Research ArticleHepatologyMetabolism Open Access | 10.1172/jci.insight.184396

Se-Hyung Park,1 Taghreed Fadhul,1 Lindsey R. Conroy,2 Harrison A Clarke,2,3 Ramon C. Sun,2,3 Kristina Wallenius,4 Jeremie Boucher,4,5 Gavin O’Mahony,6 Alessandro Boianelli,7 Marie Persson,7 Sunhee Jung,8 Cholsoon Jang,8 Analia S. Loria,9 Genesee J. Martinez,9 Zachary A. Kipp,9 Evelyn A. Bates,9 Terry D. Hinds Jr.,9 Senad Divanovic,10 and Samir Softic1,9,11

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Park, S. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Fadhul, T. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Conroy, L. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Clarke, H. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

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1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Wallenius, K. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

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1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by O’Mahony, G. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

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1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Persson, M. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Jung, S. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Jang, C. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Loria, A. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Martinez, G. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Kipp, Z. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Bates, E. in: JCI | PubMed | Google Scholar

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

Find articles by Hinds, T. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

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1Department of Pediatrics and Division of Pediatric Gastroenterology and

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.

3Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA.

4Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

6Medicinal Chemistry and

7DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

8Department of Biological Chemistry, School of Medicine; and Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California, USA.

9Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

10Department of Pediatrics, University of Cincinnati College of Medicine; and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

11Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Samir Softic, University of Kentucky, 900 South Limestone, Wethington, Rm 527, Lexington, Kentucky, 40536, USA. Phone: 859.218.1379; Email: samir.softic@uky.edu.

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Published October 17, 2024 - More info

Published in Volume 9, Issue 23 on December 6, 2024
JCI Insight. 2024;9(23):e184396. https://doi.org/10.1172/jci.insight.184396.
© 2024 Park et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published October 17, 2024 - Version history
Received: July 5, 2024; Accepted: October 11, 2024 View PDF Abstract

Excessive fructose intake is a risk factor for the development of obesity and its complications. Targeting ketohexokinase (KHK), the first enzyme of fructose metabolism, has been investigated for the management of metabolic dysfunction–associated steatotic liver disease (MASLD). We compared the effects of systemic, small molecule inhibitor of KHK enzymatic activity with hepatocyte-specific, N-acetylgalactosamine siRNA–mediated knockdown of KHK in mice on an HFD. We measured KHK enzymatic activity, extensively quantified glycogen accumulation, performed RNA-Seq analysis, and enumerated hepatic metabolites using mass spectrometry. Both KHK siRNA and KHK inhibitor led to an improvement in liver steatosis; however, via substantially different mechanisms, KHK knockdown decreased the de novo lipogenesis pathway, whereas the inhibitor increased the fatty acid oxidation pathway. Moreover, KHK knockdown completely prevented hepatic fructolysis and improved glucose tolerance. Conversely, the KHK inhibitor only partially reduced fructolysis, but it also targeted triokinase, mediating the third step of fructolysis. This led to the accumulation of fructose-1 phosphate, resulting in glycogen accumulation, hepatomegaly, and impaired glucose tolerance. Overexpression of wild-type, but not kinase-dead, KHK in cultured hepatocytes increased hepatocyte injury and glycogen accumulation after treatment with fructose. The differences between KHK inhibition and knockdown are, in part, explained by the kinase-dependent and -independent effects of KHK on hepatic metabolism.

Introduction

High intake of dietary sugar has undoubtedly been linked to the development of obesity-associated complications, such as metabolic dysfunction–associated steatotic liver disease (MASLD). Therefore, the World Health Organization (1), and several leading medical societies, such as the American Heart Association (2), the Canadian Diabetes Association (3), and 3 European medical groups (EASL, EASD, EASO) (4), recommend reducing sugar intake as a way to ameliorate metabolic dysfunction.

The adverse effects of sugar have mainly been attributed to its fructose component. Several properties of dietary fructose make it uniquely suitable to promote the development of obesity-associated complications, such as MASLD (5). Fructose strongly enhances hepatic de novo lipogenesis (DNL) by acting as a substrate for fatty acid synthesis and by upregulating SREBP1c and carbohydrate response element binding protein (ChREBP) lipogenic transcription factors (6, 7). On the other hand, fructose restriction improves hepatic steatosis (8) and lowers body mass index (9). Furthermore, fructose decreases fatty acid oxidation (FAO) (10), either indirectly through DNL intermediate malonyl-CoA or directly through suppression of carnitine palmitoyltransferase 1a (CPT1α) (11). Additionally, fructose has been proposed to induce hepatic insulin resistance (12), elevate uric acid production (13), promote endoplasmic reticulum stress (14), and propagate mitochondrial dysfunction (15). Indeed, fructose consumption is 2- to 3-fold higher in adults with biopsy-confirmed MASLD (16) and correlates with a higher incidence of liver fibrosis (17).

The effects of dietary fructose are dependent on its catabolism via ketohexokinase (KHK), the first enzyme of fructolysis. Thus, mice with whole-body knockout (KO) of KHK on an obesogenic diet are protected from MASLD (18, 19). We and others have shown that liver-specific deletion of KHK is sufficient to reverse MASLD (7, 20). The strong premise that fructose contributes to metabolic dysfunction and that KHK deletion prevents it has led to the development of small molecule inhibitors of KHK enzymatic activity. The inhibitors target the ATP binding domain of KHK, which prevents fructose phosphorylation to fructose-1 phosphate (F1P) (21). Phosphorylation of fructose, similar to the phosphorylation of glucose, is required for its downstream metabolism. An early KHK inhibitor was efficacious in preclinical studies (22), but this compound has not been tested in clinical trials. Many enzymes contain an ATP binding domain, so the initial inhibitors were not selective enough for KHK activity. Within the last decade, a new class of compounds, allegedly 600 times more specific for KHK activity, have been developed. These inhibitors were likewise found to effectively reduce steatosis in rats (23) but also in human liver tissue (24). Moreover, recent clinical trials reported that the new KHK inhibitors significantly reduced whole liver fat in patients with MASLD (25, 26). Despite the positive data, the leading developer unexpectedly announced that it was stopping further advancement of the KHK inhibitor (27).

In this study, we compared head-to-head the effects of systemic, small molecule KHK inhibitor (PF-06835919) versus liver-specific knockdown (KD) of KHK using N-acetylgalactosamine–conjugated (GalNAc-conjugated) siRNA. Our laboratory was the first to suggest that KHK has kinase-independent functions (28,