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Scientific article
English

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

Published inHuman molecular genetics, vol. 20, no. 14, p. 2823-2833
Publication date2011
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
  • Adenoviridae
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cholesterol/biosynthesis/genetics
  • Cholesterol Side-Chain Cleavage Enzyme/genetics/metabolism
  • Cyclin D1/genetics/metabolism
  • Cyclin E/genetics/metabolism
  • Cytokines/genetics/metabolism
  • Diabetes Mellitus, Experimental/genetics/metabolism/pathology
  • Estrogen Receptor alpha/genetics/metabolism
  • Estrogens/genetics/metabolism
  • Gene Expression Regulation
  • Humans
  • Insulin/genetics/secretion
  • Insulin-Secreting Cells/metabolism
  • Mice
  • Mice, Knockout
  • Oncogene Proteins/genetics/metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Cytoplasmic and Nuclear/biosynthesis/genetics
  • Steroid 11-beta-Hydroxylase/genetics/metabolism
  • Stress, Physiological
  • Bcl-X Protein/genetics/metabolism
Funding
  • Swiss National Science Foundation - NRP48
Citation (ISO format)
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. 2823–2833. doi: 10.1093/hmg/ddr193
Main files (1)
Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal0964-6906
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