Journal Article

Dietary fructose improves intestinal cell survival and nutrient absorption

Pozovskiy, Rita, Vasan, Neil, Hwang, Seo-Kyoung, Goncalves, Marcus D., Rhee, Kyu Y., Sebra, Robert P., Taylor, Samuel R., Shah, Manish A., Cantley, Lewis C., Ramsamooj, Shakti, Dow, Lukas E., Dannenberg, Andrew J., Johnson, Jared L., Katti, Alyna, Nahiyaan, Navid, Schatoff, Emma M., Liang, Roger J., Francoeur, Nancy J.

2021

Overview

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. A high-fructose diet in mice improves the survival of intestinal epithelial cells, which leads to an increase in gut surface area, enhanced absorption of lipids and the promotion of tumour growth and obesity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/31 / 13/51 / 14/19 / 631/443/319/2723 / 631/45/320 / 631/67/2327 / 64 / 64/60 / 82 / Ablation / Absorption / Adipose tissue / Allosteric properties / Animal models / Animals / Apoptosis / Cell growth / Cell survival / Cell Survival - drug effects / Corn / Corn syrup / Diet / Elongation / Enzyme Activation / Epithelium / Female / Fructokinases - metabolism / Fructose / Fructose - metabolism / Fructose - pharmacology / Glucose transporter / Glucose transporter type 5 / High fat diet / High Fructose Corn Syrup - metabolism / High Fructose Corn Syrup - pharmacology / Humanities and Social Sciences / Hyperplasia / Hypoxia / Hypoxia - diet therapy / Hypoxia - pathology / Intestinal Absorption - drug effects / Intestinal Mucosa - cytology / Intestinal Mucosa - drug effects / Intestinal Mucosa - metabolism / Intestine / Ketohexokinase / Kinases / Lipid Metabolism - drug effects / Male / Metabolism / Metabolites / Mice / Morbidity / multidisciplinary / Nutrients / Nutrients - metabolism / Obesity / Pyruvate kinase / Pyruvate Kinase - metabolism / Pyruvic acid / Science / Science (multidisciplinary) / Small intestine / Sucrose / Survival / Syrup / Tumorigenesis / Tumors / Villus