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

TitleKetohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice.
Publication TypeJournal Article
Year of Publication2018
AuthorsLanaspa, MA, Andres-Hernando, A, Orlicky, DJ, Cicerchi, C, Jang, C, Li, N, Milagres, T, Kuwabara, M, Wempe, MF, Rabinowitz, JD, Johnson, RJ, Tolan, DR
JournalJ Clin Invest
Volume128
Issue6
Pagination2226-2238
Date Published2018 06 01
ISSN1558-8238
KeywordsAnimals, Fructokinases, Fructose, Fructose Intolerance, Fructose-Bisphosphate Aldolase, Isoenzymes, Mice, Mice, Knockout
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.

DOI10.1172/JCI94427
Alternate JournalJ. Clin. Invest.
PubMed ID29533924
PubMed Central IDPMC5983342
Grant ListP30 DK048520 / DK / NIDDK NIH HHS / United States
R03 DK105041 / DK / NIDDK NIH HHS / United States
R01 DK108408 / DK / NIDDK NIH HHS / United States
K01 DK095930 / DK / NIDDK NIH HHS / United States
R01 DK108859 / DK / NIDDK NIH HHS / United States