ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver.
The transcription factor carbohydrate-responsive element-binding protein (ChREBP) has emerged as a central regulator of lipid synthesis in liver because it is required for glucose-induced expression of the glycolytic enzyme liver-pyruvate kinase (L-PK) and acts in synergy with SREBP to induce lipogenic genes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Liver X receptors (LXRs) are also important regulators of the lipogenic pathway, and the recent finding that ChREBP is a direct target of LXRs and that glucose itself can bind and activate LXRs prompted us to study the role of LXRs in the induction of glucose-regulated genes in liver. Using an LXR agonist in wild-type mice, we found that LXR stimulation did not promote ChREBP phosphorylation or nuclear localization in the absence of an increased intrahepatic glucose flux. Furthermore, the induction of ChREBP, L-PK, and ACC by glucose or high-carbohydrate diet was similar in LXRalpha/beta knockout compared with wild-type mice, suggesting that the activation of these genes by glucose occurs by an LXR-independent mechanism. We used fluorescence resonance energy transfer analysis to demonstrate that glucose failed to promote the interaction of LXRalpha/beta with specific cofactors. Finally, siRNA silencing of ChREBP in LXRalpha/beta knockout hepatocytes abrogated glucose-induced expression of L-PK and ACC, further demonstrating the central role of ChREBP in glucose signaling. Taken together, our results demonstrate that glucose is required for ChREBP functional activity and that LXRs are not necessary for the induction of glucose-regulated genes in liver.
Denechaud
Pierre-Damien
PD
Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS, UMR 8104, Paris, France.
Bossard
Pascale
P
Lobaccaro
Jean-Marc A
JM
Millatt
Lesley
L
Staels
Bart
B
Girard
Jean
J
Postic
Catherine
C
D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D021581:Active Transport, Cell Nucleus; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000502:physiology*; D057093:Orphan Nuclear Receptors; D010766:Phosphorylation; D011770:Pyruvate Kinase / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C506001:Mlxipl protein, mouse; C000605214:Nr1h3 protein, mouse; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D011770:Pyruvate Kinase; D000103:Acetyl-CoA Carboxylase; D005947:Glucose