Adaptive and maladaptive roles for ChREBP in the liver and pancreatic islets

Figure 1. Feed-forward regulation of ChREBP-beta expression. Carbohydrate-derived metabolites activate ChREBP-alpha, which binds to carbohydrate response elements (ChoREs) in proximity to Exon 1b and induces transcription of ChREBP-beta, which is constitutively active as it is missing the LID domain. ChREBP-beta protein may activate its own expression by binding to the ChoREs near its promoter. A combination of metabolite-activated ChREBP-alpha and constitutively active ChREBP-beta mediates activation of other ChREBP target genes.

Figure 2. ChREBP mediates G6P homeostasis. Sugar consumption particularly with sugars containing fructose increases hepatocellular hexose-phosphate levels including G6P. G6P or a closely related metabolite activates ChREBP, which transactivates expression of enzymes involved in G6P disposal. This includes enzymes of glycolysis such as Pklr and enzymes of de novo lipogenesis including ACC and FASN. This also includes enzymes involved in glucose production such as G6PC. Catabolism of G6P either via glycolysis or glucose production reduces G6P inhibiting ChREBP and returning the system to a homeostatic equilibrium. Enzymes noted in red are ChREBP transcriptional targets.

Figure 3. Liver ChREBP loss- and gain-of-function models increase and decrease hepatocellular G6P and glycogen levels, respectively but produce overlapping phenotypes with respect to systemicfuel metabolism.A, liver ChREBP KO reduces the expression of enzymes involved in glycolysis, glucose production, lipogenesis, and VLDL packaging and secretion, which increases hepatocellular G6P and glycogen with variable effects on liver fat content. Through unknown mechanisms, this also reduces body weight and insulin resistance. B, liver ChREBP overexpression increases the expression of enzymes involved in glycolysis, glucose production, lipogenesis, and VLDL packaging and secretion, which reduces hepatocellular G6P and glycogen levels with variable effects on liver fat content. ChREBP overexpression also markedly increases circulating FGF21, which has pleiotropic metabolic effects including enhancing browning of white adipose tissue, which may enhance systemic fuel metabolism. Enzymes noted in red are ChREBP transcriptional targets.