The absence of hepatic glucose-6 phosphatase/ChREBP couple is incompatible with survival in mice.

Abstract Objective Glucose production into the blood requires the expression of glucose-6 phosphatase (G6Pase), a key enzyme that allows glucose-6 phosphate (G6P) hydrolysis into free glucose and inorganic phosphate. We previously reported that the hepatic suppression of G6Pase leads to G6P accumulation and to metabolic reprogramming in hepatocytes from liver G6Pase deficient mice (L.G6pc-/-). Interestingly, the activity of the transcription factor carbohydrate response element-binding protein (ChREBP), central for de novo lipid synthesis, is markedly activated in L.G6pc-/- mice that in consequence rapidly develop NAFLD-like pathology. In the current work, we wished to address whether a selective deletion of ChREBP could prevent hepatic lipid accumulation and NAFLD initiation in L.G6pc-/- mice. Methods We generated liver-specific ChREBP (L.Chrebp-/-) and/or G6Pase (L.G6pc-/-) deficient mice using a Cre-lox strategy in B6.SACreERT2 mice. Mice were fed a standard chow diet or a high fat diet for 10 days. Markers of hepatic metabolism and cellular stress were analysed in liver of control, L. G6pc-/-, L. Chrebp-/-, and double knockout (i.e L.G6pc-/-.Chrebp-/-) mice. Results We observed that the deletion of ChREBP in liver of L.G6pc-/-.Chrebp-/- mice drastically decreased lipid accumulation. Importantly, it also exacerbated glycogen accumulation leading to hepatic water retention and aggravated hepatomegaly. At the mechanistic level, in the absence of ChREBP, elevated G6P concentrations caused by lack of G6Pase are rerouted towards glycogen synthesis. This caused animal distress and hepatocyte damage, characterized by ballooning and moderate fibrosis, paralleled with acute endoplasmic reticulum stress. Conclusions Altogether, our study reveals the crucial role of the ChREBP-G6Pase duo in the regulation of G6P-regulated pathways in the liver.