Stulnig Thomas M, Steffensen Knut R, Gao Hui, Reimers Mark, Dahlman-Wright Karin, Schuster Gertrud U, Gustafsson Jan-Ake
Department of Medical Nutrition and Biosciences, Karolinska Institutet, Huddinge, Sweden.
Mol Pharmacol. 2002 Dec;62(6):1299-305. doi: 10.1124/mol.62.6.1299.
Liver X receptor (LXR) alpha and LXRbeta are nuclear oxysterol receptors whose biological function has so far been elucidated only with respect to cholesterol and lipid metabolism. To expose novel biological roles for LXRs, we performed genome-wide gene expression profiling studies in liver and white and brown adipose tissue from wild-type (LXRalpha(+/+)beta(+/+)) and knockout mice (LXRalpha(-/-)beta(-/-)) treated with a synthetic LXR agonist. By an adapted statistical analysis, we detected 319 genes significantly regulated by LXR agonist treatment in wild-type but not in knockout mice, fulfilling most stringent criteria with an overall confidence of 94%. Down-regulation of essential enzymes of gluconeogenesis in liver could point to possible beneficial effects of LXR agonists in diabetes mellitus. LXR agonist treatment also altered expression of genes involved in steroid hormone synthesis and growth hormone receptor signaling, emphasizing a potential impact on endocrine function. Notably, LXR agonist treatment up-regulated CYP4A10 and CYP4A14 together with cytochrome P450 reductase, indicating a possible enhancement of microsomal lipid peroxidation. In conclusion, these gene expression profiling data identify novel areas of regulation by LXRs and provide a highly valuable basis for further research on the biological functions of these nuclear receptors and the pharmacological characteristics of their ligands.
肝X受体（LXR）α和LXRβ是核氧化甾醇受体，迄今为止，其生物学功能仅在胆固醇和脂质代谢方面得到阐明。为了揭示LXR的新生物学作用，我们对野生型（LXRα(+/+)β(+/+)）和基因敲除小鼠（LXRα(-/-)β(-/-)）经合成LXR激动剂处理后的肝脏、白色和棕色脂肪组织进行了全基因组基因表达谱研究。通过适应性统计分析，我们在野生型小鼠中检测到319个受LXR激动剂处理显著调控的基因，而在基因敲除小鼠中未检测到，这些基因符合最严格的标准，总体置信度为94%。肝脏中糖异生关键酶的下调可能表明LXR激动剂对糖尿病具有潜在的有益作用。LXR激动剂处理还改变了参与类固醇激素合成和生长激素受体信号传导的基因表达，强调了其对内分泌功能的潜在影响。值得注意的是，LXR激动剂处理上调了CYP4A10和CYP4A14以及细胞色素P450还原酶，表明微粒体脂质过氧化可能增强。总之，这些基因表达谱数据确定了LXR调控的新领域，并为进一步研究这些核受体的生物学功能及其配体的药理学特性提供了极有价值的基础。
