Identification of the fructose transporter GLUT5 (SLC2A5) as a novel target of nuclear receptor LXR

Irene Zwarts, Tim van Zutphen, Janine K Kruit, Weilin Liu, Maaike H Oosterveer, Henkjan J Verkade, N Henriette Uhlenhaut, Johan W Jonker

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Abstract

Fructose has become a major constituent of our modern diet and is implicated as an underlying cause in the development of metabolic diseases. The fructose transporter GLUT5 (SLC2A5) is required for intestinal fructose absorption. GLUT5 expression is induced in the intestine and skeletal muscle of type 2 diabetes (T2D) patients and in certain cancers that are dependent on fructose metabolism, indicating that modulation of GLUT5 levels could have potential in the treatment of these diseases. Using an unbiased screen for transcriptional control of the human GLUT5 promoter we identified a strong and specific regulation by liver X receptor alpha (LXR alpha, NR1H3). Using promoter truncations and site-directed mutagenesis we identified a functional LXR response element (LXRE) in the human GLUT5 promoter, located at -385 bp relative to the transcriptional start site (TSS). Finally, mice treated with LXR agonist T0901317 showed an increase in Glut5 mRNA and protein levels in duodenum and adipose tissue, underscoring the in vivo relevance of its regulation by LXR. Together, our findings show that LXR alpha regulates GLUT5 in mice and humans. As a ligand-activated transcription factor, LXR alpha might provide novel pharmacologic strategies for the selective modulation of GLUT5 activity in the treatment of metabolic disease as well as cancer.

Original languageEnglish
Article number9299
Number of pages10
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 26-Jun-2019

Keywords

  • LIVER-X-RECEPTOR
  • THYROID-HORMONE RECEPTOR
  • DIETARY FRUCTOSE
  • EXPRESSION
  • GLUCOSE
  • ALPHA
  • GENE
  • INCREASES
  • MALABSORPTION
  • LOCALIZATION

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