HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease

Wilhelm Krek and colleagues find that myocardial hypoxia, which occurs during pathological cardiac hypertrophy, activates fructose metabolism in the heart in mouse models and in patients with hypertrophic cardiomyopathy through stimulation of hypoxia-inducible factor 1 (HIF1) activity. HIF1 in turn activates the splicing factor SF3B1, which mediates splice switching of the fructose metabolizing enzyme ketohexokinase-A (KHK-A) to the KHK-C isoform that has superior affinity for fructose. Pathological heart growth and contractile dysfunction can be suppressed by depleting SF3B1 or deleting KHK. Fructose is a major dietary sugar, thought to be metabolized in the liver, and its overconsumption is thought to contribute to various pathologies of metabolic syndrome. This work suggests that local hypoxia can trigger inappropriate fructose metabolism and highlights the HIF1SF3B1KHK-C axis as a promising therapeutic target.