Inserm Unit 1103 (A.V., E.M., M.B., A.D.H., J.-P.S., S.B., F.C., J.-M.A.L., D.H.V.), Génétique Reproduction et Développement (GReD), Boîte Postale 80026; Clermont Université (A.V., E.M., M.B., A.D.H., J.-P.S., S.B., F.C., J.-M.A.L., D.H.V.), Université Blaise Pascal, GReD; and Centre National de la Recherche Scientifique (A.V., E.M., M.B., A.D.H., J.-P.S., S.B., F.C., J.-M.A.L., D.H.V.), Unité Mixte de recherche 6293, GReD, F-63170 Aubière Cedex, France; Centre de Recherche en Nutrition Humaine d'Auvergne (A.V., E.M., M.B., A.D.H., J.-P.S., S.B., F.C., J.-M.A.L., D.H.V.), F-63000 Clermont-Ferrand Cedex, France; and Institute of Bioengineering (K.S.), Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Endocrinology. 2015 Feb;156(2):660-9. doi: 10.1210/en.2014-1418. Epub 2014 Nov 26.
The small heterodimer partner (SHP, nuclear receptor subfamily 0, group B, member 2; NR0B2) is an atypical nuclear receptor known mainly for its role in bile acid homeostasis in the enterohepatic tract. We previously showed that NR0B2 controls testicular functions such as testosterone synthesis. Moreover, NR0B2 mediates the deleterious testicular effects of estrogenic endocrine disruptors leading to infertility. The endocrine homeostasis is essential for health, because it controls many physiological functions. This is supported by a large number of studies demonstrating that alterations of steroid activity lead to several kinds of diseases such as obesity and infertility. Within the testis, the functions of the Leydig cells are mainly controlled by the hypothalamo-pituitary axis via LH/chorionic gonadotropin (CG). Here, we show that LH/CG represses Nr0b2 expression through the protein kinase A-AMP protein kinase pathway. Moreover, using a transgenic mouse model invalidated for Nr0b2, we point out that NR0B2 mediates the repression of testosterone synthesis and subsequent germ cell apoptosis induced by exposure to anti-GnRH compound. Together, our data demonstrate a new link between hypothalamo-pituitary axis and NR0B2 in testicular androgen metabolism, making NR0B2 a major actor of testicular physiology in case of alteration of LH/CG levels.
小异二聚体伴侣 (SHP,核受体亚家族 0,B 组,成员 2;NR0B2) 是一种非典型核受体,主要因其在肠肝内胆汁酸稳态中的作用而闻名。我们之前表明,NR0B2 控制着睾丸的功能,如睾酮合成。此外,NR0B2 介导雌激素内分泌干扰物对睾丸的有害作用,导致不育。内分泌稳态对健康至关重要,因为它控制着许多生理功能。这得到了大量研究的支持,这些研究表明,类固醇活性的改变会导致多种疾病,如肥胖和不育。在睾丸中,Leydig 细胞的功能主要通过下丘脑-垂体轴通过 LH/绒毛膜促性腺激素 (CG) 来控制。在这里,我们表明 LH/CG 通过蛋白激酶 A-AMP 蛋白激酶途径抑制 Nr0b2 表达。此外,使用 Nr0b2 无效的转基因小鼠模型,我们指出 NR0B2 介导了抗 GnRH 化合物暴露引起的睾酮合成和随后的生殖细胞凋亡的抑制。总之,我们的数据表明下丘脑-垂体轴和 NR0B2 之间在睾丸雄激素代谢中有一个新的联系,使 NR0B2 成为 LH/CG 水平改变时睾丸生理学的主要因素。