Letter

Nature 445, 219-223 (11 January 2007) | doi:10.1038/nature05449; Received 25 July 2006; Accepted 7 November 2006; Published online 24 December 2006

The nuclear receptor LXR is a glucose sensor

Nico Mitro1,2, Puiying A. Mak1, Leo Vargas1, Cristina Godio1, Eric Hampton1, Valentina Molteni1, Andreas Kreusch1 & Enrique Saez1,2

  1. Genomics Institute of the Novartis Research Foundation, 10675 John Hopkins Drive, San Diego, California 92121, USA
  2. The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

Correspondence to: Enrique Saez1,2 Correspondence and requests for materials should be addressed to E.S. (Email: esaez@scripps.edu).

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-alpha and LXR-beta. 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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