Transcription - ChREBP regulation pathway


Click on a target from the pathway image to view related information. Zoom     View Legend


ChREBP regulation pathway

The carbohydrate-responsive element binding protein (ChREBP) is a transcription factor that activates the lipogenic genes in the liver in response to excess carbohydrate in the diet. ChREBP is required both for the basal and the carbohydrate-induced expression of several liver enzymes essential for coordinated control of glucose and fatty acid metabolisms, for example L-pyruvate kinase.

ChREBP is activated by the high glucose diet and inhibited by the high fat diet and cyclic AMP. ChREBP is phosphrylated and inhibited by cAMP-dependent protein kinase (PKA). PKA phosphorylates two physiologically important sites in the ChREBP, which is located near nuclear localization signal sequence (NLS), and within the basic helix-loop-helix site, resulting in inactivation of nuclear translocation of ChREBP and of the DNA-binding activity, respectively [1].

PKA is activated by cAMP and it is the main intracellular cAMP receptor. Enzyme Adenylyl cyclase is responsible for conversion AMP to cyclic AMP (cAMP). The activity of Adenylyl cyclases is tightly regulated by G-protein coupled receptors (GPCR). Activated GPCR stimulates conversion that inactivates GDP-bound to the active GTP-bound form of G-protein alpha subunits and dissociation G-protein alpha from beta/gamma subunits. At least, nine Adenylyl cyclases, have been cloned and characterized in mammals. All of them are activated by activated G-alpha (s) subunits, whereas G-alpha (i) is capable to inhibite some forms Adenylyl cyclases, including Adenylyl cyclases I [2].

Glucose signaling may activate ChREBP via activation of phosphotase PP2A. PP2A is localized both in cytosol and nucleus. Cytosolic PP2A dephosphorylates a nuclear localization signal sequence of ChREBP and permites ChREBP to translocate into nucleus. Nuclear PP2A catalyzed dephosphorylation of DNA-binding site and permit ChREBP bind to DNA. Such PP2A abolish PKA-mediated inhibition of ChREBP. Activity of PP2A is modulated by D-xylulose 5-phosphate (xylulose-5P) [3].

Fatty acids inhibition of action ChREBP is mediated by the AMP-activated protein kinase (AMPK). Acyl-CoA synthetase is responsible for conversion of long-chain fatty acid to acyl-CoA and adenosine 5'-monophosphate (AMP) [4]. The last modulates activity of AMPK [5] AMPK phosphorylates of sites in nuclearlocalisation signal (NLS) of ChREBP resulting in inactivation of the DNA binding activity [4].


  1. Uyeda K, Yamashita H, Kawaguchi T
    Carbohydrate responsive element-binding protein (ChREBP): a key regulator of glucose metabolism and fat storage. Biochemical pharmacology 2002 Jun 15;63(12):2075-80
  2. Defer N, Best-Belpomme M, Hanoune J
    Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. American journal of physiology. Renal physiology 2000 Sep;279(3):F400-16
  3. Kabashima T, Kawaguchi T, Wadzinski BE, Uyeda K
    Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Proceedings of the National Academy of Sciences of the United States of America 2003 Apr 29;100(9):5107-12
  4. Kemp BE, Stapleton D, Campbell DJ, Chen ZP, Murthy S, Walter M, Gupta A, Adams JJ, Katsis F, van Denderen B, Jennings IG, Iseli T, Michell BJ, Witters LA
    AMP-activated protein kinase, super metabolic regulator. Biochemical Society transactions 2003 Feb;31(Pt 1):162-8
  5. Kawaguchi T, Osatomi K, Yamashita H, Kabashima T, Uyeda K
    Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. The Journal of biological chemistry 2002 Feb 8;277(6):3829-35

Target Details

Click on a target from the pathway image to view related information.