# Targeting fructokinase, endogenous fructose production and purine degradation for the prevention and treatment of hereditary fructose intolerance

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $121,814

## Abstract

Project Summary/Abstract
Dietary intake of sugars containing fructose has dramatically increased in our society with one-sixth of the
population eating 25% of their diet or more. While attempts to reduce sugar intake are now recommended,
it isvery difficult to avoid exposure to HFCS and sucrose in today's culture. One group that suffers
from the widespread use of added sugars are individuals with Hereditary Fructose Intolerance (HFI), an
autosomal recessive whose subjects develop severe reactions following fructose ingestion,with abdominal
pain, vomiting, diarrhea, symptomatic hypoglycemia, hyperuricemia, and even death in children. Fructose
metabolism is initiated by two enzymes, fructokinase that phosphorylates fructose to fructose-1 phosphate
causing ATP depletion and uric acid generation, and aldolase b that further splits the fructose-1 phosphate
molecule into dihydroacetone phosphate and glyceraldehyd. HFI is caused by the mutation in aldolase B
leading to accumulation of fructose-1phosphate, marked ATP depletion and uric acid generation following
fructose ingestion that is much greater than that observed in normal individuals. Our preliminary data in
aldolase b deficient mice suggest that upon exposure to fructose in diet or endogenously produced, its
deficiency is associated with fructokinase hyperactivation, growth retardation, severe hypoglycemia,
liver/intestinal injury and death which are completely blocked when fructokinase is inhibited. Of interest, the
deleterious effects observed in aldolase b deficient mice are exacerbated when mice are hyperuricemic
suggesting an important deleterious role of uric acid in the pathogenesis of HFI. These observation led us
to our overall hypothesis that the blockade of fructose metabolism to fructose-1 phoshate protects against
HFI in subjects with aldolase b deficiency. Specifically, we propose that 1) fructokinase knockout mice with
aldolase b deficiency will not develop HFI upon exposure to fructose, 2) the blockade of endogenous
fructose production by inhibition of aldose reductase and the polyol pathway is clinically relevant for people
with aldolase b deficiency and 3) lowering uric acid production and accumulation isan important therapeutic
approach in the prevention and treatment of HFI. The studies proposed in this application are clinically
relevant as they will provide insights into future therapies (targeting fructokinase, aldose reducatse, AMP
deaminase and/or xanthine oxidase) for this disease in which the only treatment (avoidance of fructose)
has become almost impossible in our society.

## Key facts

- **NIH application ID:** 10543664
- **Project number:** 7R01DK108859-06
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Miguel Angel Lanaspa Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $121,814
- **Award type:** 7
- **Project period:** 2016-04-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10543664

## Citation

> US National Institutes of Health, RePORTER application 10543664, Targeting fructokinase, endogenous fructose production and purine degradation for the prevention and treatment of hereditary fructose intolerance (7R01DK108859-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10543664. Licensed CC0.

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