title: Glucose activation of ChREBP in hepatocytes occurs via a two-step mechanism.
abstract: Carbohydrate response element binding protein (ChREBP) is a transcription factor that mediates glucose-responsive changes in gene expression in hepatocytes. In the current model for glucose regulation, inhibition of ChREBP in low glucose occurs in response to cAMP-dependent protein kinase (PKA)-mediated phosphorylation of residues S196, S626, and/or T666. Activation of ChREBP in conditions of increased glucose results simply from reversal of these inhibitory phosphorylations. To test this model, we analyzed mutant forms of ChREBP that lack one or more of the proposed PKA sites and found that these forms of ChREBP still require glucose for activation. Additionally, cAMP levels in cultured hepatocytes were negligible in low glucose conditions, indicating PKA should not be active. Finally, overall ChREBP phosphorylation did not change in response to altered glucose levels. We conclude that in addition to its repression by PKA, glucose activation of ChREBP involves a second mechanism that is independent of PKA phosphorylation.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Nikolas G
authors.initials: NG
authors.lastname: Tsatsos
authors.forename: Howard C
authors.initials: HC
authors.lastname: Towle
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D005947:Glucose / Q000502:physiology*; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C485496:MLXIP protein, human; C442825:Mlxipl protein, rat; D011993:Recombinant Fusion Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose