Hypoxia-induced consumption of fructose provokes heart disease

The study conducted by Prof Krek was published in Nature and demonstrates how alternative splicing mediates a metabolic switch that bypasses carbohydrate assimilation in cardiac cells. We congratulate our collaborators!

by Nicola Zamboni

Abstractexternal page

Fructose is a major component of dietary sugar and its overconsumption exacerbates key pathological features of metabolic syndrome. The central fructose-metabolising enzyme is ketohexokinase (KHK), which exists in two isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose compared with KHK-A and is produced primarily in the liver, thus restricting fructose metabolism almost exclusively to this organ. Here we show that myocardial hypoxia actuates fructose metabolism in human and mouse models of pathological cardiac hypertrophy through hypoxia-inducible factor 1α (HIF1α) activation of SF3B1 and SF3B1-mediated splice switching of KHK-A to KHK-C. Heart-specific depletion of SF3B1 or genetic ablation of Khk, but not Khk-Aalone, in mice, suppresses pathological stress-induced fructose metabolism, growth and contractile dysfunction, thus defining signalling components and molecular underpinnings of a fructose metabolism regulatory system crucial for pathological growth.

Reference

Mirtschink P, Krishnan J, Grimm F, Sarre A, Hörl M, Kayikci M, Fankhauser N, Christinat Y, Cortijo C, Feehan O, Vukolic A, Sossalla S, Stehr SN, Ule J, Zamboni N, Pedrazzini T, Krek W, HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease, Nature. 2015, external pagePubmed external pagedoi

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