Carbohydrate Sensing Through the Transcription Factor ChREBP

Abstract

Carbohydrate response element binding protein (ChREBP) is a carbohydrate-signaling transcription factor that in the past years has emerged as a central metabolic regulator. ChREBP expression is mostly abundant in active sites of de novo lipogenesis including liver and white and brown adipose tissues. ChREBP is also expressed in pancreatic islets, small intestine and to a lesser extent in the kidney and the brain. In response to glucose, ChREBP undergoes several post-translational modifications (PTMs) (phosphorylation, acetylation and/or O -GlcNAcylation) that will either modulate its cellular location, stability and/or its transcriptional activity. ChREBPβ is a shorter isoform of ChREBP that was first described in adipose tissue and later found to be expressed in other sites including liver and pancreatic β cells. ChREBPβ lacks an important regulatory inhibitory domain, known as LID (low glucose inhibitory domain), in its N-terminal domain and is therefore reported as a highly active isoform. In this review, we recapitulate a recent progress concerning the mechanisms governing the activity of the ChREBP isoforms, including PTMs, partners/cofactors as well as novel metabolic pathways regulated by ChREBP in key metabolic tissues, by discussing phenotypes associated with tissue-specific deletion of ChREBP in knockout mice.

Intestinal Fructose and Glucose Metabolism in Health and Disease

“…The expression of GLUT5 in the intestine can also be regulated by the carbohydrate response element-binding protein (ChREBP), a liver glucose-responsive basic helix-loop-helix-leucine zipper transcriptional factor [54]. High fructose diet feeding increases intestinal ChREBP protein levels, accompanied by increased fructose transport (GLUT5), fructolytic (fructokinase, ALDOB, TKFC, and lactate dehydrogenase) and gluconeogenic (glucose-6-phosphatae and fructose-1,6-bisphosphatase) gene expression in mice [55].…”

Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism

“…In conclusion, ChREBP is a carbohydrate-signaling transcription factor, which masters, in the liver, the storage of lipids in feeding response. Recent studies have also supported the importance of ChREBP in the regulation of fructose metabolism [48,49].…”

Ontogeny of hepatic metabolism in mule ducks highlights different gene expression profiles between carbohydrate and lipid metabolic pathways

“…Nevertheless, it is still possible that a stimulus applied up to E27 had an impact on the resulting activity of ChREBP. As a major transcription factor playing a key role in carbohydrate and lipid metabolism (28,29), it cannot be excluded that a programming protocol applied during its peak of expression may make an important contribution to the physiological response after overfeeding. Only programming experiments with different stimulus protocols and an in-depth analysis of the impact on ChREBP mRNA and protein expressions, or activity could provide a de nitive answer about its speci c role and that of other carbohydrate-related genes.…”