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

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 .