ResearchIn-Press PreviewHepatologyMetabolism Open Access | 10.1172/jci.insight.184396
1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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1Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, United States of America
2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States of America
3Bioscience, Research and Early Development, Cardiovascular, Renal and Metab, AstraZeneca, Gothenburg, Sweden
4Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal, AstraZeneca, Gothenburg, Sweden
5DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
6Department of Biological Chemistry, University of California Irvine, Irvine, United States of America
7Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
8Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, United States of America
9Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
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Published October 17, 2024 - More info
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 MASLD. We compared the effects of systemic, small molecule inhibitor of KHK enzymatic activity to hepatocyte-specific, GalNAc-siRNA mediated knockdown of KHK in mice on a HFD. We measured KHK enzymatic activity, extensively quantified glycogen accumulation, performed RNAseq 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 leads 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 when treated 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.