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

Abstract : Objective: 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. 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 the 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, characterised by ballooning and moderate fibrosis, paralleled with acute endoplasmic reticulum stress. Conclusions: Our study reveals the crucial role of the ChREBP-G6Pase duo in the regulation of G6P-regulated pathways in the liver.
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https://www.hal.inserm.fr/inserm-03038399
Contributor : Marie-Ange Di Carlo <>
Submitted on : Thursday, December 3, 2020 - 2:38:48 PM
Last modification on : Wednesday, June 2, 2021 - 4:26:07 PM
Long-term archiving on: : Thursday, March 4, 2021 - 7:19:00 PM

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Fabienne Rajas, Renaud Dentin, Alexane Cannella, Marine Silva, Margaux Raffin, et al.. The absence of hepatic glucose-6 phosphatase/ChREBP couple is incompatible with survival in mice.. Molecular metabolism, Elsevier, 2020, pp.101108. ⟨10.1016/j.molmet.2020.101108⟩. ⟨inserm-03038399⟩

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