Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1152, New York, 10029, USA.
Pharmacologic Sciences Department, Stony Brook University, Stony Brook, NY, USA.
Nat Commun. 2022 Jul 30;13(1):4423. doi: 10.1038/s41467-022-32162-x.
Preservation and expansion of β-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPβ) is a nuclear effector of hyperglycemic stress occurring in β-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPβ is necessary for adaptive β-cell expansion in response to metabolic challenges. Conversely, chronic excessive β-cell-specific overexpression of ChREBPβ results in loss of β-cell identity, apoptosis, loss of β-cell mass, and diabetes. Furthermore, β-cell "glucolipotoxicity" can be prevented by deletion of ChREBPβ. Moreover, ChREBPβ-mediated cell death is mitigated by overexpression of the alternate CHREBP gene product, ChREBPα, or by activation of the antioxidant Nrf2 pathway in rodent and human β-cells. We conclude that ChREBPβ, whether adaptive or maladaptive, is an important determinant of β-cell fate and a potential target for the preservation of β-cell mass in diabetes.
β 细胞质量的保存和扩增是糖尿病的治疗目标。在这里，我们表明，碳水化合物反应元件结合蛋白（ChREBPβ）的高活性异构体是β 细胞中发生的高血糖应激的核效应因子，这种应激是对长期葡萄糖暴露、高脂肪饮食和糖尿病的反应。我们表明，ChREBPβ 的短暂正反馈诱导对于适应代谢挑战的β 细胞扩增是必要的。相反，慢性过度的β 细胞特异性过表达 ChREBPβ 会导致β 细胞丧失身份、凋亡、β 细胞质量丧失和糖尿病。此外，ChREBPβ 介导的细胞死亡可以通过 ChREBPβ 的缺失来预防。此外，在啮齿动物和人类β细胞中，ChREBPα 的替代 CHREBP 基因产物的过表达或抗氧化 Nrf2 途径的激活可以减轻 ChREBPβ 介导的细胞死亡。我们得出结论，ChREBPβ 无论是适应性的还是失调性的，都是β 细胞命运的重要决定因素，也是糖尿病中保存β 细胞质量的潜在靶点。
