Liver X receptor regulates hepatic nuclear O-GlcNAc signaling and carbohydrate responsive element-binding protein activity.
Liver X receptor (LXR)α and LXRβ play key roles in hepatic de novo lipogenesis through their regulation of lipogenic genes, including sterol regulatory element-binding protein (SREBP)-1c and carbohydrate responsive element-binding protein (ChREBP). LXRs activate lipogenic gene transcription in response to feeding, which is believed to be mediated by insulin. We have previously shown that LXRs are targets for glucose-hexosamine-derived O-linked β-N-acetylglucosamine (O-GlcNAc) modification enhancing their ability to regulate SREBP-1c promoter activity in vitro. To elucidate insulin-independent effects of feeding on LXR-mediated lipogenic gene expression in vivo, we subjected control and streptozotocin-treated LXRα/β(+/+) and LXRα/β(-/-) mice to a fasting-refeeding regime. We show that under hyperglycemic and hypoinsulinemic conditions, LXRs maintain their ability to upregulate the expression of glycolytic and lipogenic enzymes, including glucokinase (GK), SREBP-1c, ChREBPα, and the newly identified shorter isoform ChREBPβ. Furthermore, glucose-dependent increases in LXR/retinoid X receptor-regulated luciferase activity driven by the ChREBPα promoter was mediated, at least in part, by O-GlcNAc transferase (OGT) signaling in Huh7 cells. Moreover, we show that LXR and OGT interact and colocalize in the nucleus and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling and ChREBPα promoter binding activity in vivo. In summary, our study provides evidence that LXRs act as nutrient and glucose metabolic sensors upstream of ChREBP by modulating GK expression, nuclear O-GlcNAc signaling, and ChREBP expression and activity.
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0316 Oslo, Norway.
Christian
C
Bindesbøll
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0316 Oslo, Norway.
Qiong
Q
Fan
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0316 Oslo, Norway.
Rikke C
RC
Nørgaard
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada.
Laura
L
MacPherson
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06519 Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06519.
Hai-Bin
HB
Ruan
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06519 Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06519.
Jing
J
Wu
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Thomas Å
TÅ
Pedersen
Division of Clinical Chemistry Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, C174, SE-141 86 Stockholm, Sweden.
Knut R
KR
Steffensen
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06519 Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06519 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06519.
Xiaoyong
X
Yang
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0316 Oslo, Norway Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada.
Jason
J
Matthews
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Susanne
S
Mandrup
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0316 Oslo, Norway.
Hilde I
HI
Nebb
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0316 Oslo, Norway.
Line M
LM
Grønning-Wang
D000117:Acetylglucosamine / Q000378:metabolism*; D000215:Acylation / Q000187:drug effects; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D004435:Eating; D005215:Fasting; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000172:deficiency / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011770:Pyruvate Kinase / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin / Q000009:adverse effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000096:biosynthesis / Q000097:blood
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071518:Liver X Receptors; C506001:Mlxipl protein, mouse; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D014157:Transcription Factors; D014280:Triglycerides; D013311:Streptozocin; D011770:Pyruvate Kinase; D005947:Glucose; D000117:Acetylglucosamine
O-linked β-N-acetylglucosamine; O-linked β-N-acetylglucosamine transferase; carbohydrate responsive element-binding protein α; carbohydrate responsive element-binding protein β; chromatin immunoprecipitation; glucose; insulin; lipid metabolism