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The nuclear receptor LXR is a glucose sensor

Abstract

The liver has a central role in glucose homeostasis, as it has the distinctive ability to produce and consume glucose1. On feeding, glucose influx triggers gene expression changes in hepatocytes to suppress endogenous glucose production and convert excess glucose into glycogen or fatty acids to be stored in adipose tissue2. This process is controlled by insulin, although debate exists as to whether insulin acts directly or indirectly on the liver3. In addition to stimulating pancreatic insulin release, glucose also regulates the activity of ChREBP, a transcription factor that modulates lipogenesis4. Here we describe another mechanism whereby glucose determines its own fate: we show that glucose binds and stimulates the transcriptional activity of the liver X receptor (LXR), a nuclear receptor that coordinates hepatic lipid metabolism. d-Glucose and d-glucose-6-phosphate are direct agonists of both LXR-α and LXR-β. Glucose activates LXR at physiological concentrations expected in the liver and induces expression of LXR target genes with efficacy similar to that of oxysterols, the known LXR ligands. Cholesterol homeostasis genes that require LXR for expression are upregulated in liver and intestine of fasted mice re-fed with a glucose diet, indicating that glucose is an endogenous LXR ligand. Our results identify LXR as a transcriptional switch that integrates hepatic glucose metabolism and fatty acid synthesis.

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Figure 1: Glucose induces LXR transcriptional activity.
Figure 2: Glucose is a direct LXR agonist.
Figure 3: Glucose displaces a labelled high-affinity LXR ligand.
Figure 4: Glucose regulates direct LXR target genes in vivo.

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Acknowledgements

We thank S. Bohan, R. Romeo, B. Geierstanger, M. Chalmers, P. Griffin, N. Gekakis, M. Crestani, H. Shimano, T. Matsuzaka, P. Tontonoz, B. Laffitte, S. Joseph, A. Brock, E. Peters and K. Nettles for technical help and/or useful comments. C.G. was a visiting scientist supported by a fellowship from the Department of Pharmacological Sciences, University of Milano, Italy.

Author Contributions L.V., C.G., E.H. and A.K. performed experiments; P.A.M. and V.M. designed and performed experiments and analysed data; and N.M. and E.S. designed and performed experiments, analysed data, and wrote the manuscript.

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Correspondence to Enrique Saez.

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This file contains Supplementary Figures 1-10 with legends, Supplementary Methods and Supplementary Table 1. (PDF 962 kb)

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Mitro, N., Mak, P., Vargas, L. et al. The nuclear receptor LXR is a glucose sensor. Nature 445, 219–223 (2007). https://doi.org/10.1038/nature05449

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