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 2

Metabolic responses associated with Khk deletion in AldoB-KO mice.

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Metabolic responses associated with Khk deletion in AldoB-KO mice. (A) R...
(A) Representative Western blot for aldolase B (AldoB) and ketohexokinase (Khk) in WT (lane 1), Khk/AldoB-DKO (lane 2), AldoB-KO (lane 3), and Khk-KO (lane 4) mice. (B) Distribution of different genotypes in offspring from breeding aldob heterozygous (AldoB+/–) pairs exposed to water control or 5% fructose in the drinking water with either WT (Khk+/+) (left and center) or Khk-KO background (Khk–/–) (right) (n ≥ 15 pups analyzed from at least 3 offspring per breeding pair). Total pups born in each group: left graph, WT (13/54), heterozygous (32/54), and knockouts (9/54); center graph, WT (11/36), heterozygous (22/36), and knockouts (3/36); right graph, WT (15/60), heterozygous (29/60), and knockouts (16/60). Statistical significance determined by 2-tailed χ2 test. (C) Average body weight at weaning of AldoB-KO mice (white) or Khk/AldoB-DKO mice (Khk–/– AldoB–/–) (black) from heterozygous breeding pairs. Statistical significance determined by 1-way ANOVA, Tukey’s post hoc t test. (D) Changes in body weight of 8-week-old AldoB-KO (Khk+/+ AldoB–/–) (solid circles) or Khk/AldoB-DKO (Khk–/– AldoB–/–) (open circles) mice exposed to the indicated fructose-containing sugars (5% w/v) for 14 days. Statistical significance determined by 2-tailed t test (**P < 0.01 ).(E–G) Muscle weight, serum CPK, and epididymal fat weight at day 15 after water (brown bars) or fructose (red bars) exposure in AldoB-KO (solid bars) and Khk/AldoB-DKO mice (open bars). For E, statistical significance was determined by 1-way ANOVA, Tukey’s post hoc t test. (H) Urinary fructose excretion, normalized to units of creatinine, in WT, AldoB-KO (AldoB–/–), or Khk/AldoB-DKO (Khk–/– AldoB–/–) mice exposed to water (W) (white) or 5% fructose w/v (F) (gray) for 24 hours. Statistical significance was determined by 1-way ANOVA, Tukey’s post hoc t test. *P < 0.05, **P < 0.01 (n = 7 animals per group [C–H]).