Top Qs
Timeline
Chat
Perspective
Carbohydrate-responsive element-binding protein
Protein found in humans From Wikipedia, the free encyclopedia
Remove ads
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]
Remove ads
Structure
Summarize
Perspective
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]
Remove ads
Function
Summarize
Perspective
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]
Remove ads
Clinical significance
Summarize
Perspective
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
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]
Remove ads
References
Wikiwand - on
Seamless Wikipedia browsing. On steroids.
Remove ads