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Targeting ketohexokinase (KHK), the first enzyme of fructose metabolism, has been investigated for the management of metabolic dysfunction\u2013associated steatotic liver disease (MASLD). We compared the effects of systemic, small molecule inhibitor of KHK enzymatic activity with hepatocyte-specific, N-acetylgalactosamine siRNA\u2013mediated 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.<\/jats:p>","DOI":"10.1172\/jci.insight.184396","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T12:00:36Z","timestamp":1729166436000},"source":"Crossref","is-referenced-by-count":23,"title":["Knockdown of ketohexokinase versus inhibition of its kinase activity exert divergent effects on fructose metabolism"],"prefix":"10.1172","volume":"9","author":[{"given":"Se-Hyung","family":"Park","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Division of Pediatric Gastroenterology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taghreed","family":"Fadhul","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Division of Pediatric Gastroenterology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey R.","family":"Conroy","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harrison A","family":"Clarke","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA."},{"name":"Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-1850","authenticated-orcid":true,"given":"Ramon C.","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA."},{"name":"Department of Biochemistry & Molecular Biology, Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Wallenius","sequence":"additional","affiliation":[{"name":"Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremie","family":"Boucher","sequence":"additional","affiliation":[{"name":"Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden."},{"name":"The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"O\u2019Mahony","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Boianelli","sequence":"additional","affiliation":[{"name":"DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Persson","sequence":"additional","affiliation":[{"name":"DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunhee","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, School of Medicine; 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