Carbohydrate-responsive element-binding protein (ChREBP), also known asMLX-interacting protein-like (MLXIPL),MondoB, andWBSCR14, is aprotein that in humans is encoded by theMlxiplgene.[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 andMyc /Max /Mad superfamily oftranscription 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 abasic helix-loop-helix leucine zipper (bHLH-ZIP) structure, and form heterodimers withMLX 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]
ChREBP is a member of the Mondo family oftranscription factors, and part of theMyc /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 abasic helix-loop-helix leucine zipper (bHLH-ZIP) structure, and formheterodimers withMLX 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. TheN-terminal region, contains its glucose sensing element and participates in thecellular localization of the factor. TheC-terminal region is responsible for the formation of theheterodimer ChREBP-MLX and itsbinding to DNA.[10] The second region, known as[10]
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: whileinsulin 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 tocarbohydrate 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 oftriglycerides, 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, andde novolipogenesis (DNL) inadipose tissue.[5]ChREBP is a major mediator of glucose action on glycolytic enzymes such asPklr, lipogenic enzymes such asACC andFASN, andG6P disposal, among others.[9][8] Many factors mediate the activation or inactivation of ChREBP.[10] ChREBP is also subject to post-translational modifications such asphosphorylation,acetylation, andO-linked glycosylation, which can affect its activity.[9]
TheMlxipl gene, which encodes ChREBP, is deleted inWilliams-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, includingobesity,Type 2 diabetes,fatty liver disease andmetabolic 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 withSREBP-1c, which is activated by insulin, to control glucose and lipid metabolism.[12] ChREBP also mediates the expression of the hepatokinFGF21, 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 ortype 2 diabetes can lead to excess expression of ChREBP and increased production of fatty acids, causing hepaticsteatosis or "fatty liver".[12] Innon-alcoholic fatty liver disease, about 25% of total liverlipids result fromde novo synthesis (synthesis of lipids from glucose).[11] High blood glucose and insulin enhancelipogenesis in the liver by activation of ChREBP andSREBP-1c, respectively.[11] Chronically elevated blood glucose can activate ChREBP in thepancreas and lead to excessive lipid synthesis inbeta cells, increasing lipid accumulation in those cells, leading tolipotoxicity, beta-cellapoptosis, and type 2 diabetes.[15]
In 2000, the transcription factor for ChREBP was first fully characterized. It was initially designated as WBSCR14, due to its involvement in the genetic disorderWilliams–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]
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