Martin Vázquez Eugenia, Cobo-Vuilleumier Nadia, Araujo Legido Raquel, Marín-Cañas Sandra, Nola Emanuele, Dorronsoro Akaitz, López Bermudo Lucia, Crespo Alejandra, Romero-Zerbo Silvana Y, García-Fernández Maria, Martin Montalvo Alejandro, Rojas Anabel, Comaills Valentine, Bérmudez-Silva Francisco J, Gannon Maureen, Martin Franz, Eizirik Decio, Lorenzo Petra I, Gauthier Benoit R
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain.
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium.
iScience. 2022 May 2;25(5):104345. doi: 10.1016/j.isci.2022.104345. eCollection 2022 May 20.
LRH-1/NR5A2 is implicated in islet morphogenesis postnatally, and its activation using the agonist BL001 protects islets against apoptosis, reverting hyperglycemia in mouse models of Type 1 Diabetes Mellitus. Islet transcriptome profiling revealed that the expression of PTGS2/COX2 is increased by BL001. Herein, we sought to define the role of LRH-1 in postnatal islet morphogenesis and chart the BL001 mode of action conferring beta cell protection. LRH-1 ablation within developing beta cells impeded beta cell proliferation, correlating with mouse growth retardation, weight loss, and hypoglycemia leading to lethality. LRH-1 deletion in adult beta cells abolished the BL001 antidiabetic action, correlating with beta cell destruction and blunted induction. Islet PTGS2 inactivation led to reduced PGE levels and loss of BL001 protection against cytokines as evidenced by increased cytochrome release and cleaved-PARP. The PTGER1 antagonist-ONO-8130-negated BL001-mediated islet survival. Our results define the LRH-1/PTGS2/PGE/PTGER1 signaling axis as a key pathway mediating BL001 survival properties.
肝脏受体同源物-1/LRH-1（NR5A2）在出生后胰岛形态发生中起作用，使用激动剂BL001激活它可保护胰岛免受细胞凋亡影响，在1型糖尿病小鼠模型中逆转高血糖。胰岛转录组分析显示，BL001可增加环氧化酶-2/PTGS2的表达。在此，我们试图确定LRH-1在出生后胰岛形态发生中的作用，并阐明BL001赋予β细胞保护作用的作用机制。发育中的β细胞内LRH-1缺失会阻碍β细胞增殖，这与小鼠生长迟缓、体重减轻和低血糖导致的死亡相关。成年β细胞中LRH-1缺失消除了BL001的抗糖尿病作用，这与β细胞破坏和诱导减弱相关。胰岛PTGS2失活导致前列腺素E水平降低以及BL001对细胞因子的保护作用丧失，这表现为细胞色素释放增加和PARP裂解。前列腺素E受体1拮抗剂ONO-8130消除了BL001介导的胰岛存活作用。我们的结果确定LRH-1/PTGS2/前列腺素E/PTGER1信号轴是介导BL001存活特性的关键途径。
