Dehydroepiandrosterone affects the expression of multiple genes in rat liver including 11β-hydroxysteroid dehydrogenase type 1:: A cDNA array analysis
Dehydroepiandrosterone affects the expression of multiple genes in rat liver including 11β-hydroxysteroid dehydrogenase type 1:: A cDNA array analysis
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DOI：
10.1124/mol.63.3.722
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发表时间：
2003-03-01
影响因子：
3.6
通讯作者：
Geoghegan, TE
中科院分区：
文献类型：
--
作者：
Gu, S;Ripp, SL;Geoghegan, TE
脱氢表雄酮（DHEA）是一种C-19肾上腺类固醇前体的性腺类固醇。在人类中，DHEA作为其硫酸化缀合物的循环水平在青春期和整个成年早期都很高，但随着年龄的增长而下降。饮食补充以维持高水平的DHEA据称对认知记忆，免疫系统以及脂肪和碳水化合物代谢具有有益作用。在啮齿类动物中，DHEA是一种过氧化物酶体增殖剂，可诱导与这种反应相关的经典过氧化物酶体和微粒体酶的基因。这些作用是通过激活过氧化物酶体增殖物激活受体α（PPARalpha）介导的。然而，DHEA可以独立于PPARalpha影响基因的表达，包括主要诱导药物和异生物质代谢酶细胞色素P450 3A 23的基因。为了阐明与DHEA治疗相关的生物化学，我们采用了cDNA基因表达阵列，使用DHEA或经典的过氧化物酶体增殖剂那非那平治疗的大鼠的肝脏RNA。主成分分析确定了30至35个基因的表达受到DHEA和/或nafenopin。有些基因以前被鉴定为PPAR-responsive基因。通过定量逆转录-聚合酶链反应验证了几个受影响基因表达的变化。这些包括水通道蛋白3，这是由DHEA诱导，并在较小程度上nafenopin，核酪氨酸磷酸酶，这是由两种药物诱导，和11 β-羟基类固醇脱氢酶1，这是减少与DHEA治疗剂量依赖性的方式。11 β-羟基类固醇脱氢酶1表达的调节是重要的，因为该酶被认为放大局部糖皮质激素信号传导，并且其抑制可能导致与DHEA相关的一些代谢效应。
Dehydroepiandrosterone (DHEA) is a C-19 adrenal steroid precursor to the gonadal steroids. In humans, circulating levels of DHEA, as its sulfated conjugate, are high at puberty and throughout early adulthood but decline with age. Dietary supplementation to maintain high levels of DHEA purportedly has beneficial effects on cognitive memory, the immune system, and fat and carbohydrate metabolism. In rodents, DHEA is a peroxisome proliferator that induces genes for the classical peroxisomal and microsomal enzymes associated with this response. These effects are mediated through activation of peroxisome proliferator-activated receptor alpha (PPARalpha). However, DHEA can affect the expression of genes independently of PPARalpha, including the gene for the major inducible drug and xenobiotic metabolizing enzyme, cytochrome P450 3A23. To elucidate the biochemistry associated with DHEA treatment, we employed a cDNA gene expression array using liver RNA from rats treated with DHEA or the classic peroxisome proliferator nafenopin. Principal components analysis identified 30 to 35 genes whose expression was affected by DHEA and/or nafenopin. Some were genes previously identified as PPAR-responsive genes. Changes in expression of several affected genes were verified by quantitative reverse transcriptase-polymerase chain reaction. These included aquaporin 3, which was induced by DHEA and to a lesser extent nafenopin, nuclear tyrosine phosphatase, which was induced by both agents, and 11beta-hydroxysteroid dehydrogenase 1, which was decreased by treatment with DHEA in a dose-dependent fashion. Regulation of 11beta-hydroxysteroid dehydrogenase 1 expression is important since the enzyme is believed to amplify local glucocorticoid signaling, and its repression may cause some of the metabolic effects associated with DHEA.