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 is very 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 glyceraldehyde. HFI is caused by the mutation in aldolase B leading to accumulation of fructose-1-phosphate, 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- phosphate 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 is an 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 reductase, AMP deaminase and/or xanthine oxidase) for this disease in which the only treatment (avoidance of fructose) has become almost impossible in our society. The applicant will count with an excellent group of collaborators that include Drs. Dean Tolan -a world expert in clinical hereditary fructose intolerance- and Richard Johnson -a renowned scientist in the field of sugar and fructose metabolism-. This award will allow the applicant as an early stage investigator (ESI) to develop the skills necessary and the financial needs to fully become an independent scientist and will provide for intellectual development through both didactic programs and by facilitating interactions with a variety of researchers in different departments.

Public Health Relevance

Hereditary fructose intolerance is a very severe disease characterized by symptomatic hypoglycemia, liver failure and death in response to fructose with no treatment and that results as a consequence of an inborn mutation in the aldolase b gene thus causing the accumulation of fructose-1-phosphate, ATP depletion, uric acid accumulation and the hyperactivation of fructokinase. Our preliminary data in aldolase b deficient mice suggest that blocking fructokinase, we can prevent the development of all pathogenic effects associated to acute and chronic exposure to fructose in these mice. Based on these observations, we hypothesize that the pharmacological inhibition of fructokinase could be clinically relevant as a mean to prevent HFI and will provide for the first time, an efficient treatment for subjects with aldolase b deficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK108859-03
Application #
9455680
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Laughlin, Maren R
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045