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. ChREBP has two isoforms, ChREBP-α and ChREBP-β, which are encoded by the same gene using alternative promoters.

ChREBP is a member of the Mondo family and Myc / Max / Mad superfamily of transcription factors. 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.

ChREBP is a sugar-sensing transcription factor, mediating genomic responses to carbohydrate availability in metabolic tissues such as liver and adipose tissue. 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.

ChREBP is a member of the Mondo family of transcription factors, and part of the Myc / Max / Mad superfamily. 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).

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

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. Mondo family proteins, including ChREBP, are responsible for carbohydrate-induced transcription of glycolytic and lipogenic enzymes. 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. These isoforms may have distinct functions: Combinations of ChREBP-α and ChREBP-β mediate the effects of ChREBP activation on ChREBP's genomic targets.

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.