Nature. 2021 Sep;597(7875):263-267. doi: 10.1038/s41586-021-03827-2. | PubMed

Samuel R Taylor^1,2,3,4, Shakti Ramsamooj^1,2, Roger J Liang^1,2, Alyna Katti^2,4, Rita Pozovskiy^1,2, Neil Vasan^2,5, Seo-Kyoung Hwang^1,2, Navid Nahiyaan⁶, Nancy J Francoeur⁷, Emma M Schatoff^1,2,3, Jared L Johnson², Manish A Shah², Andrew J Dannenberg², Robert P Sebra^7,8, Lukas E Dow², Lewis C Cantley², Kyu Y Rhee⁶, Marcus D Goncalves^9,10

1. Division of Endocrinology, Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
2. Meyer Cancer Center, Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
3. Weill Cornell-Rockefeller-Sloan Kettering Tri-Institutional MD-PhD program, New York, NY, USA.
4. Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.
5. Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6. Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
7. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8. Sema4, Stamford, CT, USA.
9. Division of Endocrinology, Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA. mdg9010@med.cornell.edu.
10. Meyer Cancer Center, Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA. mdg9010@med.cornell.edu.

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 cell3,4. 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 survival5-7. 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.

Presented By Samuel Taylor