ArticleJCI insight2024
Knockdown of ketohexokinase versus inhibition of its kinase activity exert divergent effects on fructose metabolism.
Article in JCI insight, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Metabolic dysfunction-associated steatotic liver disease: pathogenesis and novel treatment options.Molecular biomedicine · 2026Review
- Fructose: metabolic signal and modern hazard.Nature metabolism · 2026Review
- Kinase signaling in liver disease via clinical-trial-on-a-PamChip: A distinctive methodology for drug mechanisms and personalized medicine.The Journal of biological chemistry · 2026Article
- The effect of liver-specific ketohexokinase deletion on the intestinal-liver-kidney axis in high-fructose-induced metabolic syndrome mice.Acta biochimica et biophysica Sinica · 2026Article
- Nicotine combined with estrogen activates protein kinase PKCι and TAO, while inhibiting specific MAP kinase pathways in cultured human neurons: an atlas of kinase activities for nicotine use disorder.Frontiers in cellular neuroscience · 2026Article
- The brain's sweet spot: why microglia can run on fructose metabolism.Frontiers in immunology · 2026Review
- Beyond fructolysis: ketohexokinase orchestrates ER proteostasis in nutrient-stressed hepatocytes.American journal of physiology. Gastrointestinal and liver physiology · 2025Article
- Molecular mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD): functional analysis of glucose and fructose metabolism pathways.Clinical science (London, England : 1979) · 2025Review
- Firewater, fructose and appetite.Nature metabolism · 2025Article
- The physiology of MASLD: molecular pathways between liver and adipose tissues.Clinical science (London, England : 1979) · 2025Review
- LY3522348, A New Ketohexokinase Inhibitor: A First-in-Human Study in Healthy Adults.Diabetes therapy : research, treatment and education of diabetes and related disorders · 2025Article
- Fructose metabolism and its roles in metabolic diseases, inflammatory diseases, and cancer.Molecular biomedicine · 2025Review
- Multitissue single-cell analysis reveals differential cellular and molecular sensitivity between fructose and high-fat high-sucrose diets.Cell reports · 2025Article
- Pharmacophore-based virtual screening andFrontiers in pharmacology · 2025Article
Corrections and comments
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Authors and funding
19 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.