n. mitro et al. nature advance online publication 24 december 2006 doi:10.1038/nature05449

N. Mitro et al. Nature advance online publication 24 December 2006 doi:10.1038/nature05449http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature05449.html

N. Mitro et al. Nature advance online publication 24 December 2006 doi:10.1038/nature05449http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature05449.html

N. Mitro et al. Nature advance online publication 24 December 2006 doi:10.1038/nature05449http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature05449.html

N. Mitro et al. Nature advance online publication 24 December 2006 doi:10.1038/nature05449http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature05449.html

Glucose displaces a labelledhigh-affinity LXR ligand

a, d-Glucose and glucose-6-phosphate compete for LXR binding and displace [3H]T0901317 (25 nM) in an SPA assay. b, [3H]Glucose binds LXR. A scatchard analysis is shown in the inset. Labelled glucose did not bind the RXR LBD (data not shown). Unlabelled LXR ligands displace bound [3H]glucose (20 mM) but not completely. Values are expressed as percentage binding of labelled compound. Fractional occupancy of the receptor (see Methods) is 95% for LXR- and 98% for LXR-. c.p.m., counts per minute. c, Addition of labelled glucose to a saturating dose of [3H]T0901317 (10 µM) increases scintillation in an SPA assay; percentage efficacy is relative to 10 µM [3H]T091317. d, Addition of glucose, but not GW3965, to a maximal dose of T0901317 enhances coactivator recruitment. Note the different scales. Values are presented as fold induction versus vehicle (increase in coactivator recruitment measured as a change in 665/615 nm emission relative to vehicle). All error bars indicate s.d.; experiments performed in triplicate.

N. Mitro et al. Nature advance online publication 24 December 2006 doi:10.1038/nature05449http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature05449.html

Glucose regulates direct LXRtarget genes in vivo (a)

HepG2 cells cultured in 0 mM (white bars), 2 mM (grey bars) or 25 mM (black bars) glucose medium were treated overnight with GW3965 (1 µM), 22-(R)-hydroxycholesterol (5 µM), or D-glucose (20 mM) and gene expression was analysed using qRT-PCR. Glucose stimulates expression of direct LXR cholesterol homeostasis target genes. Note that efficacy of known LXR ligands increases with increasing glucose concentration. All error bars represent s.d.

N. Mitro et al. Nature advance online publication 24 December 2006 doi:10.1038/nature05449http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature05449.html

Glucose regulates direct LXRtarget genes in vivo (b)

Glucose induces LXR target genes in mouse liver. Mice fasted overnight were challenged orally with GW3965 (50 mg ﾊ kg-1), or re-fed with a glucose or sucrose diet and killed 6 h later. d-Glucose and GW3965 regulate the same direct LXR targets (genes involved in cholesterol and fatty acid metabolism) as well as indirect carbohydrate metabolism targets. All error bars represent s.d., n = 5-6 mice per group. Asterisk, P<0.05; double asterisk, P<0.001 treatment versus fasted.

N. Mitro et al. Nature advance online publication 24 December 2006 doi:10.1038/nature05449http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature05449.html

Schematic representation of pathways influencing

glucose fate in the liver

Glucose induces insulin secretion, suppressing hepatic gluconeogenesis and – through LXR – activating SREBP-1c expression and lipogenesis. Glucose can also bind directly to LXR to induce SREBP-1c expression, suppress hepatic glucose output, and increase ChREBP expression. ChREBP activitity is modulated by glucose metabolites, further increasing lipogenesis. For clarity, glycogen metabolism is not included in the diagram.