NR5A2/LRH-1 regulates the PTGS2-PGE(2)-PTGER1 pathway contributing to pancreatic islet survival and function.
NR5A2/LRH-1 regulates the PTGS2-PGE(2)-PTGER1 pathway contributing to pancreatic islet survival and function.
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DOI：
10.1016/j.isci.2022.104345
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发表时间：
2022-05-20
期刊：
影响因子：
5.8
通讯作者：
Gauthier, Benoit R.
中科院分区：
文献类型：
--
作者：
Martin Vazquez, Eugenia;Cobo-Vuilleumier, Nadia;Araujo Legido, Raquel;Marin-Canas, Sandra;Nola, Emanuele;Dorronsoro, Akaitz;Lopez Bermudo, Lucia;Crespo, Alejandra;Romero-Zerbo, Silvana Y.;Garcia-Fernandez, Maria;Martin Montalvo, Alejandro;Rojas, Anabel;Comaills, Valentine;Bermudez-Silva, Francisco J.;Gannon, Maureen;Martin, Franz;Eizirik, Decio;Lorenzo, Petra I.;Gauthier, Benoit R.
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 Ptgs2 induction. Islet PTGS2 inactivation led to reduced PGE2 levels and loss of BL001 protection against cytokines as evidenced by increased cytochrome c release and cleaved-PARP. The PTGER1 antagonist—ONO-8130—negated BL001-mediated islet survival. Our results define the LRH-1/PTGS2/PGE2/PTGER1 signaling axis as a key pathway mediating BL001 survival properties. LRH-1 ablation during development impedes neonatal beta cell replication LRH-1 knockout in adult beta cells negates BL001-mediated antidiabetic properties Islets lacking PTGS2 are refractory to BL001-mediated protection against cytokines PTGER1 relays the BL001/LRH-1/PTGS2/PGE2 signaling axis to islet survival Physiology; Molecular biology
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影响因子：
3.7
作者：
Blondeau B;Sahly I;Massouridès E;Singh-Estivalet A;Valtat B;Dorchene D;Jaisser F;Bréant B;Tronche F
通讯作者：
Tronche F
DOI：
10.1016/j.bbadis.2010.12.010
发表时间：
2011-08
影响因子：
6.2
作者：
Fernandez-Marcos, Pablo J.;Auwerx, Johan;Schoonjans, Kristina
通讯作者：
Schoonjans, Kristina
影响因子：
3.5
作者：
Baquie, Mathurin;St-Onge, Luc;Gauthier, Benoit R.
通讯作者：
Gauthier, Benoit R.
影响因子：
4.6
作者：
Bru-Tari, Eva;Cobo-Vuilleumier, Nadia;Quesada, Ivan
通讯作者：
Quesada, Ivan
影响因子：
4.2
作者：
Flynn, Autumn R.;Mays, Suzanne G.;Jui, Nathan T.
通讯作者：
Jui, Nathan T.