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 α (LXRα, 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 LXRα regulates GLUT5 in mice and humans. As a ligand-activated transcription factor, LXRα might provide novel pharmacologic strategies for the selective modulation of GLUT5 activity in the treatment of metabolic disease as well as cancer.
Highlights
The increasing prevalence of obesity is cause for public health concern since it is a major risk factor for the development of chronic metabolic diseases including type 2 diabetes (T2D), cardiovascular disease and certain types of cancer
Fructose transport is mediated by members of the GLUT-family of facilitated sugar transporters encoded by the solute carrier family 2A (SLC2A) genes, which are essential for intestinal fructose absorption and fructose metabolism (Reviewed in14)
Using a luciferase reporter screen for the transcriptional regulation by ligand-activated members of the nuclear receptor (NR)-family that heterodimerize with Retinoid X Receptor (RXR), we observed a strong and specific regulation of the human GLUT5 promoter (−900/+3 bp relative to the transcription start site) by thyroid hormone receptors THRα and -β and liver x receptor α (LXRα) in CV-1 cells (Fig. 1a)
Summary
The increasing prevalence of obesity is cause for public health concern since it is a major risk factor for the development of chronic metabolic diseases including type 2 diabetes (T2D), cardiovascular disease and certain types of cancer. On the other hand, can bypass this PFK regulatory block via fructokinase or ketohexokinase (KHK), allowing continued glycolytic flux independent of cellular energy status. This uncontrolled hepatic fructose metabolism increases lipogenesis and, the development of non-alcoholic fatty liver disease (NAFLD)[7,8]. Www.nature.com/scientificreports in turn is known to cause hypertension and gout but is an independent risk factor for metabolic syndrome, cardiovascular disease and the development of chronic kidney disease (CKD)[9]. Fructose transport from the intestine to the blood and uptake by the liver is mediated by GLUT2 (SLC2A2), a high-capacity, glucose-dependent fructose co-transporter primarily localized on the basolateral membrane of enterocytes and hepatocytes
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