Carbohydrate-responsive element-binding protein

File:ChREBP.png

This gene encodes a basic helix-loop-helix leucine zipper transcription factor of the Myc / Max / Mad superfamily. This protein forms a heterodimeric complex and binds and activates, in a glucose-dependent manner, carbohydrate response element (ChoRE) motifs in the promoters of triglyceride synthesis genes.

ChREBP is activated by glucose, independent of insulin.{{cite journal | vauthors = Xu X, So JS, Park JG, Lee AH | title = Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP | journal = Seminars in Liver Disease | volume = 33 | issue = 4 | pages = 301–311 | date = November 2013 | pmid = 24222088 | pmc = 4035704 | doi = 10.1055/s-0033-1358523 }} In adipose tissue, ChREBP induces de novo lipogenesis from glucose in response to a glucose flux into adipocytes.{{cite journal | vauthors = Czech MP, Tencerova M, Pedersen DJ, Aouadi M | title = Insulin signalling mechanisms for triacylglycerol storage | journal = Diabetologia | volume = 56 | issue = 5 | pages = 949–964 | date = May 2013 | pmid = 23443243 | pmc = 3652374 | doi = 10.1007/s00125-013-2869-1 }} In the liver, glucose induction of ChREBP promotes glycolysis and lipogenesis.

This gene is deleted in Williams-Beuren syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at chromosome 7q11.23.

Excess expression of ChREBP in the liver due to metabolic syndrome or type 2 diabetes can lead to steatosis in the liver. In non-alcoholic fatty liver disease, about 25% of total liver lipids result from de novo synthesis (synthesis of lipids from glucose).{{cite journal | vauthors = Ortega-Prieto P, Postic C | title = Carbohydrate Sensing Through the Transcription Factor ChREBP | journal = Frontiers in Genetics | volume = 10 | pages = 472 | year = 2019 | pmid = 31275349 | pmc = 6593282 | doi = 10.3389/fgene.2019.00472 | doi-access = free }} High blood glucose and insulin enhance lipogenesis in the liver by activation of ChREBP and SREBP-1c, respectively.

Chronically elevated blood glucose can activate ChREBP in the pancreas can lead to excessive lipid synthesis in beta cells, increasing lipid accumulation in those cells, leading to lipotoxicity, beta-cell apoptosis, and type 2 diabetes.{{cite journal | vauthors = Song Z, Yang H, Zhou L, Yang F | title = Glucose-Sensing Transcription Factor MondoA/ChREBP as Targets for Type 2 Diabetes: Opportunities and Challenges | journal = International Journal of Molecular Sciences | volume = 20 | issue = 20 | pages = E5132 | date = October 2019 | pmid = 31623194 | pmc = 6829382 | doi = 10.3390/ijms20205132 | doi-access = free }}

MLXIPL has been shown to interact with MLX.{{cite journal | vauthors = Cairo S, Merla G, Urbinati F, Ballabio A, Reymond A | title = WBSCR14, a gene mapping to the Williams--Beuren syndrome deleted region, is a new member of the Mlx transcription factor network | journal = Human Molecular Genetics | volume = 10 | issue = 6 | pages = 617–627 | date = March 2001 | pmid = 11230181 | doi = 10.1093/hmg/10.6.617 | doi-access = free }}

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ChREBP is translocated to the nucleus and binds to DNA after dephosphorylation of a p-Ser and a p-Thr residue by PP2A, which itself is activated by xylulose-5-phosphate. Xu5p is produced in the pentose phosphate pathway when levels of Glucose-6-phosphate are high (the cell has ample glucose). In the liver, ChREBP mediates activation of several regulatory enzymes of glycolysis and lipogenesis including L-type pyruvate kinase (L-PK), acetyl CoA carboxylase, and fatty acid synthase.

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• {{cite journal | vauthors = de Luis O, Valero MC, Jurado LA | title = WBSCR14, a putative transcription factor gene deleted in Williams-Beuren syndrome: complete characterisation of the human gene and the mouse ortholog | journal = European Journal of Human Genetics | volume = 8 | issue = 3 | pages = 215–222 | date = March 2000 | pmid = 10780788 | doi = 10.1038/sj.ejhg.5200435 | doi-access = free }}
• {{cite journal | vauthors = Kawaguchi T, Takenoshita M, Kabashima T, Uyeda K | title = Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 24 | pages = 13710–13715 | date = November 2001 | pmid = 11698644 | pmc = 61106 | doi = 10.1073/pnas.231370798 | bibcode = 2001PNAS...9813710K | doi-access = free }}
• {{cite journal | vauthors = Kawaguchi T, Osatomi K, Yamashita H, Kabashima T, Uyeda K | title = Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase | journal = The Journal of Biological Chemistry | volume = 277 | issue = 6 | pages = 3829–3835 | date = February 2002 | pmid = 11724780 | doi = 10.1074/jbc.M107895200 | doi-access = free }}
• {{cite journal | vauthors = Hillman RT, Green RE, Brenner SE | title = An unappreciated role for RNA surveillance | journal = Genome Biology | volume = 5 | issue = 2 | pages = R8 | year = 2005 | pmid = 14759258 | pmc = 395752 | doi = 10.1186/gb-2004-5-2-r8 | doi-access = free }}
• {{cite journal | vauthors = Merla G, Howald C, Antonarakis SE, Reymond A | title = The subcellular localization of the ChoRE-binding protein, encoded by the Williams-Beuren syndrome critical region gene 14, is regulated by 14-3-3 | journal = Human Molecular Genetics | volume = 13 | issue = 14 | pages = 1505–1514 | date = July 2004 | pmid = 15163635 | doi = 10.1093/hmg/ddh163 | doi-access = free }}
• {{cite journal | vauthors = Li MV, Chang B, Imamura M, Poungvarin N, Chan L | title = Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module | journal = Diabetes | volume = 55 | issue = 5 | pages = 1179–1189 | date = May 2006 | pmid = 16644671 | doi = 10.2337/db05-0822 | doi-access = free }}

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{{Transcription factors and intracellular receptors}}

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