Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice
Miguel A. Lanaspa, … , Richard J. Johnson, Dean R. Tolan
Miguel A. Lanaspa, … , Richard J. Johnson, Dean R. Tolan
Published March 13, 2018
Citation Information: J Clin Invest. 2018;128(6):2226-2238. https://doi.org/10.1172/JCI94427.
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Research Article Genetics Metabolism

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

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.

Authors

Miguel A. Lanaspa, Ana Andres-Hernando, David J. Orlicky, Christina Cicerchi, Cholsoon Jang, Nanxing Li, Tamara Milagres, Masanari Kuwabara, Michael F. Wempe, Joshua D. Rabinowitz, Richard J. Johnson, Dean R. Tolan

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Figure 1

Lack of aldolase B is associated with increased ATP depletion and Khk activation in response to fructose.

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Lack of aldolase B is associated with increased ATP depletion and Khk ac...
(A) Schematic describing fructose metabolism and its association with the purine degradation pathway leading to uric acid generation. The loss of the aldolase B gene (indicate by the X) is associated with Fru1-P accumulation, phosphate and ATP depletion, and increased nucleotide turnover, resulting in uric acid accumulation. (B and C) Intrahepatic ATP and phosphate levels in WT, AldoB-KO (AldoB–/–), and Khk-KO (Khk–/–) mice acutely exposed to water vehicle (V) or fructose (F) (1 g/kg for 90 minutes). (D) Representative Western blot for aldolase B (AldoB) and ketohexokinase (KHK) in liver extracts from WT, heterozygous (Het), and AldoB-KO (KO) mice with or without fructose exposure (1 g/kg for 90 minutes). Densitometry values from n = 15 animals per group are shown. (E) Ketohexokinase activity in liver extracts from WT (WT AldoB), heterozygous for AldoB-KO (Het AldoB), AldoB-KO (KO AldoB), and Khk-KO (KO Khk) mice. Values were evaluated for statistically significant differences (1-way ANOVA, Tukey post hoc t test analysis, n = 7 animals per group; *P < 0.05, **P < 0.01 versus respective vehicle controls or #P < 0.05, ##P < 0.01 versus respective genotypes).