Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor alpha.
The insulin-responsive glucose transporter GLUT4 plays a crucial role in insulin-mediated facilitated glucose uptake into adipose tissue and muscle, and impaired expression of GLUT4 has been linked to obesity and diabetes. In this study, we demonstrate that liver X receptors (LXRs) regulate the expression of GLUT4 through direct interaction with a conserved LXR response element in the GLUT4 promoter. The expression of GLUT4 in WAT is induced by a potent LXR agonist in wild type, LXR alpha-/-, and LXR beta-/- mice but not in LXR alpha-/-beta-/- mice, demonstrating that both LXRs are able to mediate ligand activated transcription of the GLUT4 gene. However, basal and insulin stimulated expression of GLUT4 in epididymal WAT is reduced only in mice carrying ablation of the LXR alpha isoform. The expression of GLUT4 is furthermore correlated to the induction of LXR alpha during mouse and human adipocyte differentiation. LXR beta is thus apparently not able to rescue basal expression of GLUT4 in the absence of LXR alpha. We have previously demonstrated that LXR alpha is down-regulated in animal models of obesity and diabetes, thus revealing a striking correlation between GLUT4 and LXR alpha expression in insulin-resistant conditions. This suggests that the LXR alpha isoform has a unique role in adipose expression of GLUT4 and suggests that alteration of adipose tissue expression of LXR alpha might be a novel tool to normalize the expression of a gene that is dysregulated in diabetic and insulin-resistant conditions.
Dalen
Knut Tomas
KT
Institute for Nutrition Research, University of Oslo, N-0316 Oslo, Norway.
Ulven
Stine Marie
SM
Bamberg
Krister
K
Gustafsson
Jan-Ake
JA
Nebb
Hilde I
HI
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002454:Cell Differentiation; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D003920:Diabetes Mellitus / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000502:physiology*; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D000071518:Liver X Receptors; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis*; D009124:Muscle Proteins; D009765:Obesity / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D021381:Protein Transport; D012313:RNA / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D008024:Ligands; D000071518:Liver X Receptors; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D012313:RNA; D005947:Glucose