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Regulation of rat hepatic 11beta-hydroxysteroid dehydrogenase 1 expression by DHEA.

机译：DHEA对大鼠肝11β-羟类固醇脱氢酶1表达的调节。

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摘要

Dehydroepiandrosterone (DHEA) is a C-19 adrenal steroid. Unlike other steroid hormones, it circulates at high levels in humans. Its level also changes with age, highest in the late twenties and decreasing thereafter. The decreased levels of DHEA have been associated with several age-related conditions, including cardiovascular disease, osteoporosis, Alzheimer's disease, cancer, and diabetes. Supplementation in rodents has protective effects against these conditions. However, it also induces peroxisome proliferation in the liver, an effect mediated by the nuclear receptor, peroxisome proliferators-activated receptor (PPARalpha). PPARalpha results in transcriptional induction of genes involved in lipid metabolism, including CYP4A genes. DHEA also induces expression of genes independent of PPARalpha activation, such as CYP3A23, and suppresses expression of other genes including CYP2C11.; In this dissertation, I used cDNA microarrays to identify genes whose expression in the liver was affected by DHEA treatment. The analysis identified 35 genes, some of which were known target genes in peroxisome proliferation. Others had not previously been identified as DHEA-responsive genes. In particular, the mRNA for 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) was decreased by 2--3 fold by DHEA treatment. 11beta-HSD1 is an enzyme that converts inactive to active glucocorticoids in local tissue. The decreased expression of 11beta-HSD1 should result in decreased glucocorticoid action in the liver, something which was confirmed by decreased expression of serum/glucocorticoid-regulated protein kinase. Because 11beta-HSD1 deficient mice are resistant to hyperglycemia induced by obesity, and have increased insulin sensitivity, I think some of the effects of DHEA supplementation can be explained by its negative regulation of 11beta-HSD1 expression.; I also studied the regulation of 11beta-HSD1 expression at the molecular level, using luciferase reporter systems and transient transfection assays. The basal expression of 11beta-HSD1 was dependent on transcription factor C/EBPalpha. The C/EBPalpha-dependent activity was suppressed by PPARalpha overexpression. In addition, glucocorticoid receptor increased promoter activity, suggesting a feed-forward mechanism to amplify glucocorticoid action. Using real-time RT-PCR, I also demonstrated that DHEA treatment increased mRNA expression of PPARalpha in rat liver. This could be a mechanism, by which DHEA suppresses expression of 11beta-HSD1 in rat liver.
机译：脱氢表雄酮（DHEA）是一种C-19肾上腺类固醇。与其他类固醇激素不同，它在人体中以高水平循环。它的水平也随着年龄而变化，在二十年代后期最高，然后下降。脱氢表雄酮（DHEA）水平的下降与几种与年龄有关的疾病有关，包括心血管疾病，骨质疏松症，阿尔茨海默氏病，癌症和糖尿病。补充啮齿动物对这些情况有保护作用。但是，它也诱导肝脏中的过氧化物酶体增殖，这是由核受体，过氧化物酶体增殖物激活受体（PPARalpha）介导的。 PPARalpha导致涉及脂质代谢的基因（包括CYP4A基因）的转录诱导。 DHEA还诱导表达独立于PPARalpha激活的基因，例如CYP3A23，并抑制其他基因的表达，包括CYP2C11。在本文中，我使用cDNA微阵列技术鉴定了在DHEA处理中肝脏中表达受到影响的基因。分析确定了35个基因，其中一些是过氧化物酶体增殖的已知靶基因。其他人以前没有被鉴定为DHEA反应基因。特别是，通过DHEA处理，11β-羟基类固醇脱氢酶1（11beta-HSD1）的mRNA降低了2--3倍。 11beta-HSD1是一种在局部组织中将非活性糖皮质激素转化为活性糖皮质激素的酶。 11beta-HSD1表达的降低应导致肝脏中糖皮质激素的作用降低，这可通过血清/糖皮质激素调节的蛋白激酶的表达降低来证实。因为缺乏11beta-HSD1的小鼠对肥胖引起的高血糖症具有抵抗力，并且胰岛素敏感性增强，所以我认为补充DHEA的某些作用可以由其对11beta-HSD1表达的负调控来解释。我还使用荧光素酶报告系统和瞬时转染试验研究了11β-HSD1在分子水平上的表达调控。 11beta-HSD1的基础表达取决于转录因子C / EBPalpha。 C / EBPalpha依赖的活动被PPARalpha过表达抑制。另外，糖皮质激素受体增加了启动子活性，提示了前馈机制来放大糖皮质激素的作用。使用实时RT-PCR，我还证明了DHEA处理可增加大鼠肝脏中PPARalpha的mRNA表达。这可能是DHEA抑制大鼠肝脏11beta-HSD1表达的机制。

著录项

  • 作者

    Gu, Shi.;

  • 作者单位

    University of Louisville.;

  • 授予单位 University of Louisville.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 198 p.
  • 总页数 198
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;
  • 关键词

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