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Pathways Regulation And Function Of ChREBP in Liver
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Description: Description: Liver is the major site for carbohydrate metabolism (glycolysis and glycogen synthesis) and triglyceride synthesis (lipogenesis). While insulin was long thought to be the major regulator of hepatic gene expression, emerging evidence show that nutrients, in particular, glucose and fatty acids, are also able to regulate hepatic genes. This diagram illustrates how glucose metabolite, rather than glucose itself, contributes to the coordinated regulation of carbohydrate and lipid homeostasis in liver through phosphorylation-dependent regulation of ChREBP (carbohydrate responsive element binding protein).

ChREBP is a basic helix-loop helix/leucine zipper (bHLH/LZ) transcription factor, shuttling between the cytoplasm and nucleus in a glucose-responsive manner in hepatocytes. When serum glucose is elevated, glucose transporter (GLUT2) and glucokinase (GCK) allow for rapid uptake and equilibration of intracellular glucose levels. This flux of glucose promotes, via the hexose monophosphate shunt pathway (HMP Shunt), the formation of xylulose-5-phosphate (Xu-5-P), which activates protein phosphatase 2A (PP2A) to dephosphorylate ChREBP (Ser196) and promote its nuclear localization. PP2A further dephosphorylates ChREBP in the nucleus, allowing it to dimerize with the bHLH/LZ transcription factor Max-like protein X (MLX) and activate transcription of a number of glycolytic and lipogenic genes containing a ChoRE, such as liver-type pyruvate kinase (L-PK), acetyl-CoA carboxylase 1 (ACACA), and fatty acid synthase (FASN).

Upon starvation or high-fat feeding, intrahepatic levels of cAMP and AMP are elevated to activate protein kinase A (PKA) and AMP-dependent protein kinase (AMPK), respectively. PKA-mediated phosphorylation of Thr666 and Ser626 inhibits the DNA binding capacity of ChREBP; so does AMPK-mediated modification of Ser568. PKA-dependent phosphorylation of Ser196 promotes interaction with 14-3-3 and thus sequesters ChREBP in the cytosol.

In summary, the phosphorylated form of ChREBP is rendered inactive due to its diminished DNA binding capacity and subcellular compartmentalization. Glucose metabolism triggers dephosphorylation of ChREBP, allowing it to enter the nucleus and activate the transcription of both glycolytic and lipogenic gene expression in liver. The fact that ChREBP–/– mice are intolerant to glucose and insulin resistant suggests that ChREBP may also play a role in the pathogenesis of type 2 diabetes.
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references: references: Dentin R, Girard J, Postic C. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie. 2005 Jan;87(1):81-6. Revi

Dentin R, Pegorier JP, Benhamed F, Foufelle F, Ferre P, Fauveau V, Magnuson MA, Girard J, Postic C. Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression. J Biol Chem. 2004 May 7;279(

Ma L, Robinson LN, Towle HC. ChREBP/Mlx is the principal mediator of glucose-induced gene expression in the liver. J Biol Chem. 2006 Aug 2

Towle HC. Glucose as a regulator of eukaryotic gene transcription. Trends Endocrinol Metab. 2005 Dec;16(10):489-94.

Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006 Aug;4(2):107-10.

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