Advanced glycation end products increase lipids accumulation in macrophages through upregulation of receptor of advanced glycation end products: increasing uptake, esterification and decreasing efflux of cholesterol.
Advanced glycation end products increase lipids accumulation in macrophages through upregulation of receptor of advanced glycation end products: increasing uptake, esterification and decreasing efflux of cholesterol.
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晚期糖基化终末产物通过上调晚期糖基化终末产物受体来增加巨噬细胞中的脂质积累：增加摄取、酯化并减少胆固醇的流出
DOI：
10.1186/s12944-016-0334-0
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发表时间：
2016-09-19
影响因子：
4.5
通讯作者：
Feng B
中科院分区：
文献类型：
--
作者：
Xu L;Wang YR;Li PC;Feng B
背景研究表明，晚期糖基化终产物（AGEs）参与了糖尿病大血管病变的发病过程。我们前期的研究发现AGEs可增加糖尿病大鼠动脉粥样硬化斑块中脂滴的积聚，但目前对AGEs影响巨噬细胞脂质积聚、加速动脉粥样硬化的机制尚不完全清楚。在本研究中，我们研究了AGEs对巨噬细胞脂质积聚的作用及其可能的分子机制，包括胆固醇内流，方法用PMA诱导THP-1细胞分化为巨噬细胞，用浓度为300 μg/ml和600 μg/ml的AGEs处理THP-1细胞后，加入或不加入抗人巨噬细胞抗体（AGEs受体）抗体，然后用氧化LDL（oxLDL）或Dil-oxLDL刺激。油红染色法检测脂质沉积。用荧光显微镜、酶法试剂盒和荧光微板分别检测胆固醇的摄取、酯化和外排。采用定量RT-PCR和Western blot方法检测巨噬细胞中参与胆固醇摄取、合成/酯化和外排的分子的表达。600 μg/ml AGEs通过调节CD 36、清道夫受体（SR）A2、HMG-CoA还原酶（HMGCR）、ACAT 1和ATP结合盒转运体G1（ABCG 1）等主要分子的表达，显著上调巨噬细胞对oxLDL的摄取，增加巨噬细胞胆固醇酯水平，降低HDL介导的胆固醇外排。结论AGEs主要通过与β-淀粉样蛋白结合，调节胆固醇的摄取、酯化和外排，从而增加巨噬细胞内脂质的积聚，为AGEs促进糖尿病动脉粥样硬化的发生机制提供了新的认识。
BackgroundPrevious reports have suggested that advanced glycation end products (AGEs) participate in the pathogenesis of diabetic macroangiopathy. Our previous study have found that AGEs can increase the lipid droplets accumulation in aortas of diabetic rats, but the current understanding of the mechanisms remains incomplete by which AGEs affect lipids accumulation in macrophages and accelerate atherosclerosis. In this study, we investigated the role of AGEs on lipids accumulation in macrophages and the possible molecular mechanisms including cholesterol influx, esterification and efflux of macrophages.MethodsTHP-1 cells were incubated with PMA to differentiate to be macrophages which were treated with AGEs in the concentration of 300 μg/ml and 600 μg/ml with or without anti-RAGE (receptor for AGEs) antibody and then stimulated by oxidized-LDL (oxLDL) or Dil-oxLDL. Lipids accumulation was examined by oil red staining. The cholesterol uptake, esterification and efflux were detected respectively by fluorescence microscope, enzymatic assay kit and fluorescence microplate. Quantitative RT-PCR and Western blot were used to measure expression of the moleculars involved in cholesterol uptake, synthesis/esterification and efflux.ResultsAGEs increased lipids accumulation in macrophages in a concentration-dependent manner. 600 μg/ml AGEs obviously upregulated oxLDL uptake, increased levels of cholesterol ester in macrophages, and decreased the HDL-mediated cholesterol efflux by regulating the main molecular expression including CD36, Scavenger receptors (SR) A2, HMG-CoA reductase (HMGCR), ACAT1 and ATP-binding cassette transporter G1 (ABCG1). The changes above were inversed when the cells were pretreated with anti-RAGE antibody.ConclusionsThe current study suggest that AGEs can increase lipids accumulation in macrophages by regulating cholesterol uptake, esterification and efflux mainly through binding with RAGE, which provide a deep understanding of mechanisms how AGEs accelerating diabetic atherogenesis.
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DOI：
10.1111/j.1432-1033.1995.0408h.x
发表时间：
1995-06-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
ARAKI, N;HIGASHI, T;HORIUCHI, S
通讯作者：
HORIUCHI, S
影响因子：
7.4
作者：
Baynes, JW;Thorpe, SR
通讯作者：
Thorpe, SR
影响因子：
4.8
作者：
Forbes, JM;Thallas, V;Cooper, ME
通讯作者：
Cooper, ME
影响因子：
5.3
作者：
Lin, RY;Choudhury, RP;Vlassara, H
通讯作者：
Vlassara, H
影响因子：
37.8
作者：
Bucciarelli, LG;Wendt, T;Schmidt, AM
通讯作者：
Schmidt, AM