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J Clin Invest. 2018 Jun 1;128(6):2226-2238. doi: 10.1172/JCI94427. Epub 2018 Apr 23.

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

Author information

1
Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
2
Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
3
Department of Pharmacology, University of Colorado, Aurora, Colorado, USA.
4
Department of Biology, Boston University, Boston, Massachusetts, USA.

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.

KEYWORDS:

Genetic diseases; Genetics; Metabolism; Molecular pathology

PMID:
29533924
PMCID:
PMC5983342
DOI:
10.1172/JCI94427
[Indexed for MEDLINE]
Free PMC Article

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