ChREBP

ChREBP, short for carbohydrate-responsive element-binding protein, is a basic helix-loop-helix/leucine zipper transcription factor encoded by the MLXIPL gene in humans. It forms a heterodimer with MLX and binds carbohydrate response elements (ChoREs) in the promoters of genes involved in glycolysis and lipogenesis, coordinating glucose metabolism with fatty acid synthesis. ChREBP activity is especially prominent in liver and adipose tissue, where de novo lipogenesis occurs.

Regulation of ChREBP involves nutrient- and energy-sensing pathways. In low glucose, ChREBP is phosphorylated by protein kinases, promoting binding to 14-3-3 proteins and retention in the cytosol. High glucose increases flux through the pentose phosphate pathway, generating xylulose-5-phosphate, which activates PP2A to dephosphorylate ChREBP. Dephosphorylated ChREBP translocates to the nucleus, binds MLX, and activates transcription of target genes via ChoREs.

Two major isoforms exist: ChREBP-α, the full-length form, and ChREBP-β, a shorter, more active isoform produced by alternative transcription that lacks portions of the regulatory domain. ChREBP-β is more responsive to glucose and can drive sustained transcriptional activation under high carbohydrate conditions.

Target genes include enzymes of glycolysis and fatty acid synthesis, such as acetyl-CoA carboxylase 1 (ACACA), fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD1), and liver-type pyruvate kinase (Pklr). Through these genes, ChREBP promotes lipogenesis and helps maintain glucose homeostasis, while dysregulation of ChREBP signaling has been associated with hepatic steatosis, obesity, and metabolic disease, making it a potential target for therapeutic intervention.