The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects β-cells against stress-induced apoptosis
The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects β-cells against stress-induced apoptosis
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DOI：
10.1093/hmg/ddr193
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发表时间：
2011-07-15
影响因子：
3.5
通讯作者：
Gauthier, Benoit R.
中科院分区：
文献类型：
--
作者：
Baquie, Mathurin;St-Onge, Luc;Gauthier, Benoit R.
肝受体同源物（LRH-1）是一种孤儿核受体（NR 5A 2），其调节内胚层来源的组织中的胆固醇稳态和细胞可塑性。雌激素增加LRH-1表达，传递细胞保护和增殖。独立地，雌激素也保护分离的人胰岛免受苦参碱诱导的细胞凋亡。在此，我们证明了LRH-1在胰岛中表达，包括β细胞，并且转录水平通过雌激素受体（ER）α而不是ER β信号通路由17 β-雌二醇调节。通过siRNA抑制LRH-1可消除雌激素对大鼠胰岛细胞抗细胞因子的保护作用。腺病毒介导的LRH-1在人类胰岛中的过表达并不改变增殖，但对细胞因子和链脲佐菌素诱导的细胞凋亡提供保护。细胞周期基因cyclin D1和cyclin E1以及抗凋亡基因bcl-xl的表达水平在表达LRH-1的胰岛中没有改变。相反，参与糖皮质激素生物合成的类固醇生成酶CYP 11 A1和CYP 11B 1在转导的胰岛中都受到刺激。同时，LRH-1的分级过表达剂量依赖性地损害葡萄糖诱导的胰岛素分泌。我们的研究结果证实了雌激素靶基因nr 5a 2在保护人类胰岛抵抗应激诱导的细胞凋亡中的关键作用。我们推测这种作用是通过增加糖皮质激素的产生来介导的，糖皮质激素的产生减弱了胰岛的促炎反应。
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.