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

Authors :
Ana Andres-Hernando
David J. Orlicky
Masanari Kuwabara
Christina Cicerchi
Michelle Pedler
Mark J. Petrash
Richard J. Johnson
Dean R. Tolan
Miguel A. Lanaspa
Source :
Nutrients, Vol 15, Iss 20, p 4376 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

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.

Details

Language :
English
ISSN :
20726643
Volume :
15
Issue :
20
Database :
Directory of Open Access Journals
Journal :
Nutrients
Publication Type :
Academic Journal
Accession number :
edsdoj.b02ac6a21bda49e29c4307af65de930a
Document Type :
article
Full Text :
https://doi.org/10.3390/nu15204376