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

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 metabolis...

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Bibliographic Details
Published in:The Journal of clinical investigation 2018-06, Vol.128 (6), p.2226-2238
Main 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
Format: Article
Language:English
Subjects:
Adenosine triphosphate
Beverages
Biomedical research
Diabetes
Diet
Enzymes
Epidemics
Fanconi syndrome
Fatty liver
Fructose
Hyperuricemia
Hypoglycemia
Hypotheses
Intestine
Intolerance
Ketohexokinase
Kinases
Liver
Metabolic syndrome
Obesity
Rodents
Sucrose
Sugar
Systematic review
Uric acid
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI94427