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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenoviridae
-
Animals
-
Apoptosis*
-
Cell Line, Tumor
-
Cholesterol / biosynthesis
-
Cholesterol / genetics
-
Cholesterol Side-Chain Cleavage Enzyme / genetics
-
Cholesterol Side-Chain Cleavage Enzyme / metabolism
-
Cyclin D1 / genetics
-
Cyclin D1 / metabolism
-
Cyclin E / genetics
-
Cyclin E / metabolism
-
Cytokines / genetics
-
Cytokines / metabolism
-
Diabetes Mellitus, Experimental / genetics
-
Diabetes Mellitus, Experimental / metabolism
-
Diabetes Mellitus, Experimental / pathology
-
Estrogen Receptor alpha / genetics
-
Estrogen Receptor alpha / metabolism
-
Estrogens / genetics
-
Estrogens / metabolism
-
Gene Expression Regulation*
-
Humans
-
Insulin / genetics
-
Insulin / metabolism
-
Insulin Secretion
-
Insulin-Secreting Cells / metabolism*
-
Mice
-
Mice, Knockout
-
Oncogene Proteins / genetics
-
Oncogene Proteins / metabolism
-
Rats
-
Rats, Wistar
-
Receptors, Cytoplasmic and Nuclear / biosynthesis*
-
Receptors, Cytoplasmic and Nuclear / genetics
-
Steroid 11-beta-Hydroxylase / genetics
-
Steroid 11-beta-Hydroxylase / metabolism
-
Stress, Physiological*
-
bcl-X Protein / genetics
-
bcl-X Protein / metabolism
Substances
-
BCL2L1 protein, human
-
Bcl2l1 protein, mouse
-
Bcl2l1 protein, rat
-
CCND1 protein, human
-
CCNE1 protein, human
-
Ccnd1 protein, mouse
-
Ccnd1 protein, rat
-
Cyclin E
-
Cytokines
-
Estrogen Receptor alpha
-
Estrogens
-
Insulin
-
NR5A2 protein, human
-
Nr5a2 protein, mouse
-
Oncogene Proteins
-
Receptors, Cytoplasmic and Nuclear
-
bcl-X Protein
-
Cyclin D1
-
Cholesterol
-
Steroid 11-beta-Hydroxylase
-
Cholesterol Side-Chain Cleavage Enzyme