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

Authors: 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 
Citation: Lanaspa MA, etal., J Clin Invest. 2018 Jun 1;128(6):2226-2238. doi: 10.1172/JCI94427. Epub 2018 Apr 23.
Pubmed: (View Article at PubMed) PMID:29533924
DOI: Full-text: DOI:10.1172/JCI94427

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.


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CRRD Object Information
CRRD ID: 13673910
Created: 2018-07-05
Species: All species
Last Modified: 2018-07-05
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.