Trends in Endocrinology & Metabolism
ReviewFeature ReviewNovel insights into ChREBP regulation and function
Section snippets
Glucose signaling through ChREBP and Mlx
It has long been recognized that glucose not only serves as an energetic substrate but as a basic anabolic building block used to synthesize numerous macromolecules. However, several lines of evidence have also demonstrated that glucose also acts as a signaling molecule in adipose tissue [1] and in liver [2]. In these tissues, glucose stimulates the transcription of several genes encoding glycolytic and lipogenic enzymes: liver-pyruvate kinase (L-PK), acetyl-CoA carboxylase (ACC), fatty acid
Structure
ChREBP, is a large protein (864 amino acids, relative molecular weight 94 600 KDa) that contains several key domains including a nuclear localization signal (NLS) near the N terminus, polyproline domains, a bHLH/LZ domain, and a leucine zipper-like (Zip-like) domain (Figure 1a). The structure of the ChREBP gene is highly conserved among species. Structure/function analysis identified within ChREBP a glucose-sensing module (GSM), evolutionally conserved in Mondo proteins [also known as Mondo
Modulation of ChREBP phosphorylation status in response to glucose
ChREBP activity is regulated through multiple post-translational modifications ([26] for review). Several phosphorylation sites have been identified on the ChREBP protein 27, 28. Under fasting conditions (i.e., when circulating blood glucose levels are low, and fatty acids or plasma glucagon levels are high), phosphorylation of serine 196 on the ChREBP N-terminal region (Figure 1a), by cAMP-dependent protein kinase (PKA), sequesters the protein in the cytosol, and in association with the 14.3.3
Metabolites affecting ChREBP activity
As mentioned above, the mechanisms by which glucose activates ChREBP are complex. At least three metabolites have been implicated: (i) xylulose-5-P (Xu-5P), an intermediate in the pentose phosphate pathway [30]; (ii) glucose 6-phosphate (G6P), the first intermediate in glucose metabolism 33, 43; and, more recently (iii) Fructose-2,6-P2 (F2,6P2), the major regulator of glycolysis and gluconeogenesis [32] (Figure 2). Initial studies on ChREBP activation pointed to Xu-5P as the activating signal
The yin and yang of ChREBP in insulin sensitivity
Studies in mice have revealed that ChREBP is a crucial modulator of hepatic fatty acid content through its transcriptional control of lipogenic genes 4, 11, but have also underlined its complex relationship with systemic insulin-sensitivity. Indeed, global ChREBP deficiency leads to impaired glucose tolerance and insulin resistance in C57BL/6J mice [11]. By contrast, ChREBP deficiency 50, 51 or expression of a dominant Mlx isoform [52] in an obese background decreases hepatic steatosis and
ChREBP function during pancreatic β cell development:
Several publications have described the role of ChREBP in pancreatic β cell maintenance and/or dysfunction. ChREBP is expressed during fetal development in rodents, and that its expression progressively increases from an early stage (E14.5), in pancreatic and duodenal homeobox 1 (PDX1)-positive progenitors cells (PDX1+ cells), to after birth, in mature β cells 63, 64. During development, PDX1+ cells give rise to neurogenin-3 positive pro-endocrine progenitors (Ngn3+ cells), essential for
A novel role for ChREBP in cell proliferation
The balance between proliferation and differentiation is a fundamental tenet of development and postnatal tissue homeostasis, and plays a critical role in diseases such as cancer. In this context, ChREBP has recently emerged as a potential mediator of glucose-driven proliferation in normal and malignant cells, and a direct correlation between ChREBP protein levels and cell proliferation rate, in response to mitogenic signals, has been reported in several cell types, including hematopoietic and
Concluding remarks
In the past few years, important progress has been made regarding our understanding of the structure, function, and regulatory role of ChREBP in hepatocytes, adipocytes, and pancreatic β cells, where it contributes to the regulation of glucose sensing and/or de novo fatty acid synthesis. ChIP sequencing analysis in HepG2 has confirmed that ChREBP target genes are predominantly associated with lipid metabolism, but also identified clusters of genes implicated in transport, development, and/or
Acknowledgments
The authors would like to thank Hervé Guillou (Institut National de la Recherche Agronomique, ToxAlim, Toulouse, France) for critical reading of the manuscript. Research was funded by the INSERM, Fondation pour la Recherche Médicale, Agence Nationale de la Recherche (CRISALIS, ObeLIP), Ville de Paris, and the European Commission framework program FLORINASH.
Glossary
- Akt
- also known as protein kinase B (PKB), Akt is a serine/threonine-specific protein kinase and signaling molecule in the insulin signaling pathway that plays crucial role in glucose metabolism.
- ARNT/HIF1β
- hydrocarbon nuclear translocator (ARNT), also known as hypoxia-inducible factor-1β (HIF1β), is a transcription factor that regulates several cellular processes. Studies reported that ARNT/HIF1β expression levels decrease significantly in pancreatic islets from patients with T2D, suggesting that
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