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 .
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 .
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) .
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) . The last modulates activity of AMPK  AMPK phosphorylates of sites in nuclearlocalisation signal (NLS) of ChREBP resulting in inactivation of the DNA binding activity .
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