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Mondo/ChREBP-Mlx-regulated transcriptional network is essential for dietary sugar tolerance in Drosophila
Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
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2013 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 4, article id e1003438Article in journal (Refereed) Published
Abstract [en]

Sugars are important nutrients for many animals, but are also proposed to contribute to overnutrition-derived metabolic diseases in humans. Understanding the genetic factors governing dietary sugar tolerance therefore has profound biological and medical significance. Paralogous Mondo transcription factors ChREBP and MondoA, with their common binding partner Mlx, are key sensors of intracellular glucose flux in mammals. Here we report analysis of the in vivo function of Drosophila melanogaster Mlx and its binding partner Mondo (ChREBP) in respect to tolerance to dietary sugars. Larvae lacking mlx or having reduced mondo expression show strikingly reduced survival on a diet with moderate or high levels of sucrose, glucose, and fructose. mlx null mutants display widespread changes in lipid and phospholipid profiles, signs of amino acid catabolism, as well as strongly elevated circulating glucose levels. Systematic loss-of-function analysis of Mlx target genes reveals that circulating glucose levels and dietary sugar tolerance can be genetically uncoupled: Krüppel-like transcription factor Cabut and carbonyl detoxifying enzyme Aldehyde dehydrogenase type III are essential for dietary sugar tolerance, but display no influence on circulating glucose levels. On the other hand, Phosphofructokinase 2, a regulator of the glycolysis pathway, is needed for both dietary sugar tolerance and maintenance of circulating glucose homeostasis. Furthermore, we show evidence that fatty acid synthesis, which is a highly conserved Mondo-Mlx-regulated process, does not promote dietary sugar tolerance. In contrast, survival of larvae with reduced fatty acid synthase expression is sugar-dependent. Our data demonstrate that the transcriptional network regulated by Mondo-Mlx is a critical determinant of the healthful dietary spectrum allowing Drosophila to exploit sugar-rich nutrient sources.

Place, publisher, year, edition, pages
Public Library of Science , 2013. Vol. 9, no 4, article id e1003438
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:oru:diva-63680DOI: 10.1371/journal.pgen.1003438ISI: 000318073300032PubMedID: 23593032Scopus ID: 2-s2.0-84876866223OAI: oai:DiVA.org:oru-63680DiVA, id: diva2:1169246
Funder
Academy of Finland
Note

Sigrid Juselius Foundation

Biocentrum Helsinki

European Research Council

Emil Aaltonen Foundation

Diabetes Research Foundation

Helsinki Graduate Program in Biotechnology and Molecular Biology

Viikki Doctoral Programme in Molecular Biosciences

University of Helsinki Research Foundation

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-01-30Bibliographically approved

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Hyötyläinen, Tuulia

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