title: Mondo-Mlx Mediates Organismal Sugar Sensing through the Gli-Similar Transcription Factor Sugarbabe.
abstract: The ChREBP/Mondo-Mlx transcription factors are activated by sugars and are essential for sugar tolerance. They promote the conversion of sugars to lipids, but beyond this, their physiological roles are insufficiently understood. Here, we demonstrate that in an organism-wide setting in Drosophila, Mondo-Mlx controls the majority of sugar-regulated genes involved in nutrient digestion and transport as well as carbohydrate, amino acid, and lipid metabolism. Furthermore, human orthologs of the Mondo-Mlx targets display enrichment among gene variants associated with high circulating triglycerides. In addition to direct regulation of metabolic genes, Mondo-Mlx maintains metabolic homeostasis through downstream effectors, including the Activin ligand Dawdle and the Gli-similar transcription factor Sugarbabe. Sugarbabe controls a subset of Mondo-Mlx-dependent processes, including de novo lipogenesis and fatty acid desaturation. In sum, Mondo-Mlx is a master regulator of other sugar-responsive pathways essential for adaptation to a high-sugar diet.
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki 00790, Finland; Institute of Biotechnology, University of Helsinki, Helsinki 00790, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Mattila
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki 00790, Finland; Institute of Biotechnology, University of Helsinki, Helsinki 00790, Finland.
authors.forename: Essi
authors.initials: E
authors.lastname: Havula
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki 00790, Finland; Institute of Biotechnology, University of Helsinki, Helsinki 00790, Finland.
authors.forename: Erja
authors.initials: E
authors.lastname: Suominen
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki 00790, Finland; Institute of Biotechnology, University of Helsinki, Helsinki 00790, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Teesalu
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00270, Finland; Department of Health, National Institute for Health and Welfare, Helsinki 00251, Finland.
authors.forename: Ida
authors.initials: I
authors.lastname: Surakka
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki 00790, Finland; Institute of Biotechnology, University of Helsinki, Helsinki 00790, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Hynynen
authors.affiliation: EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Kilpinen
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki 00790, Finland.
authors.forename: Juho
authors.initials: J
authors.lastname: Väänänen
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki 00790, Finland; Department of Health, National Institute for Health and Welfare, Helsinki 00251, Finland.
authors.forename: Iiris
authors.initials: I
authors.lastname: Hovatta
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki 00790, Finland.
authors.forename: Reijo
authors.initials: R
authors.lastname: Käkelä
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00270, Finland; Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki 00251, Finland; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sandmann
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki 00790, Finland; Institute of Biotechnology, University of Helsinki, Helsinki 00790, Finland. Electronic address: ville.hietakangas@helsinki.fi.
authors.forename: Ville
authors.initials: V
authors.lastname: Hietakangas
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050260:Carbohydrate Metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D000596:Amino Acids; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C517156:Daw protein, Drosophila; D029721:Drosophila Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C581832:bigmax protein, Drosophila; C484002:mio protein, Drosophila; C469740:sug protein, Drosophila