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Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice

Author(s): Lanaspa, Miguel A.; Andres-Hernando, Ana; Orlicky, David J.; Cicerchi, Christina; Jang, Cholsoon; et al

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Abstract: Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of aldolase B results in the accumulation of intracellular phosphorylated fructose, leading to phosphate sequestration and depletion, increased adenosine triphosphate (ATP) turnover, and a plethora of conditions that lead to clinical manifestations such as fatty liver, hyperuricemia, Fanconi syndrome, and severe hypoglycemia. Unfortunately, there is currently no treatment for HFI, and avoiding sugar and fructose has become challenging in our society. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI. Herein we provide evidence for the first time to our knowledge of a potential therapeutic approach for HFI. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI.
Publication Date: Jun-2018
Citation: Lanaspa, Miguel A., Andres-Hernando, Ana, Orlicky, David J., Cicerchi, Christina, Jang, Cholsoon, Li, Nanxing, Milagres, Tamara, Kuwabara, Masanari, Wempe, Michael F., Rabinowitz, Joshua D., Johnson, Richard J., Tolan, Dean R. (2018). Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice.. The Journal of clinical investigation, 128 (6), 2226 - 2238. doi:10.1172/JCI94427
DOI: doi:10.1172/JCI94427
ISSN: 0021-9738
EISSN: 1558-8238
Pages: 128.6:2226-2238
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: The Journal of clinical investigation
Version: Final published version. This is an open access article.
Notes: Journal of Clinical Investigation. Volume 128, Issue 6, 1 June 2018, Pages 2226-2238.

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