机构:[1]College of Life Sciences, Nankai University, Tianjin 300071, China,[2]College of Chemistry, Nankai University, Tianjin 300071, China,[3]Key Lab of Bioactive Materials of the Ministry of Education of China, Nankai University, Tianjin 300071, China,[4]Department of Neurobiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China,首都医科大学宣武医院[5]Center of Vascular Biology and Department of Pathology, Weill Medical College of Cornell University, New York, New York 10065
ATP-binding cassette transporter A1 (ABCA1), a molecule mediating free cholesterol efflux from peripheral tissues to apoAI and high density lipoprotein (HDL), inhibits the formation of lipid-laden macrophage/foam cells and the development of atherosclerosis. ERK1/2 are important signaling molecules regulating cellular growth and differentiation. The ERK1/2 signaling pathway is implicated in cardiac development and hypertrophy. However, the role of ERK1/2 in the development of atherosclerosis, particularly in macrophage cholesterol homeostasis, is unknown. In this study, we investigated the effects of ERK1/2 activity on macrophage ABCA1 expression and cholesterol efflux. Compared with a minor effect by inhibition of other kinases, inhibition of ERK1/2 significantly increased macrophage cholesterol efflux to apoAI and HDL. In contrast, activation of ERK1/2 reduced macrophage cholesterol efflux and ABCA1 expression. The increased cholesterol efflux by ERK1/2 inhibitors was associated with the increased ABCA1 levels and the binding of apoAI to cells. The increased ABCA1 by ERK1/2 inhibitors was due to increased ABCA1 mRNA and protein stability. The induction of ABCA1 expression and cholesterol efflux by ERK1/2 inhibitors was concentration-dependent. The mechanism study indicated that activation of liver X receptor (LXR) had little effect on ERK1/2 expression and activation. ERK1/2 inhibitors had no effect on macrophage LXR alpha/beta expression, whereas they did not influence the activation or the inhibition of the ABCA1 promoter by LXR or sterol regulatory element-binding protein (SREBP). However, inhibition of ERK1/2 and activation of LXR synergistically induced macrophage cholesterol efflux and ABCA1 expression. Our data suggest that ERK1/2 activity can play an important role in macrophage cholesterol trafficking.
基金:
National Institutes of Health Grant P01HL046403, the Julia and Gross Foundation, a 973 Basic Research Program of China Grant 2010CB945003,
Natural Science Foundation of China (NSFC) Grant 30971271, the Tianjin Municipal Science and Technology Commission of China (Grant 08ZCKFSH04400),
the Ministry of Science and Technology of China (Grant 2006AA02A408), the National Key Scientific Program of China (Grant 2007CB914801)
第一作者机构:[1]College of Life Sciences, Nankai University, Tianjin 300071, China,[4]Department of Neurobiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China,[5]Center of Vascular Biology and Department of Pathology, Weill Medical College of Cornell University, New York, New York 10065
通讯作者:
通讯机构:[*]Center of Vascular Biology, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10065
推荐引用方式(GB/T 7714):
Xiaoye Zhou,Zhinan Yin,Xianzhi Guo,et al.Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux[J].JOURNAL OF BIOLOGICAL CHEMISTRY.2010,285(9):6316-6326.doi:10.1074/jbc.M109.073601.
APA:
Xiaoye Zhou,Zhinan Yin,Xianzhi Guo,David P. Hajjar&Jihong Han.(2010).Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux.JOURNAL OF BIOLOGICAL CHEMISTRY,285,(9)
MLA:
Xiaoye Zhou,et al."Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux".JOURNAL OF BIOLOGICAL CHEMISTRY 285..9(2010):6316-6326