Carbohydrate-responsive element-binding protein
Carbohydrate-responsive element-binding protein (ChREBP), also known as MLX-interacting protein-like (MLXIPL), MondoB, and WBSCR14, is a protein that in humans is encoded by the Mlxipl gene.[5] ChREBP has two isoforms, ChREBP-α and ChREBP-β, which are encoded by the same gene using alternative promoters.[6]
ChREBP is a member of the Mondo family and Myc / Max / Mad superfamily of transcription factors.[7] The two main members of the Mondo family are MondoA (MLX-interacting protein or MLXIP) and ChREBP (MondoB, MLXIPL). Both are characterized by a basic helix-loop-helix leucine zipper (bHLH-ZIP) structure, and form heterodimers with MLX protein.[8]
ChREBP is a sugar-sensing transcription factor, mediating genomic responses to carbohydrate availability in metabolic tissues such as liver and adipose tissue.[9] ChREBP is crucial in nutrient sensing, glucose uptake and regulation of nutrient metabolism and energy homeostasis through metabolic processes such as glycolysis and lipogenesis. However, many of the mechanisms involved are not yet well understood.[9][5][10]
Structure
[edit]
ChREBP is a member of the Mondo family of transcription factors, and part of the Myc / Max / Mad superfamily.[7] Proteins in the Mondo family are involved in nutrient-sensing and regulation of metabolism, responding particularly to glucose levels. They are characterized by a basic helix-loop-helix leucine zipper (bHLH-ZIP) structure, and form heterodimers with MLX protein. The two main members of this family are MondoA (MLX-interacting protein or MLXIP) and ChREBP (MondoB, MLXIPL).[8]
Two regions within ChREBP have been identified as key to its mechanisms of action. The N-terminal region, contains its glucose sensing element and participates in the cellular localization of the factor. The C-terminal region is responsible for the formation of the heterodimer ChREBP-MLX and its binding to DNA.[10] The second region, known as [10]
Function
[edit]ChREBP is highly expressed in the liver and other metabolic tissues such as white and brown adipose tissue, pancreatic islet cells, small intestine, and kidney. It is expressed at lower levels in tissues such as skeletal muscle.[9] Mondo family proteins, including ChREBP, are responsible for carbohydrate-induced transcription of glycolytic and lipogenic enzymes.[6] They are crucial in regulating nutrient metabolism and energy homeostasis.[5]
ChREBP's activation by glucose is a key mechanism for converting excess carbohydrate into stored fat. This occurs independent of insulin signaling: while insulin also helps to regulate glucose metabolism, the activation of ChREBP is separately triggered by glucose levels.[12] Carbohydrate metabolites activate the canonical form of ChREBP, ChREBP-α, which stimulates production of a potent, constitutively active ChREBP isoform called ChREBP-β.[9] These isoforms may have distinct functions: Combinations of ChREBP-α and ChREBP-β mediate the effects of ChREBP activation on ChREBP's genomic targets.[9]
ChREBP forms heterodimers with other bHLH-Zip proteins, particularly Mlx, and binds to carbohydrate response element (ChoRE) sequences. ChoRE sequences are typically found in regions of DNA where gene expression is transcriptionally induced by glucose. ChoRE sequences serve as binding sites for transcription factors that respond to changes in glucose levels. The ChoRE-ChREBP pathway is a key mechanism through which glucose regulates the synthesis of triglycerides, by controlling the expression of genes that encode enzymes.[7]
ChREBP's ability to bind DNA and transactivate gene expression depends upon its dimerization with MLX protein.[9] For full functional activity, two heterodimeric ChREBP-MLX complexes (each containing one ChREBP and one MLX molecule) join together to form a heterotetramer that binds to a ChoRE DNA sequence consisting of two adjacent E-boxes. This forms the active transcriptional complex.[10]
ChREBP regulates the expression of genes involved in glucose and lipid metabolism, glycolysis in the liver, and de novo lipogenesis (DNL) in adipose tissue.[5] ChREBP is a major mediator of glucose action on glycolytic enzymes such as Pklr, lipogenic enzymes such as ACC and FASN, and G6P disposal, among others.[9][8] Many factors mediate the activation or inactivation of ChREBP.[10] ChREBP is also subject to post-translational modifications such as phosphorylation, acetylation, and O-linked glycosylation, which can affect its activity.[9]
Clinical significance
[edit]The Mlxipl gene, which encodes ChREBP, is deleted in Williams-Beuren syndrome. Williams-Beuren syndrome is a multisystem developmental disorder caused by the deletion of contiguous genes at chromosome 7q11.23.[13]
ChREBP, activated by glucose-derived metabolites, plays a key role in metabolic homeostasis. It is a factor in diseases where metabolic homeostasis is disrupted, including obesity, Type 2 diabetes, fatty liver disease and metabolic syndrome.[10]
Generally ChREBP promotes lipid synthesis.[10] ChREBP also plays an important role in insulin sensitivity, redirecting excess glucose to fatty acid production and modulating the composition of lipids.[10] In the liver, ChREBP acts in coordination with SREBP-1c, which is activated by insulin, to control glucose and lipid metabolism.[12] ChREBP also mediates the expression of the hepatokin FGF21, which is increased in obesity and can increase glucose tolerance and reduce hypertriglyceridemia.[10] ChREBP activates enzymes that both utilize and produce glucose, suggesting that ChREBP works as a mediator of intracellular G6P homeostasis.[14]
Conditions such as metametabolic syndrome or type 2 diabetes can lead to excess expression of ChREBP and increased production of fatty acids, causing hepatic steatosis or "fatty liver".[12] In non-alcoholic fatty liver disease, about 25% of total liver lipids result from de novo synthesis (synthesis of lipids from glucose).[11] High blood glucose and insulin enhance lipogenesis in the liver by activation of ChREBP and SREBP-1c, respectively.[11] Chronically elevated blood glucose can activate ChREBP in the pancreas and lead to excessive lipid synthesis in beta cells, increasing lipid accumulation in those cells, leading to lipotoxicity, beta-cell apoptosis, and type 2 diabetes.[15]
History
[edit]In 2000, the transcription factor for ChREBP was first fully characterized. It was initially designated as WBSCR14, due to its involvement in the genetic disorder Williams–Beuren syndrome.[10][16] Concommitently, Donald Ayer identified MondoA as a transcription factor and MLX-interacting protein (MLXIP) active in muscle tissue. Given that there were some similarities between MondoA and WBSCR14, WBSCR14 became referred to as MondoB.[17] In 2001, Kosaku Uyeda and others identified the transcription factor's major role in glucose-responsive regulation and lipid metabolism. Once it was characterized as a carbohydrate sensor, it became known as ChREBP.[9][18] The discoveries of MondoA and ChREBP defined basic helix–loop-helix leucine zipper (bHLH/LZ) transcriptional activators as a family.[17] Because of their interactions with Max-like X protein (MLX), MondoA is also known as MLX interacting protein (MLXIP) and ChREBP is known as MLX interacting protein-like (MLXIPL).[10] In 2012, the ChREBP-β isoform was identified.[17][10]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000009950 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005373 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d Ahn B (16 May 2023). "The Function of MondoA and ChREBP Nutrient-Sensing Factors in Metabolic Disease". International Journal of Molecular Sciences. 24 (10): 8811. doi:10.3390/ijms24108811. PMC 10218701. PMID 37240157.
- ^ a b Song Z, Xiaoli A, Yang F (29 September 2018). "Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues". Nutrients. 10 (10): 1383. doi:10.3390/nu10101383. PMC 6213738. PMID 30274245.
- ^ a b c Cadena Del Castillo C, Deniz O, van Geest F, Rosseels L, Stockmans I, Robciuc M, et al. (14 March 2025). "MLX phosphorylation stabilizes the ChREBP-MLX heterotetramer on tandem E-boxes to control carbohydrate and lipid metabolism". Science Advances. 11 (11) eadt4548. Bibcode:2025SciA...11.4548C. doi:10.1126/sciadv.adt4548. PMC 11900861. PMID 40073115.
- ^ a b c Ke H, Luan Y, Wu S, Zhu Y, Tong X (2021). "The Role of Mondo Family Transcription Factors in Nutrient-Sensing and Obesity". Frontiers in Endocrinology. 12 653972: 653972. doi:10.3389/fendo.2021.653972. PMC 8044463. PMID 33868181.
- ^ a b c d e f g h i Katz L, Baumel-Alterzon S, Scott D, Herman M (January 2021). "Adaptive and maladaptive roles for ChREBP in the liver and pancreatic islets". The Journal of Biological Chemistry. 296 100623: 100623. doi:10.1016/j.jbc.2021.100623. PMC 8102921. PMID 33812993.
- ^ a b c d e f g h i j k l Bravo-Ruiz I, Medina M, Martínez-Poveda B (30 April 2021). "From Food to Genes: Transcriptional Regulation of Metabolism by Lipids and Carbohydrates". Nutrients. 13 (5): 1513. doi:10.3390/nu13051513. PMC 8145205. PMID 33946267.
- ^ a b c Ortega-Prieto P, Postic C (2019). "Carbohydrate Sensing Through the Transcription Factor ChREBP". Frontiers in Genetics. 10 472: 472. doi:10.3389/fgene.2019.00472. PMC 6593282. PMID 31275349.
- ^ a b c 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.
- ^ "Entrez Gene: MLXIPL MLX interacting protein-like".
- ^ Katz LS, Baumel-Alterzon S, Scott DK, Herman MA (January 2021). "Adaptive and maladaptive roles for ChREBP in the liver and pancreatic islets". The Journal of Biological Chemistry. 296 100623. doi:10.1016/j.jbc.2021.100623. PMC 8102921. PMID 33812993.
- ^ 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.
- ^ de Luis O, Valero M, Jurado L (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 : EJHG. 8 (3): 215–222. doi:10.1038/sj.ejhg.5200435. PMID 10780788.
- ^ a b c Richards P, Ourabah S, Montagne J, Burnol A, Postic C, Guilmeau S (May 2017). "MondoA/ChREBP: The usual suspects of transcriptional glucose sensing; Implication in pathophysiology". Metabolism: Clinical and Experimental. 70: 133–151. doi:10.1016/j.metabol.2017.01.033. PMID 28403938.
- ^ Yamashita H, Takenoshita M, Sakurai M, Bruick R, Henzel W, Shillinglaw W, et al. (31 July 2001). "A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver". Proceedings of the National Academy of Sciences of the United States of America. 98 (16): 9116–9121. Bibcode:2001PNAS...98.9116Y. doi:10.1073/pnas.161284298. PMC 55382. PMID 11470916.