Lala D S, Syka P M, Lazarchik S B, Mangelsdorf D J, Parker K L, Heyman R A
Departments of Orphan Nuclear Receptor and Retinoid Research, Ligand Pharmaceuticals, 10255 Science Center Drive, San Diego, CA 92121, USA.
Proc Natl Acad Sci U S A. 1997 May 13;94(10):4895-900. doi: 10.1073/pnas.94.10.4895.
Steroidogenic factor 1 (SF-1), an orphan member of the intracellular receptor superfamily, plays an essential role in the development and function of multiple endocrine organs. It is expressed in all steroidogenic tissues where it regulates the P450 steroidogenic genes to generate physiologically active steroids. Although many of the functions of SF-1 in vivo have been defined, an unresolved question is whether a ligand modulates its transcriptional activity. Here, we show that 25-, 26-, or 27-hydroxycholesterol, known suppressors of cholesterol biosynthesis, enhance SF-1-dependent transcriptional activity. This activation is dependent upon the SF-1 activation function domain, and, is specific for SF-1 as several other receptors do not respond to these molecules. The oxysterols activate at concentrations comparable to those previously shown to inhibit cholesterol biosynthesis, and, can be derived from cholesterol by P450c27, an enzyme expressed within steroidogenic tissues. Recent studies have shown that the nuclear receptor LXR also is activated by oxysterols. We demonstrate that different oxysterols differ in their rank order potency for these two receptors, with 25-hydroxycholesterol preferentially activating SF-1 and 22(R)-hydroxycholesterol preferentially activating LXR. These results suggest that specific oxysterols may mediate transcriptional activation via different intracellular receptors. Finally, ligand-dependent transactivation of SF-1 by oxysterols may play an important role in enhancing steroidogenesis in vivo.
类固醇生成因子1（SF-1）是细胞内受体超家族的一个孤儿成员，在多个内分泌器官的发育和功能中发挥着至关重要的作用。它在所有类固醇生成组织中表达，在这些组织中调节P450类固醇生成基因以产生具有生理活性的类固醇。尽管SF-1在体内的许多功能已被明确，但一个尚未解决的问题是是否有一种配体调节其转录活性。在此，我们表明，已知的胆固醇生物合成抑制剂25-、26-或27-羟基胆固醇可增强SF-1依赖性转录活性。这种激活依赖于SF-1激活功能域，并且对SF-1具有特异性，因为其他几种受体对这些分子没有反应。氧化固醇在与先前显示抑制胆固醇生物合成的浓度相当的浓度下激活，并且可以由类固醇生成组织中表达的一种酶P450c27从胆固醇衍生而来。最近的研究表明，核受体LXR也被氧化固醇激活。我们证明，不同的氧化固醇对这两种受体的激活效力顺序不同，25-羟基胆固醇优先激活SF-1，22(R)-羟基胆固醇优先激活LXR。这些结果表明，特定的氧化固醇可能通过不同的细胞内受体介导转录激活。最后，氧化固醇对SF-1的配体依赖性反式激活可能在增强体内类固醇生成中起重要作用。
