Dietary fructose improves intestinal cell survival and nutrient absorption
Open accessAbstract
Fructose consumption is linked to the rising incidence of obesity and cancer, which are two of the leading causes of morbidity and mortality globally 1,2. Dietary fructose metabolism begins at the epithelium of the small intestine, where fructose is transported by glucose transporter type 5 (GLUT5; encoded by SLC2A5) and phosphorylated by ketohexokinase to form fructose 1-phosphate, which accumulates to high levels in the cell 3,4. Although this pathway has been implicated in obesity and tumour promotion, the exact mechanism that drives these pathologies in the intestine remains unclear. Here we show that dietary fructose improves the survival of intestinal cells and increases intestinal villus length in several mouse models. The increase in villus length expands the surface area of the gut and increases nutrient absorption and adiposity in mice that are fed a high-fat diet. In hypoxic intestinal cells, fructose 1-phosphate inhibits the M2 isoform of pyruvate kinase to promote cell survival 5-7. Genetic ablation of ketohexokinase or stimulation of pyruvate kinase prevents villus elongation and abolishes the nutrient absorption and tumour growth that are induced by feeding mice with high-fructose corn syrup. The ability of fructose to promote cell survival through an allosteric metabolite thus provides additional insights into the excess adiposity generated by a Western diet, and a compelling explanation for the promotion of tumour growth by high-fructose corn syrup.
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In mouse models, dietary fructose improves the survival of intestinal cells and increases the length of intestinal villus, resulting in an expanded surface area of the gut and increased nutrient absorption and adiposity.
“A recent animal study showed that dietary fructose improves the survival of intestinal cells and increases the length of intestinal villus in mouse models, resulting in an expanded surface area of the gut and increased nutrient absorption and adiposity in mice.101”
From Dietary sugar consumption and health: umbrella review (2023) · cites this paper as [101]
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- Authors
- Taylor, S. R., Ramsamooj, S., Liang, R. J., Katti, A., Pozovskiy, R., Vasan, N., Hwang, S.-K., Nahiyaan, N., Francoeur, N. J., Schatoff, E. M., Johnson, J. L., Shah, M. A., Dannenberg, A. J., Sebra, R. P., Dow, L. E., Cantley, L. C., Rhee, K. Y., & Goncalves, M. D.
- Affiliations
- Weill Cornell Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- Icahn School of Medicine at Mount Sinai (US)
- Sema4 (United States) (US)
- Corresponding author
- Goncalves, Marcus D.
- ORCID
- Venue
- Nature
- Published
- 2021-08-18
- Volume
- 597
- Issue
- 7875
- Pages
- 263-267
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8686685
- OpenAlex
- W3194553971
- Cited by
- 288
- References
- 47
- Citations by year
- 2026: 41 · 2025: 62 · 2024: 59 · 2023: 64 · 2022: 47 · 2021: 15
- FWCI
- 34.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eCommons (Cornell University) (submittedVersion)
- Funders
- National Cancer Institute (F31CA247351, K08CA230318, P30CA008748, R35CA197588)
- National Institute of General Medical Sciences (T32GM007739)
- National Institute of Allergy and Infectious Diseases (R25AI140472)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
- Keywords
- dietary fructose, fructose-1-phosphate, villus length, nutrient absorption, ketohexokinase, PKM2, high fructose corn syrup, tumor growth, obesity, high-fat diet, intestinal hypoxia, fat absorption, Western diet
- MeSH terms
- Nutrients, Animals, Hypoxia, Cell Survival, Enzyme Activation, Female, Fructokinases, Fructose, Intestinal Absorption, Intestinal Mucosa, Male, Pyruvate Kinase, Lipid Metabolism, Mice, High Fructose Corn Syrup
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