NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function

被引：9

作者：

Martin Vazquez, Eugenia ^{[1
]}

Cobo-Vuilleumier, Nadia ^{[1
]}

Araujo Legido, Raquel ^{[1
]}

Marin-Canas, Sandra ^{[2
]}

Nola, Emanuele ^{[1
]}

Dorronsoro, Akaitz ^{[1
]}

Lopez Bermudo, Lucia ^{[1
,3
]}

Crespo, Alejandra ^{[1
]}

Romero-Zerbo, Silvana Y. ^{[4
,5
]}

Garcia-Fernandez, Maria ^{[5
]}

Martin Montalvo, Alejandro ^{[1
,3
]}

Rojas, Anabel ^{[1
,3
]}

Comaills, Valentine ^{[1
]}

Bermudez-Silva, Francisco J. ^{[3
,4
]}

Gannon, Maureen ^{[6
]}

Martin, Franz ^{[1
,3
]}

Eizirik, Decio ^{[2
]}

Lorenzo, Petra I. ^{[1
]}

Gauthier, Benoit R. ^{[1
,3
]}

机构：

[1] Univ Seville, Univ Pablo de Olavide, CSIC, Andalusian Ctr Mol Biol & Regenerat Med CABIMER, Seville, Spain

[2] Univ Libre Bruxelles, Fac Med, Ctr Diabet Res, Brussels, Belgium

[3] Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain

[4] Univ Malaga, Hosp Reg Univ Malaga, Inst Invest Biomed Malaga IBIMA UGC Endocrinol &, Malaga, Spain

[5] Univ Malaga, Fac Med, Dept Fisiol Humana Anat Patol & Educ Fis Deport, Malaga, Spain

[6] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA

来源：

ISCIENCE | 2022年 / 25卷 / 05期

关键词：

LIVER RECEPTOR HOMOLOG-1; BETA-CELL REPLICATION; KINASE-C-EPSILON; PRIMARY MECHANISM; LRH-1; MOUSE; PROSTAGLANDIN-E-2; STREPTOZOTOCIN; APOPTOSIS; INSIGHTS;

D O I：

10.1016/j.isci.2022.104345

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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/PGE(2)/PTGER1 signaling axis as a key pathway mediating BL001 survival properties.

引用

页数：24

共 28 条

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