ATF5 is a regulator of ER stress and β-cell apoptosis in different mouse models of genetic- and diet-induced obesity and diabetes mellitus
ATF5 is a regulator of ER stress and β-cell apoptosis in different mouse models of genetic- and diet-induced obesity and diabetes mellitus
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ATF5 是遗传和饮食诱导的肥胖和糖尿病的不同小鼠模型中 ER 应激和 β 细胞凋亡的调节剂
DOI：
10.1016/j.cellsig.2022.110535
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发表时间：
2022-12-02
影响因子：
4.8
通讯作者：
Tong，Nanwei
中科院分区：
文献类型：
--
作者：
Ma，Jinfang;Liu，Yuqi;Tong，Nanwei
内质网（ER）应激与2型糖尿病（T2 D）密切相关。激活转录因子5（ATF 5）是ATF/cAMP反应元件结合蛋白（CREB）家族的成员，其水平在来自小鼠的胰岛中的应激时增加。有趣的是，ATF 5缺陷已被证明有助于增加小鼠胰岛微器官中的ER应激和细胞凋亡。我们假设，无论是缺乏或过度表达的ATF 5是同样有害的胰岛ER应激和细胞凋亡。为了验证这一点，我们使用了大量的体外和体内模型，其中ATF 5水平过表达。我们还通过使用各种肥胖和T2 D小鼠模型确定了在代谢紊乱的背景下ATF 5的调节。体外实验结果表明，ATF 5过表达促进了棕榈酸（PA）诱导的脂毒性细胞凋亡，在体内实验中，ATF 5的过表达对小鼠具有致死性，胰腺特异性的ATF 5过表达小鼠的β细胞凋亡增加。有趣的是，在本研究中使用的所有严重肥胖和T2 D小鼠模型中，ATF 5均下调。总之，在开发用于预防和治疗代谢性疾病的靶向ATF 5的新型药物时，可以考虑对ATF 5水平的严格控制。
Endoplasmic reticulum (ER) stress is closely associated with type 2 diabetes (T2D). Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element binding protein (CREB) family whose levels are increased upon stress in pancreatic islets from mice. Intriguingly, ATF5 deficiency has been shown to contribute to increased ER stress and apoptosis in mouse islet micro-organs. We hypothesized that either deficiency or overexpression of ATF5 is equally deleterious for pancreatic islets in terms of ER stress and apoptosis. To test this, we used a number ofin vitroandin vivomodels whereby ATF5 levels were overexpressed. We also determined the regulation of ATF5 in the context of metabolic derangements by using various mouse models of obesity and T2D. Ourin vitroresults show that ATF5 overexpression promoted palmitic acid (PA)-induced lipotoxic apoptosis.In vivo, global ATF5 overexpression in mice was lethal and pancreas-specific ATF5 overexpressing mice exhibit increased β-cell apoptosis. Interestingly, ATF5 is downregulated in all mouse models of severe obesity and T2D used in the current study. In conclusion, a tight control on ATF5 levels might be considered when developing novel agents targeting ATF5 for prevention and treatment of metabolic diseases.