title: Homocysteine-mediated cholesterol efflux via ABCA1 and ACAT1 DNA methylation in THP-1 monocyte-derived foam cells.
abstract: 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 phospholipids, is the rate-limiting step in lipid metabolism. Acyl-coenzyme A:cholesterol 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 24 h. 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.
authors.affiliation: Department of Laboratory Medicine,  Ningxia Medical University, Yinchuan 750004,  China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.forename: Linna
authors.initials: L
authors.lastname: Ma
authors.forename: Xin
authors.initials: X
authors.lastname: Cai
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.forename: Guizhong
authors.initials: G
authors.lastname: Li
authors.forename: Minghao
authors.initials: M
authors.lastname: Zhang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Sun
authors.forename: Yideng
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000166:cytology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D009000:Monocytes / Q000166:cytology; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D010743:Phospholipids; D012333:RNA, Messenger; D006710:Homocysteine; D002784:Cholesterol; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase