Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 11; pp. 4320 - 4325
• Main Authors: Ishimoto, Takuji, Lanaspa, Miguel A, Le, MyPhuong T, Garcia, Gabriela E, Diggle, Christine P, MacLean, Paul S, Jackman, Matthew R, Asipu, Aruna, Roncal-Jimenez, Carlos A, Kosugi, Tomoki, Rivard, Christopher J, Maruyama, Shoichi, Rodriguez-Iturbe, Bernardo, Sánchez-Lozada, Laura G, Bonthron, David T, Sautin, Yuri Y, Johnson, Richard J
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.03.2012; National Acad Sciences
• Subjects: Adenosine triphosphatase; adenosine triphosphate; Animals; Biological Sciences; Correlation analysis; Energy intake; Energy metabolism; Energy Metabolism - drug effects; fatty liver; Feeding Behavior - drug effects; fructokinase; Fructokinases - metabolism; fructose; Fructose - administration & dosage; Fructose - metabolism; Fructose - pharmacology; humans; Isoenzymes - metabolism; kidneys; laboratory animals; Lipid metabolism; Liver; Liver diseases; Metabolic syndrome; Metabolic Syndrome - enzymology; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Protein isoforms; Tap water; Uric acid
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1119908109

Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Fructose intake also causes features of metabolic syndrome in laboratory animals and humans. The first enzyme in fructose metabolism is fructokinase, which exists as two isoforms, A and C. Here we show that fructose-induced metabolic syndrome is prevented in mice lacking both isoforms but is exacerbated in mice lacking fructokinase A. Fructokinase C is expressed primarily in liver, intestine, and kidney and has high affinity for fructose, resulting in rapid metabolism and marked ATP depletion. In contrast, fructokinase A is widely distributed, has low affinity for fructose, and has less dramatic effects on ATP levels. By reducing the amount of fructose for metabolism in the liver, fructokinase A protects against fructokinase C-mediated metabolic syndrome. These studies provide insights into the mechanisms by which fructose causes obesity and metabolic syndrome.