Carbohydrate-responsive element-binding protein

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.

MLXIPL
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4GNT
Identifiers
Aliases	MLXIPL, CHREBP, MIO, MONDOB, WBSCR14, WS-bHLH, bHLHd14, MLX interacting protein like, MLX
External IDs	OMIM: 605678 MGI: 1927999 HomoloGene: 32507 GeneCards: MLXIPL
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q11.23 Start 73,593,194 bp[1] End 73,624,543 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 G2 Start 135,089,890 bp[2] End 135,138,382 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • carbohydrate response element binding • DNA binding • protein dimerization activity • protein homodimerization activity • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • transcription factor binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific • protein heterodimerization activity • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • transcription factor complex • nucleoplasm • cell nucleus • cytoplasm • cytosol Biological process • GO:0007243 intracellular signal transduction • positive regulation of lipid biosynthetic process • regulation of transcription, DNA-templated • glucose homeostasis • regulation of transcription from RNA polymerase II promoter • anatomical structure morphogenesis • negative regulation of transcription from RNA polymerase II promoter • positive regulation of fatty acid biosynthetic process • transcription, DNA-templated • negative regulation of cell cycle arrest • positive regulation of transcription, DNA-templated • fatty acid homeostasis • positive regulation of cell proliferation • negative regulation of peptidyl-serine phosphorylation • glucose mediated signaling pathway • negative regulation of oxidative phosphorylation • negative regulation of transcription, DNA-templated • positive regulation of glycolytic process • triglyceride homeostasis • positive regulation of transcription from RNA polymerase II promoter • cellular response to carbohydrate stimulus • energy homeostasis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	51085	58805
Ensembl	ENSG00000009950	ENSMUSG00000005373
UniProt	Q9NP71	Q99MZ3
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 Mb	Chr 5: 135.09 – 135.14 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[6]

ChREBP is activated by glucose, independent of insulin.[7] In adipose tissue, ChREBP induces de novo lipogenesis from glucose in response to a glucose flux into adipocytes.[8][7] In the liver, glucose induction of ChREBP promotes glycolysis and lipogenesis.[7]

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.[7] In non-alcoholic fatty liver disease, about 25% of total liver lipids result from de novo synthesis (synthesis of lipids from glucose).[9] High blood glucose and insulin enhance lipogenesis in the liver by activation of ChREBP and SREBP-1c, respectively.[9]

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. GRCh38: Ensembl release 89: ENSG00000009950 - Ensembl, May 2017
2. 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, Morris CA, Keating MT (Jan 1999). "Complete physical map of the common deletion region in Williams syndrome and identification and characterization of three novel genes". Hum Genet. 103 (5): 590–9. doi:10.1007/s004390050874. PMID 9860302.
6. "Entrez Gene: MLXIPL MLX interacting protein-like".
7. Xu X, So JS, Park JG, Lee AH (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.
8. Czech MP, Tencerova M, Pedersen DJ, Aouadi M (2013). "Insulin signalling mechanisms for triacylglycerol storage". Diabetologia. 56 (5): 949–964. doi:10.1007/s00125-013-2869-1. PMC 3652374. PMID 23443243.
9. 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.
10. Song Z, Yang H, Zhou L, Yang F (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". Hum. Mol. Genet. 10 (6): 617–27. doi:10.1093/hmg/10.6.617. PMID 11230181.

Further reading

• de Luis O, Valero MC, Jurado LA (2000). "WBSCR14, a putative transcription factor gene deleted in Williams-Beuren syndrome: complete characterisation of the human gene and the mouse ortholog". Eur. J. Hum. Genet. 8 (3): 215–22. doi:10.1038/sj.ejhg.5200435. PMID 10780788.
• Cairo S, Merla G, Urbinati F, et al. (2001). "WBSCR14, a gene mapping to the Williams--Beuren syndrome deleted region, is a new member of the Mlx transcription factor network". Hum. Mol. Genet. 10 (6): 617–27. doi:10.1093/hmg/10.6.617. PMID 11230181.
• Kawaguchi T, Takenoshita M, Kabashima T, Uyeda K (2002). "Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein". Proc. Natl. Acad. Sci. U.S.A. 98 (24): 13710–5. doi:10.1073/pnas.231370798. PMC 61106. PMID 11698644.
• Kawaguchi T, Osatomi K, Yamashita H, et al. (2002). "Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase". J. Biol. Chem. 277 (6): 3829–35. doi:10.1074/jbc.M107895200. PMID 11724780.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Hillman RT, Green RE, Brenner SE (2005). "An unappreciated role for RNA surveillance". Genome Biol. 5 (2): R8. doi:10.1186/gb-2004-5-2-r8. PMC 395752. PMID 14759258.
• Merla G, Howald C, Antonarakis SE, Reymond A (2005). "The subcellular localization of the ChoRE-binding protein, encoded by the Williams-Beuren syndrome critical region gene 14, is regulated by 14-3-3". Hum. Mol. Genet. 13 (14): 1505–14. doi:10.1093/hmg/ddh163. PMID 15163635.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Li MV, Chang B, Imamura M, et al. (2006). "Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module". Diabetes. 55 (5): 1179–89. doi:10.2337/db05-0822. PMID 16644671.