Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice
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
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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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 4

Fructokinase deficiency protects against fructose-induced severe hypoglycemia and metabolic imbalances in AldoB-KO mice.

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Fructokinase deficiency protects against fructose-induced severe hypogly...
(A) Time course of serum glucose levels in AldoB-KO mice acutely exposed to increasing levels of oral fructose. (B) Time course of serum glucose levels in AldoB-KO (AldoB–/–) and Khk/AldoB-DKO (Khk–/– AldoB–/–) mice acutely exposed to fructose (1.75 g/kg) or water (vehicle) control. (C) Representative Western blot for gluconeogenic enzymes PEPCK and G6Pase in low (0.3%) fructose-fed WT (left), AldoB-KO (center), and Khk/AldoB-DKO (right) mice. (D) Serum glucose levels after pyruvate tolerance test in the same groups as in C. (E) Representative Western blot for glycogen synthase (GS) total and inhibited (pGS) as well as total and active AMPK and total glycogen phosphorylase (PYGL) in the same groups as in C. (F) Representative Western blot for cytosolic and nuclear glucokinase expression at baseline and 15 and 90 minutes after fructose challenge in the same groups as in C. (G) Intrahepatic Fru1-P levels at baseline and 15 and 90 minutes after fructose challenge in the same groups as in C. (H) Representative PAS images from the small intestine of AldoB-KO mice (Khk+/+ AldoB–/–) (left and center) or Khk/AldoB-DKO mice (Khk–/– AldoB–/–) (right) collected 90 minutes after exposure to oral fructose (1.75 g/kg). The destruction in the tip of the papilla (green arrows) and luminal apoptotic cells (blue arrows) in the jejunum area are indicated. Values were evaluated for statistically significant differences (n = 7 animals per group, 1-way ANOVA, Tukey’s post hoc t test; *P < 0.05, **P < 0.01 versus respective vehicle controls).