Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-1213, Lyon, France.
Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France.
Mol Metab. 2021 Jan;43:101108. doi: 10.1016/j.molmet.2020.101108. Epub 2020 Oct 31.
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.SA 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.
血糖的产生需要葡萄糖-6-磷酸酶（G6Pase）的表达，这是一种关键酶，可使葡萄糖-6-磷酸（G6P）水解为游离葡萄糖和无机磷。我们之前报道过，肝脏中 G6Pase 的抑制会导致 G6P 积累，并导致来自肝脏 G6Pase 缺陷型小鼠（L.G6pc）的肝细胞代谢重编程。有趣的是，用于从头合成脂质的转录因子碳水化合物反应元件结合蛋白（ChREBP）的活性在 L.G6pc 小鼠中显著激活，这些小鼠随后迅速发展出类似于非酒精性脂肪性肝病（NAFLD）的病理。在目前的工作中，我们评估了选择性敲除 ChREBP 是否可以防止 L.G6pc 小鼠肝内脂质堆积和 NAFLD 的发生。
我们使用 Cre-lox 策略在 B6.SA 小鼠中生成肝脏特异性 ChREBP（L.Chrebp）和/或 G6Pase（L.G6pc）缺陷型小鼠。将小鼠用标准的 chow 饮食或高脂肪饮食喂养 10 天。分析对照组、L.G6pc、L.Chrebp 和双敲除（即 L.G6pc.Chrebp）小鼠肝内的肝脏代谢和细胞应激标志物。
我们观察到，L.G6pc.Chrebp 小鼠肝内脂质堆积明显减少。在机制水平上，缺乏 G6Pase 导致的 G6P 浓度升高被重新定向到糖原合成中。重要的是，这加剧了糖原积累，导致肝内水潴留和肝肿大加重。这导致动物痛苦和肝细胞损伤，表现为气球样变和中度纤维化，伴有急性内质网应激。
我们的研究揭示了 ChREBP-G6Pase 双因素在肝脏中调节 G6P 调节途径中的关键作用。
