Carbohydrate-responsive element-binding protein

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; OMA:MLXIPL - orthologs
Gene location (Human) Chr. Chromosome 7 (human) Band 7q11.23 Start 73,593,194 bp End 73,624,543 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5|5 G2 Start 135,118,744 bp End 135,167,236 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver left adrenal cortex right adrenal gland right adrenal cortex right hemisphere of cerebellum subcutaneous adipose tissue gastric mucosa gastrocnemius muscle right testis muscle of thigh Top expressed in crypt of lieberkuhn of small intestine left lobe of liver brown adipose tissue islet of Langerhans muscle of thigh proximal tubule zygote soleus muscle right kidney skeletal muscle tissue More reference expression data BioGPS More reference expression data
Gene ontology Molecular function carbohydrate response element binding DNA binding protein dimerization activity protein homodimerization activity DNA-binding transcription factor activity transcription factor binding RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA-binding transcription repressor activity, RNA polymerase II-specific protein heterodimerization activity DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component transcription regulator complex nucleoplasm nucleus cytoplasm cytosol Biological process intracellular signal transduction positive regulation of lipid biosynthetic process regulation of transcription, DNA-templated glucose homeostasis regulation of transcription by RNA polymerase II anatomical structure morphogenesis negative regulation of transcription by RNA polymerase II positive regulation of fatty acid biosynthetic process transcription, DNA-templated positive regulation of transcription, DNA-templated fatty acid homeostasis positive regulation of cell population 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 by RNA polymerase II 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: 135.12 – 135.17 Mb PubMed search
Wikidata
View/Edit Human View/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. 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.

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. In adipose tissue, ChREBP induces de novo lipogenesis from glucose in response to a glucose flux into adipocytes. 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.

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). 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.

Interactions

MLXIPL has been shown to interact with MLX.

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 (March 2000). "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. doi:10.1038/sj.ejhg.5200435. PMID 10780788.
• Kawaguchi T, Takenoshita M, Kabashima T, Uyeda K (November 2001). "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. Bibcode:2001PNAS...9813710K. doi:10.1073/pnas.231370798. PMC 61106. PMID 11698644.
• Kawaguchi T, Osatomi K, Yamashita H, Kabashima T, Uyeda K (February 2002). "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. doi:10.1074/jbc.M107895200. PMID 11724780.
• Hillman RT, Green RE, Brenner SE (2005). "An unappreciated role for RNA surveillance". Genome Biology. 5 (2): R8. doi:10.1186/gb-2004-5-2-r8. PMC 395752. PMID 14759258.
• Merla G, Howald C, Antonarakis SE, Reymond A (July 2004). "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. doi:10.1093/hmg/ddh163. PMID 15163635.
• Li MV, Chang B, Imamura M, Poungvarin N, Chan L (May 2006). "Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module". Diabetes. 55 (5): 1179–1189. doi:10.2337/db05-0822. PMID 16644671.