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

St-Onge, Luc
Kerr-Conte, Julie
Cobo-Vuilleumier, Nadia
Lorenzo, Petra I
Jimenez Moreno, Carmen M
Cederroth, Christopher R
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Published in Human molecular genetics. 2011, vol. 20, no. 14, p. 2823-33
Abstract 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 β-cells, and that transcript levels are modulated by 17β-estradiol through the estrogen receptor (ER)α but not ERβ 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.
Keywords AdenoviridaeAnimalsApoptosisCell Line, TumorCholesterol/biosynthesis/geneticsCholesterol Side-Chain Cleavage Enzyme/genetics/metabolismCyclin D1/genetics/metabolismCyclin E/genetics/metabolismCytokines/genetics/metabolismDiabetes Mellitus, Experimental/genetics/metabolism/pathologyEstrogen Receptor alpha/genetics/metabolismEstrogens/genetics/metabolismGene Expression RegulationHumansInsulin/genetics/secretionInsulin-Secreting Cells/metabolismMiceMice, KnockoutOncogene Proteins/genetics/metabolismRatsRats, WistarReceptors, Cytoplasmic and Nuclear/biosynthesis/geneticsSteroid 11-beta-Hydroxylase/genetics/metabolismStress, PhysiologicalBcl-X Protein/genetics/metabolism
PMID: 21536586
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Research group Mécanismes moléculaires et génétiques du développement sexuel (778)
Swiss National Science Foundation: NRP48
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BAQUIE, Mathurin et al. The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects {beta}-cells against stress-induced apoptosis. In: Human molecular genetics, 2011, vol. 20, n° 14, p. 2823-33. doi: 10.1093/hmg/ddr193 https://archive-ouverte.unige.ch/unige:23471

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Deposited on : 2012-10-18

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