2型糖尿病患者三磷酸腺苷结合盒转运子G1表达下调不依赖于肝X受体的调节

摘要/Abstract

摘要： 目的：研究2型糖尿病患者胆固醇外流的功能改变及调节基因三磷酸腺苷结合盒转运子G1（ATPbinding cassette transporter G1，ABCG1）的表达，并探讨肝X受体（liver X receptor，LXR）对ABCG1表达的调节作用。方法: 选取2型糖尿病和健康对照组各30例，抽取外周静脉血40 mL，分离人外周血单核细胞，经巨噬细胞集落刺激因子诱导分化为巨噬细胞。以［3H］胆固醇标记巨噬细胞，用液闪计数法测定胆固醇外流率。实时定量PCR（quantitative real-time PCR，qRT PCR）法检测人单核巨噬细胞ABCA1/G1的mRNA表达，Western blot法检测ABCA1/G1的蛋白表达；siRNA法抑制LXRα、LXRβ，观察其对ABCG1mRNA表达的影响；电泳迁移率试验方法（electrophery mobility supershift assay，EMSA）检测LXR与ABCG1启动子区LXR反应元件（liver X receptor element, LXRE）结合的DNA结合蛋白的表达。结果：与健康对照组相比，2型糖尿病患者ABCG1的mRNA及蛋白表达水平与高密度脂蛋白介导的胆固醇外流率显著降低（19.0%±1.2% vs. 12.8%±3.6%, t=2.532, P=0.016），而ABCA1的mRNA及蛋白表达水平与载脂蛋白A1（Apolipoprotein A1, ApoA1）介导的胆固醇外流率差异无统计学意义（12.0%±1.2%vs.10.2%±2.3%， t=1.771, P=0.109）。LXRα、LXRβ的mRNA表达水平以及LXRLXRE DNA结合蛋白的表达差异均无统计学意义（t=1.025，P=0.315；t=-0.531，P=0.600；t=1.483，P=0.164），且LXR的siRNA抑制对ABCG1mRNA的表达也无显著影响（t=2.143，P=0.061）。结论： 2型糖尿病患者巨噬细胞胆固醇外流功能的下降与ABCG1表达下调相关，而ABCG1的表达下调可能不依赖于LXR。

关键词: ATP结合盒转运子1, 糖尿病, 2型, 肝X受体

Abstract: Objective：To examine the cholesterol efflux and the expressions of ATP-binding cassette transporter G1 (ABCG1) in macrophages of diabetic patients and the roles of liver-X receptor (LXR) in regulation of ABCG1 expressions. Methods: Blood was collected from patients with type 2 diabetes mellitus and healthy controls. The peripheral blood monocytes were differentiated into macrophages with macrophage colony stimulating factor (M-CSF). The cells were radio labeled with ［3H］ cholesterol and were performed with cholesterol efflux assays. Quantitative real-time PCR (qRT PCR) and Western blot were performed to measure the mRNA and protein expressions of ABCA1 and ABCG1. To test the effects of LXR on ABCG1 expressions, inhibition of LXRα and LXRβ by siRNA were performed. The DNA-protein complex of LXR and LXR element (LXRE) located in the promoter region of ABCG1 gene were detected with electrophery mobility supershift assay (EMSA). Results: Macrophage ABCG1 expressions and high-density lipoprotein (HDL) induced cholesterol efflux were significantly reduced (19.0%±1.2% vs. 12.8%±3.6%, t=2.532, P=0.016) in the diabetic subjects whereas ABCA1 expressions and apolipoprotein A1 (ApoA1) induced cholesterol efflux were comparable (12.0%±1.2% vs. 10.2%±2.3%, t=1.771, P=0.109) between the diabetic patients and healthy subjects. The mRNA expressions of LXRα and LXRβ had no changes between the diabetes subjects and healthy controls (t=1.025, P=0.315; t=-0.531, P=0.600). The LXR-LXRE DNA-protein complex detected by EMSA were also similar between the diabetes subjects and healthy controls (t=1.483, P=0.164). Moreover, ABCG1 expressions were not altered by inhibition of LXRα/β siRNA (t=2.143, P=0.061). Conclusion: Our data indicated that expression of ABCG1 and HDL induced cholesterol efflux were reduced in type 2 diabetic patients. However, the LXR mRNA expression and binding complex of LXR and ABCG1 promoter were not changed. The impairment of cholesterol efflux and ABCG1 gene expressions might be regulated via an LXR-independent pathway.

Key words: ATP-binding cassette transporter 1, Diabetes mellitus, type 2, Liver X receptor

王会娟, 赵兴山, 孙华毅, 陈连凤, 严晓伟. 2型糖尿病患者三磷酸腺苷结合盒转运子G1表达下调不依赖于肝X受体的调节[J]. 北京大学学报（医学版）, 2014, 46(6): 899-905.

WANG Hui-Juan, ZHAO Xing-Shan, SUN Hua-Yi, CHEN Lian-Feng, YAN Xiao-Wei. Decline of ATP-binding cassette transporter G1 expressions with a liver X receptor-independent pathway in patients with type 2 diabetes[J]. Journal of Peking University(Health Sciences), 2014, 46(6): 899-905.

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