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

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; Ule, Jernej; Zamboni, Nicola; Pedrazzini, Thierry; Krek, Wilhelm

doi:10.1038/nature14508

Cited by 146 publications

(153 citation statements)

References 48 publications

(57 reference statements)

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“…This is supported by recent data showing that selective knockdown of KHK in mouse liver protects against fructose-induced steatosis (93). Recent data also indicate that altered splicing between KHK-A and KHK-C isoforms may contribute to the development of distinct diseases like hepatocellular carcinoma and heart failure (94,95).…”

Section: Genetic Lessons About Fructose Metabolismsupporting

confidence: 66%

Fructose metabolism and metabolic disease

Hannou

Haslam

McKeown

et al. 2018

Journal of Clinical Investigation

401

356

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Section: Genetic Lessons About Fructose Metabolismsupporting

confidence: 66%

Fructose metabolism and metabolic disease

Hannou

Haslam

McKeown

et al. 2018

Journal of Clinical Investigation

401

356

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“…This leads to upregulated expression of splice factor 3b subunit 1, which mediates splice switching of ketohexokinase-A to ketohexokinase-C and promotes fructolysis to induce cardiac hypertrophy by upregulation of protein and lipid biosynthesis. 49 …”

Section: Other Metabolitesmentioning

confidence: 99%

Metabolomic Analysis in Heart Failure

Ikegami

Shimizu

Yoshida

et al. 2018

Circ J

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10 s, resulting in the cycling of approximately 6 kg of ATP daily, and the heart displays metabolic flexibility to meet this extremely high demand for energy. 8 Under normal conditions, more than 95% of the ATP consumed in the heart is generated by oxidative phosphorylation, while glycolysis is responsible for approximately 5% and the tricarboxylic acid (TCA) cycle for the remainder. Metabolism of fatty acids generates 70-90% of the ATP required by the heart, with the rest being produced by oxidation of glucose, lactate, ketone bodies, and amino acids. 9 It is well known that utilization of fatty acids is reduced in the failing heart and there is a metabolic shift to generation of ATP from glucose. Such metabolic remodeling is considered to be reasonable because HF is associated with hypoxia and ATP generation per oxygen atom is more efficient when glucose is consumed, compared with fatty acids. 9 In patients with advanced HF, the heart is unable to utilize either metabolite and thus "runs out of fuel". 10 It is reported that the ATP level is approximately 30% lower in failing human hearts compared with non-failing hearts. 11 In addition to this classical premise about the metabolic profile of the failing heart, recent advances in the field of metabolomics have indicated that several metabolites and/or metabolic pathways have a role in HF, as described next. LipidsUnder physiological conditions, the heart mainly generates ATP from fatty acids, but this process declines with progression of HF. Under left ventricular (LV) pressure overload, excessive lipolysis occurs in visceral fat because of increased adrenergic signaling, and this leads to high circulating levels of free fatty acids (FFAs). 12 The serum I t is thought that at least 6,500 low-molecular-weight metabolites exist in humans, and these metabolites have various important roles in biological systems in addition to proteins and genes. 1 Comprehensive assessment of endogenous metabolites is called metabolomics, and recent advances in this field have enabled us to understand the critical role of previously unknown metabolites or metabolic pathways in the maintenance of homeostasis under both physiological and stress conditions. Techniques of metabolomic analysis have been elegantly reported and reviewed elsewhere, 2-4 so the details will not be repeated here. Instead, we will describe the metabolites/metabolic pathways that have been characterized using these techniques and analyzed to improve understanding of various physiological and pathological processes in the field of cardiology. In particular, we will focus on heart failure (HF) and how metabolomic analysis has contributed for improving our understanding of the pathogenesis of this critical condition. Cardiac MetabolismThe number of patients with HF continues to increase and this condition has become a major healthcare issue in many countries. Because the prognosis of severe HF is poor, there are many unmet medical needs for these patients, 5, 6 The pathogenesis of HF is complex and a simple approa...

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“…SF3B1, an Hif1α-inducible splicing factor, is upregulated in the diseased human and mouse heart and coordinates a shift in ketohexokinase isoforms. 89 Ketohexokinase is the central fructose-metabolising enzyme and exists in 2 isoforms: ketohexokinase-A and ketohexokinase-C. During hypertrophy and failure, the heart switches toward more glycolysis at the expense of fatty acid metabolism, 96 and the SF3B1-induced shift from ketohexokinase-A to ketohexokinase-C is both necessary and sufficient to enforce fructolysis in the cardiomyocyte. Intriguingly, heart-specific loss of SF3B1 or ketohexokinase prevents the metabolic switch and protects from pathological cardiac growth.…”

Section: Splice Factors In the Diseased Heartmentioning

confidence: 99%

RNA Splicing

Hoogenhof

Pinto

Creemers

2016

Circulation Research

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RNA splicing, a post-transcriptional process necessary to form a mature mRNA, was discovered in the late 1970s. 1 Two different modes of splicing have been defined, that is, constitutive splicing and alternative splicing. Constitutive splicing is the process of removing introns from the premRNA, and joining the exons together to form a mature mRNA. Alternative splicing, on the other hand, is the process where exons can be included or excluded in different combinations to create a diverse array of mRNA transcripts from a single pre-mRNA and therefore serves as a process to increase the diversity of the transcriptome. The estimated number of alternative splicing events in the human transcriptome has risen sharply over the past decades. In the 1980s, it was thought that about 5% of human genes were subjected to alternative splicing.2 In 2002, this number had risen to 60%, 3 and now, after implementation of next-generation-sequencing technologies, we know that the vast majority, >95% of mRNAs, are subjected to alternative splicing. 4 Nevertheless, the function of a large fraction of these splice isoforms remains to be elucidated. Furthermore, it is anticipated that in different tissues, or in tissues with different disease states, new isoforms still remain to be identified. 5The process of splicing is highly conserved during evolution. Splicing is more prevalent in multicellular than in unicellular eukaryotes because of the lower number of introncontaining genes in the latter. 6 Later in evolution, alternative splicing becomes more prevalent in vertebrates than in invertebrates. Interestingly, just a single exon-skipping event in the RNA-binding protein (RBP), polypyrimidine tract binding protein 1 has been shown to direct numerous alternative splicing changes between species, indicating that a single splicing event can amplify transcriptome diversity between species. 7The recent observation that the total number of protein-coding genes does not differ much between species, fueled the hypothesis that alternative splicing largely contributes to organism diversity. And indeed, as we move up the phylogenetic tree, alternative splicing complexity increases, with the highest complexity in primates. 8,9The aim of this review is to give a comprehensive overview of all aspects of constitutive and alternative splicing and their regulators, as well as the importance of these different aspects in human disease, with a focus on the heart. In addition, we discuss possible therapeutic interventions and try to uncover potential future directions of research. Major and Minor SpliceosomeRNA splicing is performed by the spliceosome, a large and dynamic ribonucleoprotein complex composed of proteins and small nuclear RNAs (snRNAs), which assembles on the pre-mRNA (Figure 1). Ribonucleoproteins consist of 1 or 2 small nuclear RNAs (snRNAs; U1, U2, U4/U6, or U5), and a variable number of complex-specific proteins.

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

Cited by 146 publications

References 48 publications

Fructose metabolism and metabolic disease

Fructose metabolism and metabolic disease

Metabolomic Analysis in Heart Failure

RNA Splicing

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