肝脏ChREBP活性的规范化并不能保护一种糖原贮积病型（Glycogen Storage Disease type Ia）的小鼠免受肝病的进展。
Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia.
发表日期：2023 Apr 21
作者：
Martijn G S Rutten, Yu Lei, Joanne H Hoogerland, Vincent W Bloks, Hong Yang, Trijnie Bos, Kishore A Krishnamurthy, Aycha Bleeker, Mirjam H Koster, Rachel E Thomas, Justina C Wolters, Hilda van den Bos, Gilles Mithieux, Fabienne Rajas, Adil Mardinoglu, Diana C J Spierings, Alain de Bruin, Bart van de Sluis, Maaike H Oosterveer
来源：
GENES & DEVELOPMENT
摘要：
1型肝糖原贮积病(GSD Ia)是一种先天性代谢错误，由于葡萄糖-6-磷酸酶(G6PC1)活性缺陷所致，导致严重的肝肿大和增加肝癌风险。肝GSD Ia的特征是一种葡萄糖敏感的转录因子--碳水化合物反应元件结合蛋白(ChREBP)的始终活化。我们之前已经显示，ChREBP活化能够限制肝GSD Ia中的非酒精性脂肪肝(NAFLD)。由于ChREBP被提出作为一种支持肿瘤进展的促癌分子开关，我们假设ChREBP规范化能够保护肝GSD Ia患者免受肝脏疾病进展的损害。将肝细胞特异性的G6pc基因敲除(L-G6pc-/-)小鼠用AAV-shChREBP处理以规范化肝脏中的ChREBP活性。结果，ChREBP规范化在GSD Ia小鼠中引起了异常增生的肝脏生长、极大的肝细胞大小，并伴有肝脏炎症的增加。此外，肝脏ChREBP规范化还导致了著名的促癌蛋白Yes Associated Protein(YAP)的核水平增加以及它的转录靶标在ChREBP规范化的GSD Ia小鼠中被诱导表达。肝脏ChREBP规范化还在GSD Ia小鼠中诱导了DNA损伤和有丝分裂活性，同时增加了染色体不稳定性、细胞质DNA传感cGAS-STING通路、衰老和肝细胞去分化的基因表达。总之，我们的发现表明，ChREBP活性限制肝肿大，同时减缓肝脏疾病进展，并保护肝GSD Ia患者免受染色体不稳定性的损伤。这些结果排除了ChREBP作为GSD Ia肝脏疾病治疗的治疗靶点的可能性。此外，它们强调了建立肝脏ChREBP的特异性作用以定义其预防或治疗晚期肝脏疾病的治疗潜力的重要性。©2023. 作者(们)。
Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia.Hepatocyte-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity.Hepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged.In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease.© 2023. The Author(s).