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10.3390/nu15204376
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Article

Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance

by
Ana Andres-Hernando
1,
David J. Orlicky
2,
Masanari Kuwabara
3,4,
Christina Cicerchi
5,
Michelle Pedler
6,
Mark J. Petrash
6,
Richard J. Johnson
5,
Dean R. Tolan
7 and
Miguel A. Lanaspa
1,*
1
Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver, Aurora, CO 80045, USA
2
Department of Pathology, University of Colorado School of Medicine, Aurora, CO 80045, USA
3
Department of Cardiology, Toranomon Hospital, Tokyo 105-8470, Japan
4
Division of Public Health, Center for Community Medicine, Jichi Medical University, Tochigi 329-0431, Japan
5
Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO 80045, USA
6
Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045, USA
7
Department of Biology, Boston University, Boston, MA 02215, USA
*
Author to whom correspondence should be addressed.
Nutrients 2023, 15(20), 4376; https://doi.org/10.3390/nu15204376
Submission received: 1 September 2023 / Revised: 6 October 2023 / Accepted: 13 October 2023 / Published: 16 October 2023
(This article belongs to the Special Issue Feature Paper in Carbohydrate 2023)
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Abstract

Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models. However, genetic disorders in fructose metabolism have very different consequences. While the deficiency of fructokinase, the first enzyme involved in fructose metabolism, is benign and somewhat desirable, missense mutations in the second enzyme, aldolase B, causes a very dramatic and sometimes lethal condition known as hereditary fructose intolerance (HFI). To date, there is no cure for HFI, and treatment is limited to avoiding fructose and sugar. Because of this, for subjects with HFI, glucose is their sole source of carbohydrates in the diet. However, clinical symptoms still occur, suggesting that either low amounts of fructose are still being consumed or, alternatively, fructose is being produced endogenously in the body. Here, we demonstrate that as a consequence of consuming high glycemic foods, the polyol pathway, a metabolic route in which fructose is produced from glucose, is activated, triggering a deleterious mechanism whereby glucose, sorbitol and alcohol induce severe liver disease and growth retardation in aldolase B knockout mice. We show that generically and pharmacologically blocking this pathway significantly improves metabolic dysfunction and thriving and increases the tolerance of aldolase B knockout mice to dietary triggers of endogenous fructose production.
Keywords: HFI; endogenous fructose; aldolase b; polyol pathway; metabolic dysfunction HFI; endogenous fructose; aldolase b; polyol pathway; metabolic dysfunction
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MDPI and ACS Style

Andres-Hernando, A.; Orlicky, D.J.; Kuwabara, M.; Cicerchi, C.; Pedler, M.; Petrash, M.J.; Johnson, R.J.; Tolan, D.R.; Lanaspa, M.A. Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance. Nutrients 2023, 15, 4376. https://doi.org/10.3390/nu15204376

AMA Style

Andres-Hernando A, Orlicky DJ, Kuwabara M, Cicerchi C, Pedler M, Petrash MJ, Johnson RJ, Tolan DR, Lanaspa MA. Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance. Nutrients. 2023; 15(20):4376. https://doi.org/10.3390/nu15204376

Chicago/Turabian Style

Andres-Hernando, Ana, David J. Orlicky, Masanari Kuwabara, Christina Cicerchi, Michelle Pedler, Mark J. Petrash, Richard J. Johnson, Dean R. Tolan, and Miguel A. Lanaspa. 2023. "Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance" Nutrients 15, no. 20: 4376. https://doi.org/10.3390/nu15204376

APA Style

Andres-Hernando, A., Orlicky, D. J., Kuwabara, M., Cicerchi, C., Pedler, M., Petrash, M. J., Johnson, R. J., Tolan, D. R., & Lanaspa, M. A. (2023). Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance. Nutrients, 15(20), 4376. https://doi.org/10.3390/nu15204376

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