Xie Xina, Song Xuhong, Yuan Song, Cai Haitao, Chen Yequn, Chang Xiaolan, Liang Bin, Huang Dongyang
Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, China.
Department of Community Surveillance, The First Affiliated Hospital of Shantou, University Medical College, Shantou, 515041, China.
Clin Sci (Lond). 2015 Dec;129(12):1151-61. doi: 10.1042/CS20150346. Epub 2015 Sep 22.
Hypercholesterolaemia and inflammation are correlated with atherogenesis. Orphan nuclear receptor NR4A1, as a key regulator of inflammation, is closely associated with lipid levels in vivo. However, the mechanism by which lipids regulate NR4A1 expression remains unknown. We aimed to elucidate the underlying mechanism of NR4A1 expression in monocytes during hypercholesterolaemia, and reveal the potential role of NR4A1 in hypercholesterolaemia-induced circulating inflammation. Circulating leucocytes were collected from blood samples of 139 patients with hypercholesterolaemia and 139 sex- and age-matched healthy subjects. We found that there was a low-grade inflammatory state and higher expression of NR4A1 in patients. Both total cholesterol and low-density lipoprotein cholesterol levels in plasma were positively correlated with NR4A1 mRNA level. ChIP revealed that acetylation of histone H3 was enriched in the NR4A1 promoter region in patients. Human mononuclear cell lines THP-1 and U937 were treated with cholesterol. Supporting our clinical observations, cholesterol enhanced p300 acetyltransferase and decreased HDAC7 (histone deacetylase 7) recruitment to the NR4A1 promoter region, resulting in histone H3 hyperacetylation and further contributing to NR4A1 up-regulation in monocytes. Moreover, cytosporone B, an NR4A1 agonist, completely reversed cholesterol-induced IL-6 (interleukin 6) and MCP-1 (monocyte chemoattractant protein 1) expression to below basal levels, and knockdown of NR4A1 expression by siRNA not only mimicked, but also exaggerated the effects of cholesterol on inflammatory biomarker up-regulation. Thus we conclude that histone acetylation contributes to the regulation of NR4A1 expression in hypercholesterolaemia, and that NR4A1 expression reduces hypercholesterolaemia-induced inflammation.
高胆固醇血症与炎症和动脉粥样硬化的发生相关。孤儿核受体NR4A1作为炎症的关键调节因子，在体内与脂质水平密切相关。然而，脂质调节NR4A1表达的机制仍不清楚。我们旨在阐明高胆固醇血症期间单核细胞中NR4A1表达的潜在机制，并揭示NR4A1在高胆固醇血症诱导的循环炎症中的潜在作用。从139例高胆固醇血症患者和139例年龄和性别匹配的健康受试者的血样中收集循环白细胞。我们发现患者存在低度炎症状态且NR4A1表达较高。血浆中的总胆固醇和低密度脂蛋白胆固醇水平均与NR4A1 mRNA水平呈正相关。染色质免疫沉淀显示患者NR4A1启动子区域的组蛋白H3乙酰化增强。用人单核细胞系THP-1和U937进行胆固醇处理。与我们的临床观察结果一致，胆固醇增强了p300乙酰转移酶的活性，并减少了HDAC7（组蛋白去乙酰化酶7）与NR4A1启动子区域的结合，导致组蛋白H3高度乙酰化，进一步促进单核细胞中NR4A1的上调。此外，NR4A1激动剂环孢菌素B完全将胆固醇诱导的IL-6（白细胞介素6）和MCP-1（单核细胞趋化蛋白1）表达逆转至基础水平以下，并且通过siRNA敲低NR4A1表达不仅模拟了胆固醇对炎症生物标志物上调的影响，而且还加剧了这种影响。因此，我们得出结论，组蛋白乙酰化有助于高胆固醇血症中NR4A1表达的调节，并且NR4A1表达减少了高胆固醇血症诱导的炎症。
