Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis  Kosaku Uyeda,

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Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis  Kosaku Uyeda, Joyce J. Repa  Cell Metabolism  Volume 4, Issue 2, Pages 107-110 (August 2006) DOI: 10.1016/j.cmet.2006.06.008 Copyright © 2006 Elsevier Inc. Terms and Conditions

Figure 1 Schematic depiction and characterization of ChREBP A) Schematic depiction of ChREBP indicating various functional domains: nuclear export signal (NES); nuclear localization signal (NLS); basic helix-loop-helix/Zipper DNA binding domain (bHLH/ZIP) and proline-rich domains implicated in protein-protein interactions. Also shown are the amino acid residues phosphorylated by PKA (Ser196, Ser626, and Thr666) and AMPK (Ser568) that regulate the cellular localization and DNA binding capacity of the murine ChREBP (Kawaguchi et al., 2001, 2002). A glucose-sensing domain has been identified consisting of an N-terminal LID (inhibitory at low glucose) and C-terminal glucose-responsive element (Li et al., 2006). B) Characterization of ChREBPs. Distribution of RNA was determined by Northern analysis (de Luis et al., 2000; Iizuka et al., 2004; Yamashita et al., 2001) and in situ hybridization (Cairo et al., 2001) revealing major sites of expression. Cell Metabolism 2006 4, 107-110DOI: (10.1016/j.cmet.2006.06.008) Copyright © 2006 Elsevier Inc. Terms and Conditions

Figure 2 Acute regulation of ChREBP activity by hormone/nutrient-mediated changes in protein phosphorylation Phosphorylated ChREBP is actively excluded from the nucleus and sequestered in the cytosol by its association with 14-3-3, thereby rendering ChREBP an inactive transcription factor. Hepatocyte exposure to glucose results in an elevated xylulose 5-phosphate (Xu-5-P) level, which promotes the action of protein phosphatase 2A (PP2A) and allows for nuclear translocation of ChREBP (these processes shown by green arrows). Nuclear ChREBP dimerizes with Mlx and binds carbohydrate responsive elements in the promoters of target genes such as liver pyruvate kinase (L-PK) to increase transcription. Conversely, glucagon and fatty acids increase the activities of cAMP- (PKA) and AMP-dependent kinases (AMPK) that phosphorylate ChREBP to reduce DNA binding capacity and promote nuclear exclusion of ChREBP (shown by red arrows). Cell Metabolism 2006 4, 107-110DOI: (10.1016/j.cmet.2006.06.008) Copyright © 2006 Elsevier Inc. Terms and Conditions

Figure 3 The central role of ChREBP in linking glycolysis and lipogenesis in hepatocytes Catabolism of glucose yields pyruvate, which can be channeled into fatty acid synthesis. Proteins are indicated in italicized uppercase letters, metabolic intermediates in lowercase letters. The allosteric regulation of early steps in glycolysis are indicated in blue: xylulose-5-phosphate (Xu-5-P) and fructose-2,6-bisphosphate (Fru-2,6-P2) positively affect key enzymes PP2A, the kinase moiety of the bifunctional enzyme PF2K-Pase, and phosphofructokinase (PFK). Transcriptional regulation of the terminal step of glycolysis (via L-PK) and key enzymes of lipogenesis is controlled by ChREBP (shown in red). Concomitant production of NADPH by the hexose monophosphate shunt pathway (HMP Shunt) in the production of Xu-5-P and the recycling of pyruvate from citrate-liberated oxaloacetate (OAA) by malic enzyme (ME) provides reducing equivalents necessary for fatty acid synthesis. Cell Metabolism 2006 4, 107-110DOI: (10.1016/j.cmet.2006.06.008) Copyright © 2006 Elsevier Inc. Terms and Conditions