Journal
HUMAN MOLECULAR GENETICS
Volume 20, Issue 14, Pages 2823-2833Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr193
Keywords
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Funding
- Swiss National Science Foundation [310030-119763, 310000-116750/1, 32003B-120376]
- Juvenile Diabetes Research Foundation [9-2004-384]
- Fundacion Progreso y Salud
- Junta de Andalucia, Consejeria de Salud [PI-0727-2010]
- Swiss National Science Foundation (SNF) [32003B_120376, 310030_119763] Funding Source: Swiss National Science Foundation (SNF)
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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.
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