeks. Dietary fructose increased by 40-fold plasma fructose in KHK-KO compared to the other three groups (p < 0.05). Obesity (no differences in epididymal fat or body weight) or altered insulin was not observed in either genotype. The femurs of KHK-KO mice with the highest levels of plasma fructose were shorter (2%). Surprisingly, despite the long-term blockade of KHK, fructose feeding resulted in greater bone mineral density, percent volume, and number of trabeculae as measured by µCT in the distal femur of KHK-KO. Moreover, higher plasma fructose concentrations correlated with greater trabecular bone volume, greater work-to-fracture in three-point bending of the femur mid-shaft, and greater plasma sclerostin. Since the metabolism of fructose is severely inhibited in the KHK-KO condition, our data suggest mechanism(s) that alter bone growth may be related to the plasma concentration of fructose.
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Affiliation(s)
- Edek A J Williams
- Department of Biomedical Engineering, Graduate School, Rutgers University, New Brunswick, NJ, USA
| | - Veronique Douard
- MICALIS Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | | | - Hiroshi Inui
- Center for Research and Development of Bioresources & Department of Clinical Nutrition, College of Health and Human Sciences, Osaka Prefecture University, Habikino, Osaka, Japan
| | - Fabienne Devime
- MICALIS Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Xufei Zhang
- MICALIS Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Kunihiro Kishida
- Department of Science and Technology On Food Safety, Kindai University, Wakayama, Japan
| | - Ronaldo P Ferraris
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, NJ, USA
| | - J Christopher Fritton
- Department of Biomedical Engineering, Graduate School, Rutgers University, New Brunswick, NJ, USA.
- Departments of Mechanical and Biomedical Engineering, Grove School of Engineering, The City College of New York, 160 Convent Avenue, Steinman Hall T401, New York, NY, 10031, USA.
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34
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Softic S, Stanhope KL, Boucher J, Divanovic S, Lanaspa MA, Johnson RJ, Kahn CR. Fructose and hepatic insulin resistance. Crit Rev Clin Lab Sci 2020; 57:308-322. [PMID: 31935149 DOI: 10.1080/10408363.2019.1711360] [Citation(s) in RCA: 141] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Excessive caloric intake in a form of high-fat diet (HFD) was long thought to be the major risk factor for development of obesity and its complications, such as fatty liver disease and insulin resistance. Recently, there has been a paradigm shift and more attention is attributed to the effects of sugar-sweetened beverages (SSBs) as one of the culprits of the obesity epidemic. In this review, we present the data invoking fructose intake with development of hepatic insulin resistance in human studies and discuss the pathways by which fructose impairs hepatic insulin action in experimental animal models. First, we described well-characterized pathways by which fructose metabolism indirectly leads to hepatic insulin resistance. These include unequivocal effects of fructose to promote de novo lipogenesis (DNL), impair fatty acid oxidation (FAO), induce endoplasmic reticulum (ER) stress and trigger hepatic inflammation. Additionally, we entertained the hypothesis that fructose can directly impede insulin signaling in the liver. This appears to be mediated by reduced insulin receptor and insulin receptor substrate 2 (IRS2) expression, increased protein-tyrosine phosphatase 1B (PTP1b) activity, whereas knockdown of ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, increased insulin sensitivity. In summary, dietary fructose intake strongly promotes hepatic insulin resistance via complex interplay of several metabolic pathways, at least some of which are independent of increased weight gain and caloric intake. The current evidence shows that the fructose, but not glucose, component of dietary sugar drives metabolic complications and contradicts the notion that fructose is merely a source of palatable calories that leads to increased weight gain and insulin resistance.
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Affiliation(s)
- Samir Softic
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Kentucky College of Medicine and Kentucky Children's Hospital, Lexington, KY, USA.,Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA
| | - Kimber L Stanhope
- Department of Molecular Biosciences, University of California, Davis, Davis, CA, USA
| | - Jeremie Boucher
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.,The Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.,Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.,Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Miguel A Lanaspa
- Division of Renal Diseases and Hypertension, University of Colorado, Aurora, CO, USA
| | - Richard J Johnson
- Division of Renal Diseases and Hypertension, University of Colorado, Aurora, CO, USA
| | - C Ronald Kahn
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA
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35
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Francois JM, Alkim C, Morin N. Engineering microbial pathways for production of bio-based chemicals from lignocellulosic sugars: current status and perspectives. BIOTECHNOLOGY FOR BIOFUELS 2020; 13:118. [PMID: 32670405 PMCID: PMC7341569 DOI: 10.1186/s13068-020-01744-6] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 06/01/2020] [Indexed: 05/08/2023]
Abstract
Lignocellulose is the most abundant biomass on earth with an annual production of about 2 × 1011 tons. It is an inedible renewable carbonaceous resource that is very rich in pentose and hexose sugars. The ability of microorganisms to use lignocellulosic sugars can be exploited for the production of biofuels and chemicals, and their concurrent biotechnological processes could advantageously replace petrochemicals' processes in a medium to long term, sustaining the emerging of a new economy based on bio-based products from renewable carbon sources. One of the major issues to reach this objective is to rewire the microbial metabolism to optimally configure conversion of these lignocellulosic-derived sugars into bio-based products in a sustainable and competitive manner. Systems' metabolic engineering encompassing synthetic biology and evolutionary engineering appears to be the most promising scientific and technological approaches to meet this challenge. In this review, we examine the most recent advances and strategies to redesign natural and to implement non-natural pathways in microbial metabolic framework for the assimilation and conversion of pentose and hexose sugars derived from lignocellulosic material into industrial relevant chemical compounds leading to maximal yield, titer and productivity. These include glycolic, glutaric, mesaconic and 3,4-dihydroxybutyric acid as organic acids, monoethylene glycol, 1,4-butanediol and 1,2,4-butanetriol, as alcohols. We also discuss the big challenges that still remain to enable microbial processes to become industrially attractive and economically profitable.
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Affiliation(s)
- Jean Marie Francois
- Toulouse Biotechnology Institute, CNRS, INRA, LISBP INSA, 135 Avenue de Rangueil, Toulouse Cedex 04, 31077 France
- Toulouse White Biotechnology (TWB, UMS INRA/INSA/CNRS), NAPA CENTER Bât B, 3 Rue Ariane 31520, Ramonville Saint-Agnes, France
| | - Ceren Alkim
- Toulouse Biotechnology Institute, CNRS, INRA, LISBP INSA, 135 Avenue de Rangueil, Toulouse Cedex 04, 31077 France
- Toulouse White Biotechnology (TWB, UMS INRA/INSA/CNRS), NAPA CENTER Bât B, 3 Rue Ariane 31520, Ramonville Saint-Agnes, France
| | - Nicolas Morin
- Toulouse Biotechnology Institute, CNRS, INRA, LISBP INSA, 135 Avenue de Rangueil, Toulouse Cedex 04, 31077 France
- Toulouse White Biotechnology (TWB, UMS INRA/INSA/CNRS), NAPA CENTER Bât B, 3 Rue Ariane 31520, Ramonville Saint-Agnes, France
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36
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Merino B, Fernández-Díaz CM, Cózar-Castellano I, Perdomo G. Intestinal Fructose and Glucose Metabolism in Health and Disease. Nutrients 2019; 12:E94. [PMID: 31905727 PMCID: PMC7019254 DOI: 10.3390/nu12010094] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 12/26/2019] [Accepted: 12/26/2019] [Indexed: 02/06/2023] Open
Abstract
The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease. Finally, the peripheral and central effects of dietary sugars on the gut-brain axis will be reviewed.
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Affiliation(s)
- Beatriz Merino
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
| | - Cristina M. Fernández-Díaz
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
| | - Irene Cózar-Castellano
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain
| | - German Perdomo
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
- Departamento de Ciencias de la Salud, Universidad de Burgos, Burgos 09001, Spain
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Yang X, Shao F, Shi S, Feng X, Wang W, Wang Y, Guo W, Wang J, Gao S, Gao Y, Lu Z, He J. Prognostic Impact of Metabolism Reprogramming Markers Acetyl-CoA Synthetase 2 Phosphorylation and Ketohexokinase-A Expression in Non-Small-Cell Lung Carcinoma. Front Oncol 2019; 9:1123. [PMID: 31750240 PMCID: PMC6848158 DOI: 10.3389/fonc.2019.01123] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 10/09/2019] [Indexed: 01/04/2023] Open
Abstract
Background: The identification of prognostic markers for non-small-cell lung carcinoma (NSCLC) is needed for clinical practice. The metabolism-reprogramming marker ketohexokinase (KHK)-A and acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659 (ACSS2 pS659) play important roles in tumorigenesis and tumor development. However, the clinical significance of KHK-A and ACSS2 pS659 in NSCLC is largely unknown. Methods: The expression levels of KHK-A and ACSS2 pS659 were assessed by immunohistochemistry analyses of surgical specimens from 303 NSCLC patients. The prognostic values of KHK-A and ACSS2 pS659 were evaluated by Kaplan-Meier methods and Cox regression models. Results: The expression levels of KHK-A and ACSS2 pS659 were significantly higher in NSCLC tissues than those in adjacent non-tumor tissues (P < 0.0001). KHK-A or ACSS2 pS659 alone and the combination of KHK-A and ACSS2 pS659 were inversely correlated with overall survival in NSCLC patients (P < 0.001). The multivariate analysis indicated that KHK-A or ACSS2 pS659 and KHK-A/ACSS2 pS659 were independent prognostic biomarkers for NSCLC (P = 0.008 for KHK-A, P < 0.001 for ACSS2 pS659, and P < 0.001 for KHK-A/ACSS2 pS659). Furthermore, the combination of KHK-A and ACSS2 pS659 can be used as a prognostic indicator for all stages of NSCLC. Conclusions: KHK-A or ACSS2 pS659 alone and the combination of KHK-A and ACSS2 pS659 can be used as prognostic markers for NSCLC. Our findings highlight the important role of metabolic reprogramming in NSCLC progression.
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Affiliation(s)
- Xueying Yang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fei Shao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China.,Qingdao Cancer Institute, Qingdao, China
| | - Susheng Shi
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoli Feng
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yalong Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Guo
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Juhong Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shugeng Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yibo Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhimin Lu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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38
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Chabbert CD, Eberhart T, Guccini I, Krek W, Kovacs WJ. Correction of gene model annotations improves isoform abundance estimates: the example of ketohexokinase ( Khk). F1000Res 2018; 7:1956. [PMID: 31001414 PMCID: PMC6464065 DOI: 10.12688/f1000research.17082.2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/20/2019] [Indexed: 12/13/2022] Open
Abstract
Next generation sequencing protocols such as RNA-seq have made the genome-wide characterization of the transcriptome a crucial part of many research projects in biology. Analyses of the resulting data provide key information on gene expression and in certain cases on exon or isoform usage. The emergence of transcript quantification software such as Salmon has enabled researchers to efficiently estimate isoform and gene expressions across the genome while tremendously reducing the necessary computational power. Although overall gene expression estimations were shown to be accurate, isoform expression quantifications appear to be a more challenging task. Low expression levels and uneven or insufficient coverage were reported as potential explanations for inconsistent estimates. Here, through the example of the ketohexokinase (
Khk) gene in mouse, we demonstrate that the use of an incorrect gene annotation can also result in erroneous isoform quantification results. Manual correction of the input
Khk gene model provided a much more accurate estimation of relative
Khk isoform expression when compared to quantitative PCR (qPCR measurements). In particular, removal of an unexpressed retained intron and a proper adjustment of the 5’ and 3’ untranslated regions both had a strong impact on the correction of erroneous estimates. Finally, we observed a better concordance in isoform quantification between datasets and sequencing strategies when relying on the newly generated
Khk annotations. These results highlight the importance of accurate gene models and annotations for correct isoform quantification and reassert the need for orthogonal methods of estimation of isoform expression to confirm important findings.
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Affiliation(s)
| | - Tanja Eberhart
- Institute of Molecular Health Sciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Ilaria Guccini
- Institute of Molecular Health Sciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Wilhelm Krek
- Institute of Molecular Health Sciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Werner J Kovacs
- Institute of Molecular Health Sciences, ETH Zurich, Zurich, 8093, Switzerland
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39
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Strawbridge RJ, Ward J, Lyall LM, Tunbridge EM, Cullen B, Graham N, Ferguson A, Johnston KJA, Lyall DM, Mackay D, Cavanagh J, Howard DM, Adams MJ, Deary I, Escott-Price V, O'Donovan M, McIntosh AM, Bailey MES, Pell JP, Harrison PJ, Smith DJ. Genetics of self-reported risk-taking behaviour, trans-ethnic consistency and relevance to brain gene expression. Transl Psychiatry 2018; 8:178. [PMID: 30181555 PMCID: PMC6123450 DOI: 10.1038/s41398-018-0236-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 08/05/2018] [Indexed: 12/25/2022] Open
Abstract
Risk-taking behaviour is an important component of several psychiatric disorders, including attention-deficit hyperactivity disorder, schizophrenia and bipolar disorder. Previously, two genetic loci have been associated with self-reported risk taking and significant genetic overlap with psychiatric disorders was identified within a subsample of UK Biobank. Using the white British participants of the full UK Biobank cohort (n = 83,677 risk takers versus 244,662 controls) for our primary analysis, we conducted a genome-wide association study of self-reported risk-taking behaviour. In secondary analyses, we assessed sex-specific effects, trans-ethnic heterogeneity and genetic overlap with psychiatric traits. We also investigated the impact of risk-taking-associated SNPs on both gene expression and structural brain imaging. We identified 10 independent loci for risk-taking behaviour, of which eight were novel and two replicated previous findings. In addition, we found two further sex-specific risk-taking loci. There were strong positive genetic correlations between risk-taking and attention-deficit hyperactivity disorder, bipolar disorder and schizophrenia. Index genetic variants demonstrated effects generally consistent with the discovery analysis in individuals of non-British White, South Asian, African-Caribbean or mixed ethnicity. Polygenic risk scores comprising alleles associated with increased risk taking were associated with lower white matter integrity. Genotype-specific expression pattern analyses highlighted DPYSL5, CGREF1 and C15orf59 as plausible candidate genes. Overall, our findings substantially advance our understanding of the biology of risk-taking behaviour, including the possibility of sex-specific contributions, and reveal consistency across ethnicities. We further highlight several putative novel candidate genes, which may mediate these genetic effects.
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Affiliation(s)
- Rona J Strawbridge
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
- Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
| | - Joey Ward
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Laura M Lyall
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Elizabeth M Tunbridge
- Department of Psychiatry, University of Oxford, Oxford, UK
- Oxford Health NHS Foundation Trust, Oxford, UK
| | - Breda Cullen
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Nicholas Graham
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Amy Ferguson
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Keira J A Johnston
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
- School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Division of Psychiatry, College of Medicine, University of Edinburgh, Edinburgh, UK
| | - Donald M Lyall
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Daniel Mackay
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Jonathan Cavanagh
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - David M Howard
- Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, EH10 5HF, UK
| | - Mark J Adams
- Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, EH10 5HF, UK
| | - Ian Deary
- Department of Psychology, University of Edinburgh, Edinburgh, EH8 9YL, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9YL, UK
| | | | - Michael O'Donovan
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - Andrew M McIntosh
- Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, EH10 5HF, UK
| | - Mark E S Bailey
- School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Jill P Pell
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Paul J Harrison
- Department of Psychiatry, University of Oxford, Oxford, UK
- Oxford Health NHS Foundation Trust, Oxford, UK
| | - Daniel J Smith
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
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40
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Allen RJ, Musante CJ. A mathematical analysis of adaptations to the metabolic fate of fructose in essential fructosuria subjects. Am J Physiol Endocrinol Metab 2018; 315:E394-E403. [PMID: 29664676 DOI: 10.1152/ajpendo.00317.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Fructose is a major component of Western diets and is implicated in the pathogenesis of obesity and type 2 diabetes. In response to an oral challenge, the majority of fructose is cleared during "first-pass" liver metabolism, primarily via phosphorylation by ketohexokinase (KHK). A rare benign genetic deficiency in KHK, called essential fructosuria (EF), leads to altered fructose metabolism. The only reported symptom of EF is the appearance of fructose in the urine following either oral or intravenous fructose administration. Here we develop and use a mathematical model to investigate the adaptations to altered fructose metabolism in people with EF. First, the model is calibrated to fit available data in normal healthy subjects. Then, to mathematically represent EF subjects, we systematically implement metabolic adaptations such that model simulations match available data for this phenotype. We hypothesize that these modifications represent the major metabolic adaptations present in these subjects. This modeling approach suggests that several other aspects of fructose metabolism, beyond hepatic KHK deficiency, are altered and contribute to the etiology of this benign condition. Specifically, we predict that fructose absorption into the portal vein is altered, peripheral metabolism is slowed, renal reabsorption of fructose is mostly ablated, and alternate pathways for hepatic metabolism of fructose are upregulated. Moreover, these findings have implications for drug discovery and development, suggesting that the therapeutic targeting of fructose metabolism could lead to unexpected metabolic adaptations, potentially due to a physiological response to high-fructose conditions.
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Affiliation(s)
- Richard J Allen
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, Massachusetts
| | - Cynthia J Musante
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, Massachusetts
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41
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Tappy L. Fructose metabolism and noncommunicable diseases: recent findings and new research perspectives. Curr Opin Clin Nutr Metab Care 2018; 21:214-222. [PMID: 29406418 DOI: 10.1097/mco.0000000000000460] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW There is increasing concern that dietary fructose may contribute to the development of noncommunicable diseases. This review identifies major new findings related to fructose's physiological or adverse effects. RECENT FINDINGS Fructose is mainly processed in splanchnic organs (gut, liver, kidneys) to glucose, lactate, and fatty acids, which can then be oxidized in extrasplanchnic organs and tissues. There is growing evidence that splanchnic lactate production, linked to extrasplanchnic lactate metabolism, represents a major fructose disposal pathway during and after exercise. Chronic excess fructose intake can be directly responsible for an increase in intrahepatic fat concentration and for the development of hepatic, but not muscle insulin resistance. Although it has long been thought that fructose was exclusively metabolized in splanchnic organs, several recent reports provide indirect that some fructose may also be metabolized in extrasplanchnic cells, such as adipocytes, muscle, or brain cells; the quantity of fructose directly metabolized in extrasplanchnic cells, and its physiological consequences, remain however unknown. There is also growing evidence that endogenous fructose production from glucose occurs in humans and may have important physiological functions, but may also be associated with adverse health effects. SUMMARY Fructose is a physiological nutrient which, when consumed in excess, may have adverse metabolic effects, mainly in the liver (hepatic insulin resistance and fat storage). There is also concern that exogenous or endogenously produced fructose may be directly metabolized in extrasplanchnic cells in which it may exert adverse metabolic effects.
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Affiliation(s)
- Luc Tappy
- Physiology Department, Faculty of Biology and Medicine, University of Lausanne, Lausanne
- Metabolic Center, Hôpital Intercantonal de la Broye, Estavayer-le-lac, Switzerland
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42
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Lu Z, Hunter T. Metabolic Kinases Moonlighting as Protein Kinases. Trends Biochem Sci 2018; 43:301-310. [PMID: 29463470 PMCID: PMC5879014 DOI: 10.1016/j.tibs.2018.01.006] [Citation(s) in RCA: 176] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 01/15/2018] [Accepted: 01/25/2018] [Indexed: 12/17/2022]
Abstract
Protein kinases regulate every aspect of cellular activity, whereas metabolic enzymes are responsible for energy production and catabolic and anabolic processes. Emerging evidence demonstrates that some metabolic enzymes, such as pyruvate kinase M2 (PKM2), phosphoglycerate kinase 1 (PGK1), ketohexokinase (KHK) isoform A (KHK-A), hexokinase (HK), and nucleoside diphosphate kinase 1 and 2 (NME1/2), that phosphorylate soluble metabolites can also function as protein kinases and phosphorylate a variety of protein substrates to regulate the Warburg effect, gene expression, cell cycle progression and proliferation, apoptosis, autophagy, exosome secretion, T cell activation, iron transport, ion channel opening, and many other fundamental cellular functions. The elevated protein kinase functions of these moonlighting metabolic enzymes in tumor development make them promising therapeutic targets for cancer.
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Affiliation(s)
- Zhimin Lu
- Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA.
| | - Tony Hunter
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
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43
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Hannou SA, Haslam DE, McKeown NM, Herman MA. Fructose metabolism and metabolic disease. J Clin Invest 2018; 128:545-555. [PMID: 29388924 DOI: 10.1172/jci96702] [Citation(s) in RCA: 354] [Impact Index Per Article: 50.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Here we review the biology of fructose metabolism as well as potential mechanisms by which excessive fructose consumption may contribute to cardiometabolic disease.
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Affiliation(s)
- Sarah A Hannou
- Division of Endocrinology and Metabolism and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA
| | - Danielle E Haslam
- Nutritional Epidemiology Program, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA
| | - Nicola M McKeown
- Nutritional Epidemiology Program, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA
| | - Mark A Herman
- Division of Endocrinology and Metabolism and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA
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44
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Softic S, Gupta MK, Wang GX, Fujisaka S, O'Neill BT, Rao TN, Willoughby J, Harbison C, Fitzgerald K, Ilkayeva O, Newgard CB, Cohen DE, Kahn CR. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest 2017; 127:4059-4074. [PMID: 28972537 DOI: 10.1172/jci94585] [Citation(s) in RCA: 237] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 08/10/2017] [Indexed: 12/18/2022] Open
Abstract
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.
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Affiliation(s)
- Samir Softic
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.,Boston Children's Hospital, Division of Gastroenterology, Boston, Massachusetts, USA
| | - Manoj K Gupta
- Section of Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Guo-Xiao Wang
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Shiho Fujisaka
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.,First Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Brian T O'Neill
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.,Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Tata Nageswara Rao
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.,Experimental Hematology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | | | | | | | - Olga Ilkayeva
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute and Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Christopher B Newgard
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute and Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - David E Cohen
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York, USA
| | - C Ronald Kahn
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
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45
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Geidl-Flueck B, Gerber PA. Insights into the Hexose Liver Metabolism-Glucose versus Fructose. Nutrients 2017; 9:E1026. [PMID: 28926951 PMCID: PMC5622786 DOI: 10.3390/nu9091026] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 09/09/2017] [Accepted: 09/11/2017] [Indexed: 12/15/2022] Open
Abstract
High-fructose intake in healthy men is associated with characteristics of metabolic syndrome. Extensive knowledge exists about the differences between hepatic fructose and glucose metabolism and fructose-specific mechanisms favoring the development of metabolic disturbances. Nevertheless, the causal relationship between fructose consumption and metabolic alterations is still debated. Multiple effects of fructose on hepatic metabolism are attributed to the fact that the liver represents the major sink of fructose. Fructose, as a lipogenic substrate and potent inducer of lipogenic enzyme expression, enhances fatty acid synthesis. Consequently, increased hepatic diacylglycerols (DAG) are thought to directly interfere with insulin signaling. However, independently of this effect, fructose may also counteract insulin-mediated effects on liver metabolism by a range of mechanisms. It may drive gluconeogenesis not only as a gluconeogenic substrate, but also as a potent inducer of carbohydrate responsive element binding protein (ChREBP), which induces the expression of lipogenic enzymes as well as gluconeogenic enzymes. It remains a challenge to determine the relative contributions of the impact of fructose on hepatic transcriptome, proteome and allosterome changes and consequently on the regulation of plasma glucose metabolism/homeostasis. Mathematical models exist modeling hepatic glucose metabolism. Future models should not only consider the hepatic adjustments of enzyme abundances and activities in response to changing plasma glucose and insulin/glucagon concentrations, but also to varying fructose concentrations for defining the role of fructose in the hepatic control of plasma glucose homeostasis.
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Affiliation(s)
- Bettina Geidl-Flueck
- Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, 8091 Zurich, Switzerland.
| | - Philipp A Gerber
- Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, 8091 Zurich, Switzerland.
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46
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Huard K, Ahn K, Amor P, Beebe DA, Borzilleri KA, Chrunyk BA, Coffey SB, Cong Y, Conn EL, Culp JS, Dowling MS, Gorgoglione MF, Gutierrez JA, Knafels JD, Lachapelle EA, Pandit J, Parris KD, Perez S, Pfefferkorn JA, Price DA, Raymer B, Ross TT, Shavnya A, Smith AC, Subashi TA, Tesz GJ, Thuma BA, Tu M, Weaver JD, Weng Y, Withka JM, Xing G, Magee TV. Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK). J Med Chem 2017; 60:7835-7849. [PMID: 28853885 DOI: 10.1021/acs.jmedchem.7b00947] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.
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Affiliation(s)
- Kim Huard
- Medicine Design, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Kay Ahn
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Paul Amor
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - David A Beebe
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Kris A Borzilleri
- Structural Biology and Biophysics, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Boris A Chrunyk
- Structural Biology and Biophysics, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Steven B Coffey
- Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Yang Cong
- Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Edward L Conn
- Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Jeffrey S Culp
- Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Matthew S Dowling
- Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Matthew F Gorgoglione
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Jemy A Gutierrez
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - John D Knafels
- Structural Biology and Biophysics, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Erik A Lachapelle
- Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Jayvardhan Pandit
- Structural Biology and Biophysics, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Kevin D Parris
- Structural Biology and Biophysics, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Sylvie Perez
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Jeffrey A Pfefferkorn
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - David A Price
- Medicine Design, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Brian Raymer
- Medicine Design, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Trenton T Ross
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Andre Shavnya
- Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Aaron C Smith
- Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Timothy A Subashi
- Structural Biology and Biophysics, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Gregory J Tesz
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Benjamin A Thuma
- Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Meihua Tu
- Medicine Design, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - John D Weaver
- Medicine Design, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Yan Weng
- Medicine Design, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Jane M Withka
- Structural Biology and Biophysics, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States
| | - Gang Xing
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
| | - Thomas V Magee
- Internal Medicine, Pfizer Inc. , 1 Portland Street, Cambridge, Massachusetts 02139, United States
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47
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Kozlovski I, Siegfried Z, Amar-Schwartz A, Karni R. The role of RNA alternative splicing in regulating cancer metabolism. Hum Genet 2017; 136:1113-1127. [PMID: 28429085 DOI: 10.1007/s00439-017-1803-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 04/13/2017] [Indexed: 12/12/2022]
Abstract
Tumor cells alter their metabolism by a wide array of mechanisms to promote growth and proliferation. Dysregulated expression and/or somatic mutations of key components of the glycolytic pathway/TCA cycle as well as other metabolic pathways allow tumor cells to improve their ability to survive harsh conditions such as hypoxia and the presence of reactive oxygen species, as well as the ability to obtain nutrients to increase lipids, protein, and nucleic acids biogenesis. Approximately 95% of the human protein encoding genes undergo alternative splicing (AS), a regulated process of gene expression that greatly diversifies the proteome by creating multiple proteins from a single gene. In recent years, a growing body of evidence suggests that unbalanced AS, the formation of certain pro-tumorigenic isoforms and the reduction of anti-tumorigenic isoforms, is implicated in a variety of cancers. It is becoming increasingly clear that cancer-associated AS contributes to increased growth and proliferation, partially due to effects on metabolic reprogramming. Here, we summarize the known roles of AS in regulating cancer metabolism. We present evidence supporting the idea that AS, in many types of cancer, acts as a molecular switch that alters metabolism to drive tumorigenesis. We propose that the elucidation of misregulated AS and its downstream effects on cancer metabolism emphasizes the need for new therapeutic approaches aiming to modulate the splicing machinery to selectively target cancer cells.
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Affiliation(s)
- Itamar Kozlovski
- Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel
| | - Zahava Siegfried
- Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel
| | - Adi Amar-Schwartz
- Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel
| | - Rotem Karni
- Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel.
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48
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Abstract
Human genetic variation is a determinant of nutrient efficacy and of tolerances and intolerances and has the potential to influence nutrient intake values (NIVs). Knowledge derived from the comprehensive identification of human genetic variation offers the potential to predict the physiological and pathological consequences of individual genetic differences and prevent and/or manage adverse outcomes through diet. Nutrients and genomes interact reciprocally; genomes confer differences in nutrient utilization, whereas nutrients effectively modify genome expression, stability, and viability. Understanding the interactions that occur among human genes, including all genetic variants thereof, and environmental exposures is enabling the development of genotype-specific nutritional regimens that prevent disease and promote wellness for individuals and populations throughout the life cycle. Genomic technologies may provide new criteria for establishing NIVs. The impact of a gene variant on NIVs will be dependent on its penetrance and prevalence within a population. Recent experiences indicate that few gene variants are anticipated to be sufficiently penetrant to affect average requirement (AR) values to a greater degree than environmental factors. If highly penetrant gene variants are identified that affect nutrient requirements, the prevalence of the variant in that country or region will determine the feasibility and necessity of deriving more than one AR or upper limit (UL) for affected genetic subgroups.
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Affiliation(s)
- Patrick J Stover
- Division of Nutritional Sciences, Cornell Uniersity, 315 Savage Hall, Ithaca, NY 14853, USA.
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49
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Wen L, Huang K, Zheng Y, Liu Y, Zhu H, Wang PG. A two-step strategy for the preparation of 6-deoxy-l-sorbose. Bioorg Med Chem Lett 2016; 26:4358-61. [PMID: 27485385 PMCID: PMC5067164 DOI: 10.1016/j.bmcl.2016.03.083] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 03/23/2016] [Accepted: 03/24/2016] [Indexed: 11/19/2022]
Abstract
A two-step enzymatic strategy for the efficient and convenient synthesis of 6-deoxy-l-sorbose was reported herein. In the first reaction step, the isomerization of l-fucose (6-deoxy-l-galactose) to l-fuculose (6-deoxy-l-tagatose) catalyzed by l-fucose isomerase (FucI), and the epimerization of l-fuculose to 6-deoxy-l-sorbose catalyzed by d-tagatose 3-epimerase (DTE) were coupled with the targeted phosphorylation of 6-deoxy-l-sorbose by fructose kinase from human (HK) in a one-pot reaction. The resultant 6-deoxy-l-sorbose 1-phosphate was purified by silver nitrate precipitation method. In the second reaction step, the phosphate group of the 6-deoxy-l-sorbose 1-phosphate was hydrolyzed with acid phosphatase (AphA) to produce 6-deoxy-l-sorbose in 81% yield with regard to l-fucose.
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Affiliation(s)
- Liuqing Wen
- Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
| | - Kenneth Huang
- Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
| | - Yuan Zheng
- Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
| | - Yunpeng Liu
- Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
| | - He Zhu
- Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
| | - Peng George Wang
- Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
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Cam Y, Alkim C, Trichez D, Trebosc V, Vax A, Bartolo F, Besse P, François JM, Walther T. Engineering of a Synthetic Metabolic Pathway for the Assimilation of (d)-Xylose into Value-Added Chemicals. ACS Synth Biol 2016; 5:607-18. [PMID: 26186096 DOI: 10.1021/acssynbio.5b00103] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
A synthetic pathway for (d)-xylose assimilation was stoichiometrically evaluated and implemented in Escherichia coli strains. The pathway proceeds via isomerization of (d)-xylose to (d)-xylulose, phosphorylation of (d)-xylulose to obtain (d)-xylulose-1-phosphate (X1P), and aldolytic cleavage of the latter to yield glycolaldehyde and DHAP. Stoichiometric analyses showed that this pathway provides access to ethylene glycol with a theoretical molar yield of 1. Alternatively, both glycolaldehyde and DHAP can be converted to glycolic acid with a theoretical yield that is 20% higher than for the exclusive production of this acid via the glyoxylate shunt. Simultaneous expression of xylulose-1 kinase and X1P aldolase activities, provided by human ketohexokinase-C and human aldolase-B, respectively, restored growth of a (d)-xylulose-5-kinase mutant on xylose. This strain produced ethylene glycol as the major metabolic endproduct. Metabolic engineering provided strains that assimilated the entire C2 fraction into the central metabolism or that produced 4.3 g/L glycolic acid at a molar yield of 0.9 in shake flasks.
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Affiliation(s)
- Yvan Cam
- INSA, UPS, INP, LISBP, Université de Toulouse, 135 Avenue de Rangueil, 31077 Toulouse, France
- INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés (LISBP),, 31077 Toulouse, France
- UMR5504, CNRS, 31077 Toulouse, France
- TWB, 3 rue des Satellites, Canal Biotech Building 2, 31400 Toulouse, France
| | - Ceren Alkim
- INSA, UPS, INP, LISBP, Université de Toulouse, 135 Avenue de Rangueil, 31077 Toulouse, France
- INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés (LISBP),, 31077 Toulouse, France
- UMR5504, CNRS, 31077 Toulouse, France
- TWB, 3 rue des Satellites, Canal Biotech Building 2, 31400 Toulouse, France
| | - Debora Trichez
- INSA, UPS, INP, LISBP, Université de Toulouse, 135 Avenue de Rangueil, 31077 Toulouse, France
- INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés (LISBP),, 31077 Toulouse, France
- UMR5504, CNRS, 31077 Toulouse, France
- TWB, 3 rue des Satellites, Canal Biotech Building 2, 31400 Toulouse, France
| | - Vincent Trebosc
- INSA, UPS, INP, LISBP, Université de Toulouse, 135 Avenue de Rangueil, 31077 Toulouse, France
- INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés (LISBP),, 31077 Toulouse, France
- UMR5504, CNRS, 31077 Toulouse, France
- TWB, 3 rue des Satellites, Canal Biotech Building 2, 31400 Toulouse, France
| | - Amélie Vax
- INSA, UPS, INP, LISBP, Université de Toulouse, 135 Avenue de Rangueil, 31077 Toulouse, France
- INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés (LISBP),, 31077 Toulouse, France
- UMR5504, CNRS, 31077 Toulouse, France
- TWB, 3 rue des Satellites, Canal Biotech Building 2, 31400 Toulouse, France
| | - François Bartolo
- INSA, UPS, INP, LISBP, Université de Toulouse, 135 Avenue de Rangueil, 31077 Toulouse, France
- Département Génie Mathématiques et Modélisation (GMM), 135 Avenue de Rangueil, 31077 Toulouse, France
| | - Philippe Besse
- INSA, UPS, INP, LISBP, Université de Toulouse, 135 Avenue de Rangueil, 31077 Toulouse, France
- Département Génie Mathématiques et Modélisation (GMM), 135 Avenue de Rangueil, 31077 Toulouse, France
| | - Jean Marie François
- INSA, UPS, INP, LISBP, Université de Toulouse, 135 Avenue de Rangueil, 31077 Toulouse, France
- INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés (LISBP),, 31077 Toulouse, France
- UMR5504, CNRS, 31077 Toulouse, France
- TWB, 3 rue des Satellites, Canal Biotech Building 2, 31400 Toulouse, France
| | - Thomas Walther
- INSA, UPS, INP, LISBP, Université de Toulouse, 135 Avenue de Rangueil, 31077 Toulouse, France
- INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés (LISBP),, 31077 Toulouse, France
- UMR5504, CNRS, 31077 Toulouse, France
- TWB, 3 rue des Satellites, Canal Biotech Building 2, 31400 Toulouse, France
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