Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance.

Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models. However, genetic disorders in fructose metabolism have very different consequences. While the deficiency of fructokinase, the first enzyme involved in fructose metabolism, is benign and somewhat desirable, missense mutations in the second enzyme, aldolase B, causes a very dramatic and sometimes lethal condition known as hereditary fructose intolerance (HFI). To date, there is no cure for HFI, and treatment is limited to avoiding fructose and sugar. Because of this, for subjects with HFI, glucose is their sole source of carbohydrates in the diet. However, clinical symptoms still occur, suggesting that either low amounts of fructose are still being consumed or, alternatively, fructose is being produced endogenously in the body. Here, we demonstrate that as a consequence of consuming high glycemic foods, the polyol pathway, a metabolic route in which fructose is produced from glucose, is activated, triggering a deleterious mechanism whereby glucose, sorbitol and alcohol induce severe liver disease and growth retardation in aldolase B knockout mice. We show that generically and pharmacologically blocking this pathway significantly improves metabolic dysfunction and thriving and increases the tolerance of aldolase B knockout mice to dietary triggers of endogenous fructose production.