Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis
Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis
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DOI：
10.1152/physiolgenomics.00206.2010
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发表时间：
2011-07-01
影响因子：
4.6
通讯作者：
Jetten, Anton M.
中科院分区：
文献类型：
--
作者：
Kang, Hong Soon;Okamoto, Kyoko;Jetten, Anton M.
类维生素A相关孤儿受体（ROR）α 4是脂肪组织和肝脏中表达的主要ROR α亚型。在这项研究中，我们证明，ROR α-缺陷交错小鼠（ROR α（sg/sg））与高脂饮食（HFD）相比，表现出减少肥胖和肝脏甘油三酯水平与野生型（WT）同窝仔，并抵抗肝脂肪变性，脂肪相关炎症和胰岛素抵抗的发展。基因表达谱分析表明，许多参与甘油三酯合成和储存的基因，包括Cidec，Cidea和Mogat 1，在ROR α（sg/sg）小鼠的肝脏中表达水平低得多。相反，小鼠肝癌Hepa 1 -6细胞中ROR α的过表达显著增加了ROR α（sg/sg）肝脏中被抑制的基因的表达，包括Sult 1b 1，Adfp，Cidea和ApoA 4。ChIP和启动子分析表明，这些基因中有几个直接受ROR α的调控。除了减少脂质蓄积外，喂食HFD的ROR α（sg/sg）小鼠的白色脂肪组织（WAT）中的炎症也大大减少。在ROR α（sg/sg）WAT中，巨噬细胞的浸润和许多免疫应答和促炎基因（包括编码各种化学/细胞因子、Toll样受体和TNF信号传导蛋白的基因）的表达显著降低。此外，用HFD喂养的ROR α（sg/sg）小鼠被保护免于胰岛素抵抗的发展。ROR α（sg/sg）小鼠消耗更多的氧气，产生更多的二氧化碳，这表明这种基因型的能量消耗增加。我们的研究表明，ROR α在代谢综合征的几个方面的调节中起着关键作用。因此，ROR α可能为肥胖和相关代谢疾病的管理提供新的治疗靶点。
Retinoid-related orphan receptor (ROR)alpha 4 is the major ROR alpha isoform expressed in adipose tissues and liver. In this study we demonstrate that ROR alpha-deficient staggerer mice (ROR alpha(sg/sg)) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of ROR alpha(sg/sg) mice. In contrast, overexpression of ROR alpha in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in ROR alpha(sg/sg) liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by ROR alpha. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of ROR alpha(sg/sg) mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in ROR alpha(sg/sg) WAT. Moreover, ROR alpha(sg/sg) mice fed with an HFD were protected from the development of insulin resistance. ROR alpha(sg/sg) mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that ROR alpha plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, ROR alpha may provide a novel therapeutic target in the management of obesity and associated metabolic diseases.