MedicalResearch.com Interview with: Prof. Wilhelm Krek Institute of Molecular Health Sciences Zürich, Switzerland MedicalResearch: What is the background for this study? What are the main findings? Prof. Krek: Fructose and glucose are major components of dietary sugars consumed in the western world. A current prevailing view holds that glucose is used directly by various tissues as an energy source while fructose is first and foremost metabolized to fat by the liver arguing that these dietary sugars are metabolized differently despite having identical caloric values. Accordingly, overconsumption of fructose causes fatty liver disease and through dissemination of fat to peripheral organs such that adipose tissue contributes to obesity. The key enzyme in fructose metabolism is ketohexokinase (KHK). KHK-A and KHK-C are two isoforms of KHK that are produced through mutually exclusive alternative splicing of the KHK pre-mRNA. KHK-C displays a much higher affinity for fructose than KHK-A. Unlike other tissues that normally express KHK-A, the liver produces predominantly KHK-C providing a possible explanation of the above-noted pathologies upon overconsumption of fructose. Whether fructose metabolism is subject to signal-induced changes in alternative splicing of KHK isoform expression as a mechanism to mediate context-dependent changes in cell metabolism is not known. In this work, we identify the splicing factor SF3B1 as a key mediator of ketohexokinase alternative splicing and thus activator of fructose metabolism and further show that the SF3B1-KHK system is a direct target of regulation by hypoxia and promoter of heart disease. From the analysis of a series of genetic mouse models of pathologic cardiac hypertrophy and human samples of heart disease, we conclude that activation of the newly identified HIF1α-SF3B1-KHK-C axis and the ensuing promotion of fructose metabolism is essential for pathologic stress-induced anabolic growth and the development of heart disease. (more…)