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Research ArticleHepatologyMetabolism
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10.1172/jci.insight.183247
1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China.
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany.
7Environmental Hygiene, Technical University Munich, Munich, Germany.
8Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Neuherberg, Germany.
9Department of Internal Medicine II, Medical Oncology, and Department of Neurosurgery, University Hospital Würzburg; Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Germany.
10Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
11Department of Biology, York University, Toronto, Ontario, Canada.
Address correspondence to: Kostas Pantopoulos, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote Ste-Catherine Rd., Montreal, QC, H3T 1E2, Canada. Email: kostas.pantopoulos@mcgill.ca.
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Published January 6, 2026 - More info
Published in Volume 11, Issue 4 on February 23, 2026
AbstractIron regulatory protein 1 (IRP1) is a posttranscriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of HIF2α mRNA, which increases renal erythropoietin production. Here, we show that Irp1–/– mice develop fasting hypoglycemia and are protected against high-fat diet–induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1–/– livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscles, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.
IntroductionIron regulatory proteins IRP1 and IRP2 coordinately control the expression of mRNAs containing iron responsive elements (IREs). These include Tfrc, Fth/Ftl, and Slc40α1 mRNAs, which encode proteins of iron uptake (transferrin receptor 1), storage (ferritin), and efflux (ferroportin), respectively (1). In iron-starved cells, IRE/IRP interactions protect Tfrc mRNA against degradation and inhibit translation of Fth/Ftl and Slc40α1 mRNAs, in a homeostatic response to secure adequate iron supply. Conversely, in iron-replete cells, IRP1 is converted to cytosolic aconitase at the expense of its RNA-binding activity, while IRP2 undergoes proteasomal degradation. Inactivation of IRPs permits the decay of Tfrc mRNA and the de novo synthesis of ferritin and ferroportin to prevent detrimental iron overload.
IRP1 and IRP2 exhibit extensive sequence homology but only partial functional redundancy (2). Although global or tissue-specific disruption of both IRPs has yielded lethal phenotypes (3–5), single Irp1–/– and Irp2–/– mice are viable and have distinct pathophysiological features. Thus, Irp1–/– mice develop polycythemia due to translational de-repression of the IRE-containing mRNA encoding HIF2α, which in turn stimulates erythropoiesis via transcriptional induction of erythropoietin in the kidney (6–8). On the other hand, Irp2–/– mice manifest microcytic anemia, mild iron overload in the liver and duodenum, erythropoietic protoporphyria, diabetes, and late-onset neurodegeneration (9–11).
Herein, we show that Irp1–/– mice are protected against hyperglycemia, insulin resistance, and liver steatosis. These are common clinical manifestations of metabolic syndrome, a pathological state defined by the combined presentation of at least 3 of the following conditions: abdominal obesity, hyperglycemia due to insulin resistance, dyslipidemia, and hypertension. Metabolic syndrome has a prevalence of approximately 25% in the adult US population and increases the risk for type 2 diabetes, cardiovascular and liver disease, and all-cause mortality (12). We demonstrate here that IRP1 deficiency causes mitochondrial dysfunction and metabolic rewiring that alters energy homeostasis. Our data unveil an unexpected role of IRP1 in the control of intermediary metabolism.
ResultsIrp1–/– mice are protected against high fat diet–induced hyperglycemia. Young Irp1–/– mice develop erythrocytosis due to induction of the HIF2α/erythropoietin axis (6–8), and gradually recover after the age of 8–10 weeks, where HIF2α overexpression is mitigated (6). Prompted by evidence that HIF2α also controls insulin signaling in the liver via transcriptional induction of insulin receptor substrate 2 (IRS2) (13, 14), we analyzed metabolic functions in these animals. At the age of 5 weeks, Irp1–/– mice exhibited profound fasting hypoglycemia (Figure 1A), while the phenotype of heterozygous Irp1+/– animals was indistinguishable from WT controls (data not shown). Insulin tolerance testing (ITT) caused a sharper early drop in blood glucose levels of Irp1–/– mice (Figure 1B), indicating increased insulin sensitivity. Moreover, Irp1–/– mice could not initiate a gradual return of blood glucose levels to baseline within 45–60 minutes after an insulin injection; instead, they developed hypoglycemic seizures and had to be treated for recovery. In line with the severe fasting hypoglycemia, we observed 18% reduced survival of Irp1–/– pups at the age of 4 weeks (Figure 1C), which was more pronounced in male (24%) versus female (11%) animals (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.183247DS1). Notably, blood glucose levels were normalized in older Irp1–/– mice (Figure 1D, control diet), but the age-dependent correction of hypoglycemia was abolished when animals were fed an iron-deficient diet (IDD) (Figure 1D). These data suggest that IRP1 deficiency has an impact on metabolism and are consistent with HIF2α involvement. However, while Irp1–/– mice exhibited rapid glucose clearance in an oral glucose tolerance test (GTT), hepatocyte-specific ablation of HIF2α only partially corrected this phenotype in Irp1–/– Hif2αAlb-Cre mice (Figure 1E).
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