{{Short description|Protein found in humans}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox gene}} '''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.<ref name="Ahn_2023" /> ChREBP has two isoforms, ChREBP-α and ChREBP-β, which are encoded by the same gene using alternative promoters.<ref name="Song_2018" />
ChREBP is a member of the Mondo family and Myc / Max / Mad superfamily of transcription factors.<ref name="Cadena_Del_Castillo_2025" /> 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.<ref name="Ke_2021" />
ChREBP is a sugar-sensing transcription factor, mediating genomic responses to carbohydrate availability in metabolic tissues such as liver and adipose tissue.<ref name="Katz_2021">{{cite journal |vauthors=Katz L, Baumel-Alterzon S, Scott D, Herman M |date=January 2021 |title=Adaptive and maladaptive roles for ChREBP in the liver and pancreatic islets. |journal=The Journal of Biological Chemistry |volume=296 |article-number=100623 |doi=10.1016/j.jbc.2021.100623 |pmc=8102921 |pmid=33812993 |doi-access=free }}</ref> 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.<ref name="Katz_2021" /><ref name="Ahn_2023" /><ref name="BravoRuiz_2021" />
== Structure == thumb|320x320px|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.<ref name="Ortega-Prieto_2019">{{cite journal |vauthors=Ortega-Prieto P, Postic C |year=2019 |title=Carbohydrate Sensing Through the Transcription Factor ChREBP |journal=Frontiers in Genetics |volume=10 |page=472 |doi=10.3389/fgene.2019.00472 |pmc=6593282 |pmid=31275349 |doi-access=free |article-number=472}}</ref> ChREBP is a member of the Mondo family of transcription factors, and part of the Myc / Max / Mad superfamily.<ref name="Cadena_Del_Castillo_2025" /> 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).<ref name="Ke_2021">{{cite journal | vauthors = Ke H, Luan Y, Wu S, Zhu Y, Tong X | title = The Role of Mondo Family Transcription Factors in Nutrient-Sensing and Obesity. | journal = Frontiers in Endocrinology | volume = 12 | article-number = 653972 | date = 2021 | pmid = 33868181 | pmc = 8044463 | doi = 10.3389/fendo.2021.653972 | doi-access = free }}</ref>
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.<ref name="BravoRuiz_2021" /> The second region, known as <ref name="BravoRuiz_2021" />
== Function == 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.<ref name="Katz_2021" /> Mondo family proteins, including ChREBP, are responsible for carbohydrate-induced transcription of glycolytic and lipogenic enzymes.<ref name="Song_2018">{{cite journal | vauthors = Song Z, Xiaoli A, Yang F | title = Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues. | journal = Nutrients | volume = 10 | issue = 10 | page = 1383 | date = 29 September 2018 | pmid = 30274245 | pmc = 6213738 | doi = 10.3390/nu10101383 | doi-access = free }}</ref> They are crucial in regulating nutrient metabolism and energy homeostasis.<ref name="Ahn_2023">{{cite journal | vauthors = Ahn B | title = The Function of MondoA and ChREBP Nutrient-Sensing Factors in Metabolic Disease. | journal = International Journal of Molecular Sciences | volume = 24 | issue = 10 | page = 8811 | date = 16 May 2023 | pmid = 37240157 | pmc = 10218701 | doi = 10.3390/ijms24108811 | doi-access = free }}</ref>
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.<ref name="Xu_2013">{{cite journal |vauthors=Xu X, So JS, Park JG, Lee AH |date=November 2013 |title=Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP |journal=Seminars in Liver Disease |volume=33 |issue=4 |pages=301–311 |doi=10.1055/s-0033-1358523 |pmc=4035704 |pmid=24222088}}</ref> Carbohydrate metabolites activate the canonical form of ChREBP, ChREBP-α, which stimulates production of a potent, constitutively active ChREBP isoform called ChREBP-β.<ref name="Katz_2021" /> These isoforms may have distinct functions: Combinations of ChREBP-α and ChREBP-β mediate the effects of ChREBP activation on ChREBP's genomic targets.<ref name="Katz_2021" />
The precise identity of the activating metabolite has been variously claimed to be xylulose-5-phosphate, glucose-6-phosphate and fructose-2-6-bisphosphate<ref name="Katz_2021" /> and these effects have been attributed both to direct effects and to effects mediated by post-translational modification. However, the N-terminal domain of ChREBP-α was shown to bind and be activated by glycerol-3-phosphate, suggesting a mechanism by which the backbone of triglyceride synthesis serves as the signal for synthesis of new long chain fatty acids that will be linked to it.<ref>{{cite journal | vauthors = Tiwari V, Jin B, Sun O, Lopez Gonzalez ED, Chen MH, Wu X, Shah H, Zhang A, Herman MA, Spracklen CN, Goodman RP, Brenner C | title = Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency | journal = Nature Metabolism | volume = 7 | issue = 11 | pages = 2284–2299 | date = November 2025 | pmid = 41238906 | doi = 10.1038/s42255-025-01399-3 | pmc = 12638245 }}</ref>
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.<ref name="Cadena_Del_Castillo_2025">{{cite journal | vauthors = Cadena Del Castillo C, Deniz O, van Geest F, Rosseels L, Stockmans I, Robciuc M, Carpentier S, Wölnerhanssen B, Meyer-Gerspach A, Peterli R, Hietakangas V, Shimobayashi M | title = MLX phosphorylation stabilizes the ChREBP-MLX heterotetramer on tandem E-boxes to control carbohydrate and lipid metabolism. | journal = Science Advances | volume = 11 | issue = 11 | article-number = eadt4548 | date = 14 March 2025 | pmid = 40073115 | pmc = 11900861 | doi = 10.1126/sciadv.adt4548 | bibcode = 2025SciA...11.4548C }}</ref>
ChREBP's ability to bind DNA and transactivate gene expression depends upon its dimerization with MLX protein.<ref name="Katz_2021" /> 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.<ref name="BravoRuiz_2021" />
ChREBP regulates the expression of genes involved in glucose and lipid metabolism, glycolysis in the liver, and de novo lipogenesis (DNL) in adipose tissue.<ref name="Ahn_2023" /> 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.<ref name="Katz_2021" /><ref name="Ke_2021" /> Many factors mediate the activation or inactivation of ChREBP.<ref name="BravoRuiz_2021" /> ChREBP is also subject to post-translational modifications such as phosphorylation, acetylation, and O-linked glycosylation, which can affect its activity.<ref name="Katz_2021" />
== Clinical significance == 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.<ref name="entrez">{{cite web | title = Entrez Gene: MLXIPL MLX interacting protein-like | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=51085 }}</ref>
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.<ref name="BravoRuiz_2021" />
Generally ChREBP promotes lipid synthesis.<ref name="BravoRuiz_2021" /> ChREBP also plays an important role in insulin sensitivity, redirecting excess glucose to fatty acid production and modulating the composition of lipids.<ref name="BravoRuiz_2021" /> In the liver, ChREBP acts in coordination with SREBP-1c, which is activated by insulin, to control glucose and lipid metabolism.<ref name="Xu_2013" /> ChREBP also mediates the expression of the hepatokin FGF21, which is increased in obesity and can increase glucose tolerance and reduce hypertriglyceridemia.<ref name="BravoRuiz_2021" /> ChREBP activates enzymes that both utilize and produce glucose, suggesting that ChREBP works as a mediator of intracellular G6P homeostasis.<ref name="Katz_2021" />
Conditions such as metabolic syndrome or type 2 diabetes can lead to excess expression of ChREBP and increased production of fatty acids, causing hepatic steatosis or "fatty liver".<ref name="Xu_2013" /> In non-alcoholic fatty liver disease, about 25% of total liver lipids result from de novo synthesis (synthesis of lipids from glucose).<ref name="Ortega-Prieto_2019" /> High blood glucose and insulin enhance lipogenesis in the liver by activation of ChREBP and SREBP-1c, respectively.<ref name="Ortega-Prieto_2019" /> 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.<ref name="pmid31623194">{{cite journal |vauthors=Song Z, Yang H, Zhou L, Yang F |date=October 2019 |title=Glucose-Sensing Transcription Factor MondoA/ChREBP as Targets for Type 2 Diabetes: Opportunities and Challenges |journal=International Journal of Molecular Sciences |volume=20 |issue=20 |article-number=E5132 |doi=10.3390/ijms20205132 |pmc=6829382 |pmid=31623194 |doi-access=free}}</ref>
===History===
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.<ref name="BravoRuiz_2021" /><ref>{{cite journal | vauthors = de Luis O, Valero M, Jurado L | title = WBSCR14, a putative transcription factor gene deleted in Williams-Beuren syndrome: complete characterisation of the human gene and the mouse ortholog. | journal = European Journal of Human Genetics | volume = 8 | issue = 3 | pages = 215–222 | date = March 2000 | pmid = 10780788 | doi = 10.1038/sj.ejhg.5200435 }}</ref> 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.<ref name="Richards_2017">{{cite journal | vauthors = Richards P, Ourabah S, Montagne J, Burnol A, Postic C, Guilmeau S | title = MondoA/ChREBP: The usual suspects of transcriptional glucose sensing; Implication in pathophysiology. | journal = Metabolism: Clinical and Experimental | volume = 70 | pages = 133–151 | date = May 2017 | pmid = 28403938 | doi = 10.1016/j.metabol.2017.01.033 }}</ref> 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.<ref name="Katz_2021" /><ref name="Yamashita_2001">{{cite journal | vauthors = Yamashita H, Takenoshita M, Sakurai M, Bruick R, Henzel W, Shillinglaw W, Arnot D, Uyeda K | title = A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 16 | pages = 9116–9121 | date = 31 July 2001 | pmid = 11470916 | pmc = 55382 | doi = 10.1073/pnas.161284298 | bibcode = 2001PNAS...98.9116Y | doi-access = free }}</ref> The discoveries of MondoA and ChREBP defined basic helix–loop-helix leucine zipper (bHLH/LZ) transcriptional activators as a family.<ref name="Richards_2017" /> 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).<ref name="BravoRuiz_2021" /> In 2012, the ChREBP-β isoform was identified.<ref name="Richards_2017" /><ref name="BravoRuiz_2021">{{cite journal | vauthors = Bravo-Ruiz I, Medina M, Martínez-Poveda B | title = From Food to Genes: Transcriptional Regulation of Metabolism by Lipids and Carbohydrates. | journal = Nutrients | volume = 13 | issue = 5 | date = 30 April 2021 | page = 1513 | pmid = 33946267 | pmc = 8145205 | doi = 10.3390/nu13051513 | doi-access = free }}</ref>
== References == {{reflist}}