Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. Author Miguel Lanaspa, Ana Andres-Hernando, David Orlicky, Christina Cicerchi, Cholsoon Jang, Nanxing Li, Tamara Milagres, Masanari Kuwabara, Michael Wempe, Joshua Rabinowitz, Richard Johnson, Dean Tolan Publication Year 2018 Type Journal Article 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 Animals, Mice, Mice, Knockout, Isoenzymes, Fructokinases, Fructose, Fructose Intolerance, Fructose-Bisphosphate Aldolase Journal J Clin Invest Volume 128 Issue 6 Pages 2226-2238 Date Published 2018 Jun 01 ISSN Number 1558-8238 DOI 10.1172/JCI94427 Alternate Journal J Clin Invest PMCID PMC5983342 PMID 29533924 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML