Mirtschink Peter, Krishnan Jaya, Grimm Fiona, Sarre Alexandre, Hörl Manuel, Kayikci Melis, Fankhauser Niklaus, Christinat Yann, Cortijo Cédric, Feehan Owen, Vukolic Ana, Sossalla Samuel, Stehr Sebastian N, Ule Jernej, Zamboni Nicola, Pedrazzini Thierry, Krek Wilhelm
Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
Department of Medicine, University of Lausanne, 1011 Lausanne, Switzerland.
Nature. 2015 Jun 25;522(7557):444-449. doi: 10.1038/nature14508. Epub 2015 Jun 17.
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-A alone, 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.
果糖是膳食糖的主要成分，过量摄入会加剧代谢综合征的关键病理特征。果糖代谢的核心酶是酮己糖激酶（KHK），它以两种异构体形式存在：KHK-A和KHK-C，由KHK前体mRNA的互斥可变剪接产生。与KHK-A相比，KHK-C对果糖表现出更高的亲和力，并且主要在肝脏中产生，因此几乎将果糖代谢限制在该器官。在这里，我们表明，在病理性心脏肥大的人类和小鼠模型中，心肌缺氧通过缺氧诱导因子1α（HIF1α）激活SF3B1以及SF3B1介导的KHK-A向KHK-C的剪接转换来启动果糖代谢。在小鼠中，心脏特异性敲除SF3B1或基因敲除Khk（而非单独敲除Khk-A）可抑制病理性应激诱导的果糖代谢、生长和收缩功能障碍，从而确定了对病理性生长至关重要的果糖代谢调节系统的信号成分和分子基础。
