Carbohydrate-responsive element-binding protein explained

Carbohydrate-responsive element-binding protein (ChREBP) also known as MLX-interacting protein-like (MLXIPL) is a protein that in humans is encoded by the MLXIPL gene.^{[1] [2]} The protein name derives from the protein's interaction with carbohydrate response element sequences of DNA.

Function

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.^[2]

ChREBP is activated by glucose, independent of insulin.^[3] In adipose tissue, ChREBP induces de novo lipogenesis from glucose in response to a glucose flux into adipocytes.^[4] In the liver, glucose induction of ChREBP promotes glycolysis and lipogenesis.

Clinical significance

This gene is deleted in Williams-Beuren syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at chromosome 7q11.23.^[2]

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).^[5] 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.^[6]

Interactions

MLXIPL has been shown to interact with MLX.^[7]

Role in glycolysis

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.

Further reading

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

Notes and References

1. Meng X, Lu X, Li Z, Green ED, Massa H, Trask BJ, Morris CA, Keating MT . 6 . Complete physical map of the common deletion region in Williams syndrome and identification and characterization of three novel genes . Human Genetics . 103 . 5 . 590–599 . November 1998 . 9860302 . 10.1007/s004390050874 . 23530406 .
2. Web site: Entrez Gene: MLXIPL MLX interacting protein-like.
3. Xu X, So JS, Park JG, Lee AH . Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP . Seminars in Liver Disease . 33 . 4 . 301–311 . November 2013 . 24222088 . 4035704 . 10.1055/s-0033-1358523 .
4. Czech MP, Tencerova M, Pedersen DJ, Aouadi M . Insulin signalling mechanisms for triacylglycerol storage . Diabetologia . 56 . 5 . 949–964 . May 2013 . 23443243 . 3652374 . 10.1007/s00125-013-2869-1 .
5. Ortega-Prieto P, Postic C . Carbohydrate Sensing Through the Transcription Factor ChREBP . Frontiers in Genetics . 10 . 472 . 2019 . 31275349 . 6593282 . 10.3389/fgene.2019.00472 . free .
6. Song Z, Yang H, Zhou L, Yang F . Glucose-Sensing Transcription Factor MondoA/ChREBP as Targets for Type 2 Diabetes: Opportunities and Challenges . International Journal of Molecular Sciences . 20 . 20 . E5132 . October 2019 . 31623194 . 6829382 . 10.3390/ijms20205132 . free .
7. Cairo S, Merla G, Urbinati F, Ballabio A, Reymond A . WBSCR14, a gene mapping to the Williams--Beuren syndrome deleted region, is a new member of the Mlx transcription factor network . Human Molecular Genetics . 10 . 6 . 617–627 . March 2001 . 11230181 . 10.1093/hmg/10.6.617 . free .