Nucleolin protects macrophages from oxLDL-induced foam cell formation through up-regulating ABCA1 expression.
Our recent studies have indicated that nucleolin, as a multifunctional RNA-binding protein, exerts protective effects in the myocardial cells and endothelial cells under the condition of oxidative stress. However, the function of nucleolin and its potential mechanism in macrophage-derived foam cell formation remain largely unexplored. ApoE-/- mice were fed with a high-fat diet (HFD) for 10-24 weeks. Protein expression was measured by western blotting or immunofluorescence, and gene expression at the mRNA level was detected by qRT-PCR. The level of lipid in macrophages was examined by Oil Red O staining, high-performance liquid chromatography (HPLC) and NBD-cholesterol. Actinomycin D (Act D) was used to determine the stability of ABCA1 mRNA in macrophages. The interaction of nucleolin with ABCA1 mRNA was assessed using co-immunoprecipitation (co-IP). The aortas advanced plaques demonstrated significantly lower levels of nucleolin protein compared with early plaques in ApoE-/- mice, in which the macrophage foam cells occupied main body. Nucleolin expression at the mRNA and protein levels in RAW264.7 macrophages was significantly reduced by oxidized low-density lipoprotein (oxLDL) in a dose- and time-dependent manner. Furthermore, nucleolin overexpression markedly attenuated lipid accumulation in oxLDL-challenged macrophages through increasing cholesterol efflux. In addition, nucleolin overexpression significantly increased the expression of ATP-binding cassette transporter A1 (ABCA1) at the mRNA and protein levels without affecting expressions of scavenger receptors (SR)-A, SR-B1, CD36 and ATP-binding cassette transporter G1 (ABCG1) at the mRNA level. Moreover, nucleolin overexpression increased the stability of ABCA1 mRNA in macrophages, whereas nucleolin ablation abrogated the oxLDL-induced up-regulation of ABCA1. The up-regulation of ABCA1 by nucleolin resulted from its protein-RNA interaction. Our data suggested that nucleolin inhibited foam cell formation through enhancing stability of ABCA1 mRNA and subsequently increasing cholesterol efflux.
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China.
Yuanbin
Y
Li
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China. Electronic address: jiangbimei@163.com.
Bimei
B
Jiang
Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
Pengfei
P
Liang
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China.
Zhongyi
Z
Tong
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China.
Meidong
M
Liu
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China.
Qinglan
Q
Lv
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China.
Yanjuan
Y
Liu
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China.
Xuanyou
X
Liu
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China.
Yuting
Y
Tang
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China.
Xianzhong
X
Xiao
D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport / Q000187:drug effects; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006949:Hyperlipidemias / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000097796:Nucleolin
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D001057:Apolipoproteins E; D018955:CD36 Antigens; D002784:Cholesterol; D008077:Lipoproteins, LDL; D010750:Phosphoproteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D000097796:Nucleolin; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C454739:Scarb1 protein, mouse; C099252:oxidized low density lipoprotein
ABCA1; Atherosclerosis; Lipoprotein; Nucleolin; mRNA stability