Sensing Nuclear Glucose

Abstract

The liver X receptors (LXR-α and -β) are nuclear transcription factors that have been implicated in both glucose and lipid metabolism; their activation by oxysterol ligands elicits both a decrease in atherosclerosis and antidiabetic effects. Although synthetic LXR ligands decrease hepatic gluconeogenesis and increase lipogenesis in rodent models, the normal rodent diet lacks cholesterol, which led Mitro et al . to search for other ligands. They found that glucose and glucose derivatives stimulated the transcriptional activation of a Gal4-responsive gene reporter in human HepG2 cells expressing constructs in which LXR ligand-binding domains (LBDs) were fused to the Gal4 DNA binding domain and transcriptionally activated LXR-RXR (retinoid X receptor) targets. Cell-free coactivator recruitment assays and scintillation proximity assays indicated that glucose and glucose-6-phosphate were direct LXR agonists that bound to the LXR LBD. Furthermore, glucose protected LXR-α from proteolytic attack and increased the LXR-β melting temperature. Glucose had effects on the transcription of LXR target genes in HEPG2 cells similar to those of known ligands, stimulating the expression of genes involved in fatty acid synthesis and cholesterol homeostasis and inhibiting expression of gluconeogenic genes; moreover, it potentiated the effects of LXR ligands. Similarly, glucose- or sucrose-feeding stimulated the expression of LXR target genes in the livers of fasted mice, even mice that were insulin deficient. Thus, glucose itself appears to act as a ligand for LXR, leading the authors to propose that LXR acts as a "transcriptional switch" to coordinate carbohydrate and lipid metabolism. N. Mitro, P. A. Mak, L. Vargas, C. Godio, E. Hampton, V. Molteni, A. Kreusch, E. Saez, The nuclear receptor LXR is a glucose sensor. Nature 445 , 219-223 (2007). [PubMed]