Carbohydrate-responsive element-binding protein

ChREBP is a member of the Mondo family of transcription factors, and part of the Myc / Max / Mad superfamily. 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. The second region, known as == 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. They are crucial in regulating nutrient metabolism and energy homeostasis. 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. Carbohydrate metabolites activate the canonical form of ChREBP, ChREBP-α, which stimulates production of a potent, constitutively active ChREBP isoform called ChREBP-β. 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. ChREBP's ability to bind DNA and transactivate gene expression depends upon its dimerization with MLX protein. 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. ChREBP regulates the expression of genes involved in glucose and lipid metabolism, glycolysis in the liver, and de novo lipogenesis (DNL) in adipose tissue. 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. Many factors mediate the activation or inactivation of ChREBP. ChREBP is also subject to post-translational modifications such as phosphorylation, acetylation, and O-linked glycosylation, which can affect its activity. == 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. 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. 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. 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. 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. The discoveries of MondoA and ChREBP defined basic helix–loop-helix leucine zipper (bHLH/LZ) transcriptional activators as a family. == References ==