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

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 enzy...

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Autores principales: Andres-Hernando, Ana, Orlicky, David J., Kuwabara, Masanari, Cicerchi, Christina, Pedler, Michelle, Petrash, Mark J., Johnson, Richard J., Tolan, Dean R., Lanaspa, Miguel A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609559/
https://www.ncbi.nlm.nih.gov/pubmed/37892451
http://dx.doi.org/10.3390/nu15204376
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author Andres-Hernando, Ana
Orlicky, David J.
Kuwabara, Masanari
Cicerchi, Christina
Pedler, Michelle
Petrash, Mark J.
Johnson, Richard J.
Tolan, Dean R.
Lanaspa, Miguel A.
author_facet Andres-Hernando, Ana
Orlicky, David J.
Kuwabara, Masanari
Cicerchi, Christina
Pedler, Michelle
Petrash, Mark J.
Johnson, Richard J.
Tolan, Dean R.
Lanaspa, Miguel A.
author_sort Andres-Hernando, Ana
collection PubMed
description 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.
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spelling pubmed-106095592023-10-28 Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance Andres-Hernando, Ana Orlicky, David J. Kuwabara, Masanari Cicerchi, Christina Pedler, Michelle Petrash, Mark J. Johnson, Richard J. Tolan, Dean R. Lanaspa, Miguel A. Nutrients Article 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. MDPI 2023-10-16 /pmc/articles/PMC10609559/ /pubmed/37892451 http://dx.doi.org/10.3390/nu15204376 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Andres-Hernando, Ana
Orlicky, David J.
Kuwabara, Masanari
Cicerchi, Christina
Pedler, Michelle
Petrash, Mark J.
Johnson, Richard J.
Tolan, Dean R.
Lanaspa, Miguel A.
Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance
title Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance
title_full Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance
title_fullStr Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance
title_full_unstemmed Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance
title_short Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance
title_sort endogenous fructose production and metabolism drive metabolic dysregulation and liver disease in mice with hereditary fructose intolerance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609559/
https://www.ncbi.nlm.nih.gov/pubmed/37892451
http://dx.doi.org/10.3390/nu15204376
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