title: The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects {beta}-cells against stress-induced apoptosis.
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.
authors.affiliation: Department of Sensory Neuroscience, The Rockefeller University, New York, NY, USA.
authors.forename: Mathurin
authors.initials: M
authors.lastname: Baquié
authors.forename: Luc
authors.initials: L
authors.lastname: St-Onge
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.forename: Nadia
authors.initials: N
authors.lastname: Cobo-Vuilleumier
authors.forename: Petra I
authors.initials: PI
authors.lastname: Lorenzo
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Jimenez Moreno
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cederroth
authors.forename: Serge
authors.initials: S
authors.lastname: Nef
authors.forename: Sophie
authors.initials: S
authors.lastname: Borot
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Francois
authors.initials: F
authors.lastname: Pattou
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
authors.forename: Benoit R
authors.initials: BR
authors.lastname: Gauthier
mesh_terms: D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; C530104:CCND1 protein, human; C475820:CCNE1 protein, human; C530105:Ccnd1 protein, mouse; C530106:Ccnd1 protein, rat; D019927:Cyclin E; D016207:Cytokines; D047628:Estrogen Receptor alpha; D004967:Estrogens; D007328:Insulin; C082631:NR5A2 protein, human; C431936:Nr5a2 protein, mouse; D015513:Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D051020:bcl-X Protein; D019938:Cyclin D1; D002784:Cholesterol; D013252:Steroid 11-beta-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme