ArticleMetabolism: clinical and experimental2023
Fructose induced KHK-C can increase ER stress independent of its effect on lipogenesis to drive liver disease in diet-induced and genetic models of NAFLD.
Article in Metabolism: clinical and experimental, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 26 citations in OpenAlex.
- 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
- The association between high fructose corn syrup and the development of type-2 diabetes.Frontiers in clinical diabetes and healthcare · 2026Review
- Soda consumption and the risk of metabolic syndrome in Korean adults during the period surrounding the COVID-19 pandemic.The British journal of nutrition · 2025Article
- Beyond fructolysis: ketohexokinase orchestrates ER proteostasis in nutrient-stressed hepatocytes.American journal of physiology. Gastrointestinal and liver physiology · 2025Article
- Fructose induces inflammatory activation in macrophages and microglia through the nutrient-sensing ghrelin receptor.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Sugar-sweetened beverage consumption predicts metabolic associated fatty liver disease in patients with type 2 diabetes mellitus.Frontiers in endocrinology · 2025Article
- Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.International journal of medical sciences · 2025Review
- An analysis of the intestinal microbiome combined with metabolomics to explore the mechanism of how Pangxiejiao tea improves metabolic disorders in HFFD-treated rats.Frontiers in nutrition · 2025Article
- Fructose-Induced Metabolic Dysfunction Is Dependent on the Baseline Diet, the Length of the Dietary Exposure, and Sex of the Mice.Nutrients · 2024Article
- Knockdown of ketohexokinase versus inhibition of its kinase activity exert divergent effects on fructose metabolism.JCI insight · 2024Article
- Exploring Marine-Derived Compounds: In Silico Discovery of Selective Ketohexokinase (KHK) Inhibitors for Metabolic Disease Therapy.Marine drugs · 2024Article
- Endoplasmic reticulum stress in diseases.MedComm · 2024Review
- Pathophysiological Relationship between Type 2 Diabetes Mellitus and Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Therapeutic Approaches.International journal of molecular sciences · 2024Review
- Review
- Growth Hormone Treatment Normalized Liver Enzymes in an Adolescent with Obesity and Short Statute.Annals of pediatrics · 2024Article
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23 authors at 8 institutions in 3 countries.
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in mice with genetically induced obesity or metabolic dysfunction, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.
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