Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism

Rajas, Fabienne; Gautier‐Stein, Amandine; Mithieux, Gilles

doi:10.3390/metabo9120282

Cited by 83 publications

(53 citation statements)

References 71 publications

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“…As mentioned above, G6P plays a crucial role in the induction of ChREBP activity and acts as a central hub for controlling hepatic metabolism by regulating glycogen storage, glycolysis, PPP, de novo lipogenesis and the hexosamine pathways [ 30 ]. Blocking one of these pathways in a healthy liver has generally limited consequences on liver homeostasis, whereas it can lead to metabolic imbalance in type 2 diabetes or GSDI.…”

Section: Discussionmentioning

confidence: 99%

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

Rajas

Dentin

Miliano

et al. 2021

Molecular Metabolism

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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.SA CreERT2 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 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. 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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Section: Discussionmentioning

confidence: 99%

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

Rajas

Dentin

Miliano

et al. 2021

Molecular Metabolism

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“…For a broader perspective, including the importance for human physiology, interested readers are referred to excellent reviews on the PPP [ 11 ] and on yeast glycolysis [ 12 , 13 ]. Further reviews on the functions of the PPP in other fungi, plants, bacteria, the human immune system or the liver are also available [ 14 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

The Pentose Phosphate Pathway in Yeasts–More Than a Poor Cousin of Glycolysis

2021

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The pentose phosphate pathway (PPP) is a route that can work in parallel to glycolysis in glucose degradation in most living cells. It has a unidirectional oxidative part with glucose-6-phosphate dehydrogenase as a key enzyme generating NADPH, and a non-oxidative part involving the reversible transketolase and transaldolase reactions, which interchange PPP metabolites with glycolysis. While the oxidative branch is vital to cope with oxidative stress, the non-oxidative branch provides precursors for the synthesis of nucleic, fatty and aromatic amino acids. For glucose catabolism in the baker’s yeast Saccharomyces cerevisiae, where its components were first discovered and extensively studied, the PPP plays only a minor role. In contrast, PPP and glycolysis contribute almost equally to glucose degradation in other yeasts. We here summarize the data available for the PPP enzymes focusing on S. cerevisiae and Kluyveromyces lactis, and describe the phenotypes of gene deletions and the benefits of their overproduction and modification. Reference to other yeasts and to the importance of the PPP in their biotechnological and medical applications is briefly being included. We propose future studies on the PPP in K. lactis to be of special interest for basic science and as a host for the expression of human disease genes.

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“…Figure 1 shows a schematic representation of the entire process for forming BGMs-loaded SCS (SCS-B). SCS was fabricated by mixing glucose-6-phosphate (G6P) as a cross-linker [ 15 ] with SCS hydrogels containing different chitosan succinylation rates: low-succinylated chitosan (SCS-L), medium-succinylated chitosan (SCS-M), and high-succinylated chitosan (SCS-H). At the same time, an equivalent amount of BGMs was added to the mixed solution with SCS and G6P to make a homogeneous composite.…”

Section: Resultsmentioning

confidence: 99%

The Effectiveness of Compartmentalized Bone Graft Sponges Made Using Complementary Bone Graft Materials and Succinylated Chitosan Hydrogels

et al. 2021

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Bone defects can occur from many causes, including disease or trauma. Bone graft materials (BGMs) have been used to fill damaged areas for the reconstruction of diseased bone tissues since they are cost effective and readily available. However, BGMs quickly disperse around the tissue area, which ultimately leads to it migrating away from the defect after transplantation. We tested chitosan hydrogels as a useful carrier to hold BGMs in the transplantation area. In this study, we synthesized succinylated chitosan (SCS)-based hydrogels with a high decomposition rate and excellent biocompatibility. We confirmed that BGMs were well distributed inside the SCS hydrogel. The SCS-B hydrogel showed a decrease in mechanical properties, such as compressive strength and Young’s modulus, as the succinylation rate increased. SCS-B hydrogels also exhibited a high cell growth rate and bone differentiation rate. Moreover, the in vivo results showed that the SCS hydrogel resorbed into the surrounding tissues while maintaining the BGMs in the transplantation area for up to 6 weeks. These data support the idea that SCS hydrogel can be useful as a bioactive drug carrier for a broad range of biomedical applications.

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Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism

Cited by 83 publications

References 71 publications

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

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

The Pentose Phosphate Pathway in Yeasts–More Than a Poor Cousin of Glycolysis

The Effectiveness of Compartmentalized Bone Graft Sponges Made Using Complementary Bone Graft Materials and Succinylated Chitosan Hydrogels

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