Carbohydrate-responsive element-binding protein

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MLXIPL
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMLXIPL, CHREBP, MIO, MONDOB, WBSCR14, WS-bHLH, bHLHd14, MLX interacting protein like, MLX
External IDsOMIM: 605678 MGI: 1927999 HomoloGene: 32507 GeneCards: MLXIPL
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_032951
NM_032952
NM_032953
NM_032954
NM_032994

NM_021455
NM_001359237

RefSeq (protein)

NP_116569
NP_116570
NP_116571
NP_116572

NP_067430
NP_001346166

Location (UCSC)Chr 7: 73.59 – 73.62 MbChr 5: 135.12 – 135.17 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][6] The protein name derives from the protein's interaction with carbohydrate response element sequences of DNA.

Function

Domains of ChREBP. The N-terminal glucose-sensing module consists of the low glucose inhibitory domain (LID) and the glucose activated conserved element (GRACE). The C-terminal regions consists of a polyproline-rich, a bHLH/LZ and a leucine-zipper-like (Zip-like) domain. Phosphorylation sites in red, acetylation sites in blue and O-GlcNAcylation sites in green.[7]

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.[6]

ChREBP is activated by glucose, independent of insulin.[8] In adipose tissue, ChREBP induces de novo lipogenesis from glucose in response to a glucose flux into adipocytes.[9][8] In the liver, glucose induction of ChREBP promotes glycolysis and lipogenesis.[8]

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.[6]

Excess expression of ChREBP in the liver due to metabolic syndrome or type 2 diabetes can lead to steatosis in the liver.[8] In non-alcoholic fatty liver disease, about 25% of total liver lipids result from de novo synthesis (synthesis of lipids from glucose).[7] High blood glucose and insulin enhance lipogenesis in the liver by activation of ChREBP and SREBP-1c, respectively.[7]

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.[10]

Interactions

MLXIPL has been shown to interact with MLX.[11]

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.

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000009950 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005373 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Meng X, Lu X, Li Z, Green ED, Massa H, Trask BJ, et al. (November 1998). "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. doi:10.1007/s004390050874. PMID 9860302. S2CID 23530406.
  6. ^ a b c "Entrez Gene: MLXIPL MLX interacting protein-like".
  7. ^ a b c Ortega-Prieto P, Postic C (2019). "Carbohydrate Sensing Through the Transcription Factor ChREBP". Frontiers in Genetics. 10: 472. doi:10.3389/fgene.2019.00472. PMC 6593282. PMID 31275349.
  8. ^ a b c d Xu X, So JS, Park JG, Lee AH (November 2013). "Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP". Seminars in Liver Disease. 33 (4): 301–311. doi:10.1055/s-0033-1358523. PMC 4035704. PMID 24222088.
  9. ^ Czech MP, Tencerova M, Pedersen DJ, Aouadi M (May 2013). "Insulin signalling mechanisms for triacylglycerol storage". Diabetologia. 56 (5): 949–964. doi:10.1007/s00125-013-2869-1. PMC 3652374. PMID 23443243.
  10. ^ Song Z, Yang H, Zhou L, Yang F (October 2019). "Glucose-Sensing Transcription Factor MondoA/ChREBP as Targets for Type 2 Diabetes: Opportunities and Challenges". International Journal of Molecular Sciences. 20 (20): E5132. doi:10.3390/ijms20205132. PMC 6829382. PMID 31623194.
  11. ^ Cairo S, Merla G, Urbinati F, Ballabio A, Reymond A (March 2001). "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. doi:10.1093/hmg/10.6.617. PMID 11230181.

Further reading