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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain
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cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain

机译：胆固醇24-羟化酶的基因克隆，胆固醇24-羟化酶是大脑中胆固醇稳态的介体

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摘要

The turnover of cholesterol in the brain is thougbt to occur via conversion of excess cholesterol into 24S-hydroxycholesterol, an oxysterol that is readily secreted from the central nervous system into the plasma. To gain molecular insight into this pathway of cholesterol metabolism, we used expression cloning to isolate cDNAs that encode murine and human cholesterol 24-hydroxylases. DNA se- quence analysis indicates that both proteins are localized to the endoplasmic reticulum, share 95 identity, and represent a new cytochrome P450 subfamily (CYP46). When transfected into cullured cells, the cDNAs produce an enzymatic activity that converts cholesterol into 24S-hydroxycholesterol, and to a lesser extent, 25-hydroxycholesterol. The cholesterol 24- hydroxylase gene contains 15 exons and is located on human chromosome 14q32.1. Cholesterol 24-hydroxylase is expressed predominantly in the brain as judged by RNA and protein blotting. In situ mRNA hybridization and immunohistochem- istry localize the expression of this P450 to neurons in multiple subregions of the brain. The concentrations of 24S- hydroxycholesterol in serum are low in newborn mice,reach decline to baseline levels. In contrast, cholesterol 24- hydroxylase protein is first detected in the brain of mice at birth and continues to accumulate witb age. We conclude that the cloned cDNAs encode cholesterol 24-hydroxylases that synthesize oxysterols in neurons of the brain and that secre- tion of 24S-hydroxycholesterol from this tissue in the mouse is developmentally regulated.
机译：认为大脑中的胆固醇转换是通过将过量的胆固醇转化为24S-羟基胆固醇（一种很容易从中枢神经系统分泌到血浆中的氧固醇）而发生的。为了深入了解胆固醇代谢的这一途径，我们使用了表达克隆技术来分离编码鼠类和人类胆固醇24-羟化酶的cDNA。 DNA序列分析表明这两种蛋白均定位于内质网，具有95个同一性，并代表一个新的细胞色素P450亚家族（CYP46）。当转染到残破的细胞中时，cDNA产生酶活性，该酶活性将胆固醇转化为24S-羟基胆固醇，在较小程度上转化为25-羟基胆固醇。胆固醇24-羟化酶基因包含15个外显子，位于人类染色体14q32.1上。通过RNA和蛋白质印迹判断，胆固醇24-羟化酶主要在大脑中表达。原位mRNA杂交和免疫组织化学将该P450的表达定位于大脑多个子区域的神经元。新生小鼠血清中24S-羟基胆固醇的浓度较低，可降至基线水平。相反，胆固醇24-羟化酶蛋白首先在出生时的小鼠大脑中被检测到，并随着年龄的增长而积累。我们得出的结论是，克隆的cDNAs编码胆固醇24-羟化酶，在大脑神经元中合成羟固醇，并且从小鼠的该组织中分泌的24S-羟胆固醇受到发育调节。

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