Homocysteine-mediated cholesterol efflux via ABCA1 and ACAT1 DNA methylation in THP-1 monocyte-derived foam cells  

作　　者：Yu Liang Xiaoling Yang Linna Ma Xin Cai Lei Wang Cheng Yang Guizhong Li Minghao Zhang Weiwei Sun Yideng Jiang 

机构地区：[1]Department of Laboratory Medicine, Ningxia Medical University, Yinchuan 750004, China [2]Department of Clinical Laboratory, Ningxia People's Hospital, Yinchuan 750002, China [3]Department of Pathophysiology, Ningxia Medical University, Yinchuan 750004, China

出　　处：《Acta Biochimica et Biophysica Sinica》2013年第3期220-228,共9页生物化学与生物物理学报（英文版）

基　　金：This work was supported by grants from the National Natural Science Foundation of China （30960124, 81160044, 81260105, and 81260063） and the Ministry of Education for New Century Excellent Talents Support Plans （NCET-10-0916）.

摘　　要：Homocysteine （Hcy） has been recognized as a prevalent risk factor for cardiovascular events. Cholesterol-loaded foam cells are a central component of atherosclerotic lesions. ATP-binding cassette transporter A1 （ABCA1）, which mediates the efflux of cellular cholesterol and phos-pholipids, is the rate-limiting step in lipid metabolism. Acyl-coenzyme A：cholesteroi acyltransferase-1 （ACAT1） promotes accumulation of cholesterol ester in macrophages, thereby resulting in the foam cell formation, a hallmark of early stage in atherosclerosis. In this study, cultured monocyte-derived foam cells were incubated with clinical relevant concentrations of Hcy for 24h. Both increased number of foam cells and accumulation of cholesterol were found, and the mRNA and protein expression levels of ABCA1 were decreased, while ACAT1 expression was increased in the presence of Hcy. Furthermore, the DNA methylation level of ABCA1 gene was increased whereas ACAT1 DNA methylation was decreased by using different concentrations of Hcy. Moreover, our results showed that DNA methyltransferase （DNMT） activity and DNA methyltransferase 1 （DNMT1） mRNA expression were increased by Hcy. It is indicated that DNA methylation has the function to regulate the expression of ABCA1 and ACAT1 via DNMT. In conclusion, these results suggest that ABCA1 and ACAT1 DNA methylation induced by Hcy may play a potential role in ABCA1 and ACAT1 expression and the accumulation of cholesterol in monocyte-derived foam cells.Homocysteine （Hcy） has been recognized as a prevalent risk factor for cardiovascular events. Cholesterol-loaded foam cells are a central component of atherosclerotic lesions. ATP-binding cassette transporter A1 （ABCA1）, which mediates the efflux of cellular cholesterol and phos-pholipids, is the rate-limiting step in lipid metabolism. Acyl-coenzyme A：cholesteroi acyltransferase-1 （ACAT1） promotes accumulation of cholesterol ester in macrophages, thereby resulting in the foam cell formation, a hallmark of early stage in atherosclerosis. In this study, cultured monocyte-derived foam cells were incubated with clinical relevant concentrations of Hcy for 24h. Both increased number of foam cells and accumulation of cholesterol were found, and the mRNA and protein expression levels of ABCA1 were decreased, while ACAT1 expression was increased in the presence of Hcy. Furthermore, the DNA methylation level of ABCA1 gene was increased whereas ACAT1 DNA methylation was decreased by using different concentrations of Hcy. Moreover, our results showed that DNA methyltransferase （DNMT） activity and DNA methyltransferase 1 （DNMT1） mRNA expression were increased by Hcy. It is indicated that DNA methylation has the function to regulate the expression of ABCA1 and ACAT1 via DNMT. In conclusion, these results suggest that ABCA1 and ACAT1 DNA methylation induced by Hcy may play a potential role in ABCA1 and ACAT1 expression and the accumulation of cholesterol in monocyte-derived foam cells.

关 键 词：HOMOCYSTEINE ATP-binding cassette transporter A 1 acyl-coenzyme A：cholesterol acyltransferase-I DNA methylation cholesterol effiux 

分 类 号：Q75[生物学—分子生物学] Q517