US EPA

7055898 

Journal Article 

The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects beta-cells against stress-induced apoptosis 

Baquie, M; Bosco, D; Wang, H; Marchetti, P; Pattou, F; Wollheim, CB; Gauthier, BR; St-Onge, Luc; Kerr-Conte, J; Cobo-Vuilleumier, N; Lorenzo, PI; Jimenez Moreno, CM; Cederroth, CR; Nef, S; Borot, S; , 

2011 

Yes 

Human Molecular Genetics
ISSN: 0964-6906
EISSN: 1460-2083 

OXFORD UNIV PRESS 

OXFORD 

2823-2833 

21536586 

10.1093/hmg/ddr193 

WOS:000292560300011 

Liver receptor homolog (LRH-1) is an orphan nuclear receptor (NR5A2) that regulates cholesterol homeostasis and cell plasticity in endodermal-derived tissues. Estrogen increases LRH-1 expression conveying cell protection and proliferation. Independently, estrogen also protects isolated human islets against cytokine-induced apoptosis. Herein, we demonstrate that LRH-1 is expressed in islets, including beta-cells, and that transcript levels are modulated by 17 beta-estradiol through the estrogen receptor (ER)alpha but not ER beta signaling pathway. Repression of LRH-1 by siRNA abrogated the protective effect conveyed by estrogen on rat islets against cytokines. Adenoviral-mediated overexpression of LRH-1 in human islets did not alter proliferation but conferred protection against cytokines and streptozotocin-induced apoptosis. Expression levels of the cell cycle genes cyclin D1 and cyclin E1 as well as the antiapoptotic gene bcl-xl were unaltered in LRH-1 expressing islets. In contrast, the steroidogenic enzymes CYP11A1 and CYP11B1 involved in glucocorticoid biosynthesis were both stimulated in transduced islets. In parallel, graded overexpression of LRH-1 dose-dependently impaired glucose-induced insulin secretion. Our results demonstrate the crucial role of the estrogen target gene nr5a2 in protecting human islets against-stressed-induced apoptosis. We postulate that this effect is mediated through increased glucocorticoid production that blunts the pro-inflammatory response of islets.