NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function
Eugenia Martin Vázquez,
Nadia Cobo-Vuilleumier,
Raquel Araujo Legido,
Sandra Marín-Cañas,
Emanuele Nola,
Akaitz Dorronsoro,
Lucia López Bermudo,
Alejandra Crespo,
Silvana Y. Romero-Zerbo,
Maria García-Fernández,
Alejandro Martin Montalvo,
Anabel Rojas,
Valentine Comaills,
Francisco J. Bérmudez-Silva,
Maureen Gannon,
Franz Martin,
Decio Eizirik,
Petra I. Lorenzo,
Benoit R. Gauthier
Affiliations
Eugenia Martin Vázquez
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
Nadia Cobo-Vuilleumier
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
Raquel Araujo Legido
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
Sandra Marín-Cañas
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
Emanuele Nola
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
Akaitz Dorronsoro
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
Lucia López Bermudo
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
Alejandra Crespo
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
Silvana Y. Romero-Zerbo
Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain; Facultad de Medicina, Departamento de Fisiología Humana, Anatomía Patológica y Educación Físico Deportiva, Universidad de Málaga, Málaga, Spain
Maria García-Fernández
Facultad de Medicina, Departamento de Fisiología Humana, Anatomía Patológica y Educación Físico Deportiva, Universidad de Málaga, Málaga, Spain
Alejandro Martin Montalvo
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
Anabel Rojas
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
Valentine Comaills
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
Francisco J. Bérmudez-Silva
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain; Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
Maureen Gannon
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville USA
Franz Martin
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
Decio Eizirik
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
Petra I. Lorenzo
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
Benoit R. Gauthier
Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain; Corresponding author
Summary: 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.
