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

• Published in: Molecular metabolism (Germany) Vol. 43; p. 101108
• Main Authors: Rajas, Fabienne, Dentin, Renaud, Cannella Miliano, Alexane, Silva, Marine, Raffin, Margaux, Levavasseur, Françoise, Gautier-Stein, Amandine, Postic, Catherine, Mithieux, Gilles
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.01.2021; Elsevier
• Subjects: Glucose production; Glucose-6 phosphate; Glycaemia; Glycogen storage disease type 1; Life Sciences; Neurons and Cognition; Non-alcoholic fatty liver disease; Original; Type 2 diabetes; Type 2 diabetes; glucose-6 phosphatase; alanine aminotransferase; non-esterified fatty acid; triglycerides; carbohydrate response element-binding protein; endogenous glucose production; Glycaemia; very low-density lipoproteins; Glycogen storage disease type 1; free fatty acid; Glucose production; Aspartate aminotransferase; Non-alcoholic fatty liver disease; wild-type; Glucose-6 phosphate
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2020.101108

Glucose production in 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, which consequently rapidly develop NAFLD-like pathology. In the current work, we assessed whether a selective deletion of ChREBP could prevent hepatic lipid accumulation and NAFLD initiation in L.G6pc−/− mice. 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 the liver of control, L. G6pc−/−, L. Chrebp−/− and double knockout (i.e., L.G6pc−/−.Chrebp−/−) mice. We observed that there was a dramatic decrease in lipid accumulation in the liver of L.G6pc−/−.Chrebp−/− mice. At the mechanistic level, elevated G6P concentrations caused by lack of G6Pase are rerouted towards glycogen synthesis. Importantly, this exacerbated glycogen accumulation, leading to hepatic water retention and aggravated hepatomegaly. This caused animal distress and hepatocyte damage, characterised by ballooning and moderate fibrosis, paralleled with acute endoplasmic reticulum stress. Our study reveals the crucial role of the ChREBP-G6Pase duo in the regulation of G6P-regulated pathways in the liver. •Hepatic deletion of both ChREBP and glucose-6 phosphatase collapses liver lipids.•Double deletion leads to excessive glycogen storage and a liver swollen with water.•Hepatic deletion of both ChREBP and glucose-6 phosphatase leads to death.•Glucose-6 phosphate homeostasis in hepatocytes is a vital function.