猴视网膜中胆固醇27-羟化酶（CYP27A1）的表达与定位
Expression and localization of sterol 27-hydroxylase (CYP27A1) in monkey retina.
作者信息
Lee Jung Wha, Fuda Hirotoshi, Javitt Norman B, Strott Charles A, Rodriguez Ignacio R
机构信息
Section on Mechanisms of Retinal Diseases, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
Exp Eye Res. 2006 Aug;83(2):465-9. doi: 10.1016/j.exer.2005.11.018. Epub 2006 Mar 20.
Abstract
Sterol 27-hydroxylase (CYP27A1) is a mitochondrial P-450 enzyme with broad substrate specificity for C27 sterols including 7-ketocholesterol (7kCh). CYP27A1 is widely expressed in human tissues but has not been previously demonstrated in the retina. In this study, we examined the expression and localization of CYP27A1 in the monkey retina where it localized mainly to the photoreceptor inner segments. CYP27A1 was also observed in Müller cells with faint immuno staining detected in the RPE and choriocapillaris. We also determined that the 27-hydroxylation of 7-ketocholesterol (27OH7kCh) rendered it non-toxic to cultured RPE cells. Moreover, the 27OH7kCh when mixed with 7-ketocholesterol significantly reduced the toxicity of 7-ketocholesterol. These data, when taken in context of the known functions of CYP27A1 imply that expression in the retina serves to modify the biological activity of oxidized sterols that are either transported or generated locally by photo-oxidation.
摘要
固醇27-羟化酶（CYP27A1）是一种线粒体P-450酶，对包括7-酮胆固醇（7kCh）在内的C27固醇具有广泛的底物特异性。CYP27A1在人体组织中广泛表达，但此前尚未在视网膜中得到证实。在本研究中，我们检测了CYP27A1在猴视网膜中的表达和定位，发现它主要定位于光感受器内节。在Müller细胞中也观察到了CYP27A1，在视网膜色素上皮（RPE）和脉络膜毛细血管中检测到微弱的免疫染色。我们还确定，7-酮胆固醇的27-羟化作用（27OH7kCh）使其对培养的RPE细胞无毒。此外，27OH7kCh与7-酮胆固醇混合时，可显著降低7-酮胆固醇的毒性。结合CYP27A1的已知功能来看，这些数据表明，视网膜中的表达有助于改变通过光氧化作用在局部转运或生成的氧化固醇的生物活性。
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2
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3
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4
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6
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7
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8
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9
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10
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FASEB J. 2004 Apr;18(6):693-5. doi: 10.1096/fj.03-0401fje. Epub 2004 Feb 20.
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