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Dietary fructose improves intestinal cell survival and nutrient absorption

Taylor SR, Ramsamooj S, Liang RJ, Katti A, Pozovskiy R, Vasan N, Hwang S-K, Nahiyaan N, Francoeur NJ, Schatoff EM, Johnson JL, Shah MA, Dannenberg AJ, Sebra RP, Dow LE, Cantley LC, Rhee KY, Goncalves MD (2021) Nature   Aug 18, doi: 10.1038/s41586-021-03827-2. Online ahead of print. 

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Abstract:

Fructose consumption is linked to the rising incidence of obesity and cancer, which are two of the leading causes of morbidity and mortality globally1,2.

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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