Mechanism Linking Excess Fructose Intake To Heart Disease Delineated 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.

MedicalResearch: What should clinicians and patients take away from your report?

Prof. Krek: Over the last 3-4 decades fructose spread throughout the food market as it has been considered less harmful than glucose. Unlike glucose, fructose appears not to increase blood glucose levels and insulin secretion thus avoiding frequently recurring insulin spikes after glucose intake. Fructose can be found in many foods as additive, especially in sweet beverages and soft drinks. This practice drove up per capita consumption of high fructose corn syrup in the USA between 1970 and 1997, from 230 grams per year to over 28 kilograms.
Potentially, this surplus of fructose can help trigger the mechanism described in the context of one of more of the stress factors is present, such as cardiac valve disease or high blood pressure.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Prof. Krek: This work delinates a molecular mechanism by which a specific pathologically-activated signaling pathway enacts a central component of the alternative pre-mRNA splicing machinery to promote fructose-dependent anabolic metabolism and pathologic growth of the heart. The fact that hypoxia is a central feature of many pathologies and SF3B1 has been found recurrently mutated in various human cancers point to a potential broad role of the HIF-SF3B1-KHK axis and deregulated fructose metabolism in driving diseases in various tissue contexts. Future investigations should aim at understanding the role of this signaling circuit in diverse tissue and disease contexts and providing provide rationales for the development of specific therapeutic agents that interfere with the pathologic activation of this fructose-regulatory system in human disease.


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

Peter Mirtschink, Jaya Krishnan, Fiona Grimm, Alexandre Sarre,Manuel Hörl, Melis Kayikci, Niklaus Fankhauser, Yann Christinat, Cédric Cortijo, Owen Feehan, Ana Vukolic, Samuel Sossalla, Sebastian N. Stehr, Jernej Ule, Nicola Zamboni, Thierry Pedrazzini & Wilhelm Krek

Nature (2015) doi:10.1038/nature14508

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Potentially, a surplus of fructose can help trigger the mechanisms increasing cardiac valve disease or high blood pressure. (2015). Mechanism Linking Excess Fructose Intake To Heart Disease Delineated