Transcriptional profile reveals altered hepatic lipid and cholesterol metabolism in hyposulfatemic NaS1 null mice
Transcriptional profile reveals altered hepatic lipid and cholesterol metabolism in hyposulfatemic NaS1 null mice
复制标题
DOI：
10.1152/physiolgenomics.00300.2005
复制
发表时间：
2006-07-12
影响因子：
4.6
通讯作者：
Markovich, Daniel
中科院分区：
文献类型：
--
作者：
Dawson, Paul Anthony;Gardiner, Brooke;Markovich, Daniel
硫酸盐在人体生长发育中起着至关重要的作用，其循环水平由肾脏Na+-SO 42-协同转运蛋白NaS 1维持。我们以前产生了NaS 1敲除（Nas 1（-/-））小鼠，低硫酸盐血症的动物模型，表现出生长减少和肝脏异常，包括肝肿大。在这项研究中，我们研究了肝脏基因表达谱的Nas 1（-/-）小鼠使用寡核苷酸芯片。与Nas 1（-/-）小鼠相比，Nas 1（-/-）小鼠中具有代谢、细胞信号传导、细胞防御、免疫应答、细胞结构、转录或蛋白质合成中已知功能作用的92个基因的mRNA表达水平增加（n = 51）或降低（n = 41）。在Nas 1（-/-）小鼠中，发现磺基转移酶基因Sult 3a 1（增加约500%）和Sult 2a 2（增加100%）的转录水平上调最多，而金属硫蛋白-1基因Mt 1是下调最多的基因之一（减少70%）。在Nas 1（+/+）小鼠中，发现涉及脂质和胆固醇代谢的几个基因，包括Scd 1、Acly、Gpam、Elov 16、Acsl 5、Mvd、Insig 1和Apoa 4上调（增加>= 30%）。此外，Nas 1（+/+）小鼠表现出肝脂质（增加约16%）、血清胆固醇（增加约20%）和低密度脂蛋白（增加约100%）水平升高以及肝糖原水平降低（降低约50%）。总之，这些数据表明低硫酸盐血症Nas 1（-/-）小鼠的脂质和胆固醇代谢发生改变，并为Nas 1（-/-）小鼠肝脏的代谢状态提供了新的见解。
Sulfate plays an essential role in human growth and development, and its circulating levels are maintained by the renal Na+-SO42- cotransporter, NaS1. We previously generated a NaS1 knockout ( Nas1(-/-)) mouse, an animal model for hyposulfatemia, that exhibits reduced growth and liver abnormalities including hepatomegaly. In this study, we investigated the hepatic gene expression profile of Nas1(-/-) mice using oligonucleotide microarrays. The mRNA expression levels of 92 genes with known functional roles in metabolism, cell signaling, cell defense, immune response, cell structure, transcription, or protein synthesis were increased ( n = 51) or decreased ( n = 41) in Nas1(-/-) mice when compared with Nas1(-/-) mice. The most upregulated transcript levels in Nas1(-/-) mice were found for the sulfotransferase genes, Sult3a1 ( approximate to 500% increase) and Sult2a2 ( 100% increase), whereas the metallothionein-1 gene, Mt1, was among the most downregulated genes ( 70% decrease). Several genes involved in lipid and cholesterol metabolism, including Scd1, Acly, Gpam, Elov16, Acsl5, Mvd, Insig1, and Apoa4, were found to be upregulated ( >= 30% increase) in Nas1(+/+) mice. In addition, Nas1(+/+) mice exhibited increased levels of hepatic lipid ( approximate to 16% increase), serum cholesterol ( approximate to 20% increase), and low-density lipoprotein ( approximate to 100% increase) and reduced hepatic glycogen ( approximate to 50% decrease) levels. In conclusion, these data suggest an altered lipid and cholesterol metabolism in the hyposulfatemic Nas1(-/-) mouse and provide new insights into the metabolic state of the liver in Nas1(-/-) mice.