PPARγ co-activator-1α co-activates steroidogenic factor 1 to stimulate the synthesis of luteinizing hormone and aldosterone

促黄体激素 醛固酮 内分泌学 内科学 类固醇生成因子1 化学 激素 激活剂(遗传学) 胆固醇侧链裂解酶 受体 生物 医学 转录因子 核受体 生物化学 新陈代谢 细胞色素P450 基因
作者
Liuluan Zhu,Yaojun Ke,Di Shao,Ying Cui,Aijun Qiao,Xiaojun Liu,Fude Fang,Yongsheng Chang
出处
期刊:Biochemical Journal [Portland Press]
卷期号:432 (3): 473-486 被引量:12
标识
DOI:10.1042/bj20100460
摘要

The orphan nuclear receptor SF-1 (steroidogenic factor 1) is highly expressed in the pituitary, gonad and adrenal glands and plays key roles at all levels of the hypothalamic–pituitary–steroidogenic tissue axis. In the present study, we show that PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator 1α] interacts with and co-activates SF-1 to induce LHβ (luteinizing hormone β) and αGSU (α-glycoprotein subunit) gene expression, subsequently leading to the increased secretion of LH in pituitary gonadotrope-derived αT3-1 cells. PGC-1α co-activation of LHβ expression requires an SF-1-binding element [GSE (gonadotrope-specific element)] mapped to the promoter region of LHβ. Mammalian two-hybrid and co-immunoprecipitation assays, as well as GST (glutathione transferase) pull-down experiments demonstrated that PGC-1α interacts with SF-1 in vivo and in vitro. Additionally, PGC-1α stimulates the expression of Cyp11b2 (aldosterone synthase gene), Cyp11b1 (steroid 11β-hydroxylase gene) and P450scc (cholesterol side-chain cleavage enzyme), and the synthesis of aldosterone in adrenal-cortex-derived Y-1 cells. Chromatin immunoprecipitation assays confirmed that endogenous PGC-1α co-localizes with SF-1 in the LHβ and Cyp11b2 promoter region. Knockdown of endogenous SF-1 by siRNA (small interfering RNA) abolished the PGC-1α induction of LHβ and Cyp11b2 gene expression in αT3-1 and Y-1 cells respectively. Finally, we demonstrated that PGC-1α induces SF-1 gene expression in both αT3-1 and Y-1 cells. Taken together, our findings reveal the potential role of PGC-1α and suggest that it may play important roles in steroidogenesis, gonad development and sex differentiation through SF-1.

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