Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux

Abstract

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␣/␤ 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.Development of atherosclerotic lesions in coronary arteries is an underlying cause of coronary heart disease. Lipid-laden macrophage/foam cells are a prominent part of atherosclerotic lesions (1). Cellular cholesterol content in macrophages is determined by uptake and efflux of cholesterol (2). The type A scavenger receptor and type B scavenger receptor (CD36) mediate the binding and internalization of modified low density lipoprotein (LDL), 3 thus, demonstrating pro-atherogenic properties (3, 4). In contrast, type BI scavenger receptor and ATPbinding cassette transporter A1 (ABCA1) can mediate cellular free cholesterol efflux to extracellular high density lipoprotein (HDL) or lipid-free apolipoprotein AI (apoAI) thereby inhibiting the development of atherosclerosis (5, 6). Compared with bi-directional cholesterol transport across cellular membranes that are mediated by type BI scavenger receptor (7, 8), ABCA1 stimulates free cholesterol efflux from macrophages and other peripheral cell types to apoAI and/or HDL by using the energy from ATP hydrolysis (9). The binding of free cholesterol and phospholipids to apoAI also leads to the generation of nascent HDL (10). ABCA1 can also mediate cholesterol efflux to exog...

Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI

“…In contrast, Erk1/2 inhibition and LXR activation synergistically induce macrophage ABCA1 expression and efflux (27). Another study recently implicated Mek1/2 in the regulation of PPAR␥-and LXR␤-dependent ABCA1 protein degradation in HepG2 cells (28).…”

“…First, enhanced Erk1/2 signaling increases ABCA1 expression and ABCA1-mediated phospholipid efflux via upregulation of PPAR␣ levels in lung epithelial cells (26). Second, inhibition of Erk1/2 and activation of LXR synergistically induce macrophage ABCA1 expression and cholesterol efflux (27). Third, Mek1/2 inhibition is involved in the regulation of PPAR␥-and LXR␤-dependent ABCA1 protein degradation in HepG2 cells (28).…”

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

“…In general, the SREBP transcriptional regulator proteins activate genes for cholesterol synthesis and influx, and the Liver X Receptor, (LXR) nuclear receptors activate cholesterol efflux; however, both also regulate different aspects of fatty acid metabolism (Abildayeva et al, 2006;Wang et al, 2008b;Raychaudhuri and Prinz, 2010). LXR pathways activate the apo-protein carriers such as APOAI, APOE, and the transporters such as the ATP binding cassette proteins ABC-A1, -G1, -G4, and SRBI, through which efflux proceeds to mature High density Lipoprotein, (HDL) (Tall, 2008;Zhou et al, 2010). LXR targets can be activated by oxysterols derived from the cholesterol pathway, by fatty acids, or by cross regulation from other nuclear receptors such as the steroid and xenobiotic receptor, SXR (Abildayeva et al, 2006;Tamehiro et al, 2007;Wang et al, 2008b;Zhou et al, 2009).…”

Ezetimibe suppresses cholesterol accumulation in lipid-loaded vascular smooth muscle cells in vitro via MAPK signaling

“…ERK1/2 and p44/42 mitogen-activated protein kinases (p44/42 MAPK) belong to a highly conserved family of Ser-Thr protein kinases. The role of ERK1/2 in the development of atherosclerosis was described in a previous study [43] . Inhibition of ERK1/2 significantly increases www.nature.com/aps Qin L et al Acta Pharmacologica Sinica npg cellular cholesterol efflux, which suggests that ERK1/2 activity is closely linked to cholesterol trafficking [43] .…”

“…The role of ERK1/2 in the development of atherosclerosis was described in a previous study [43] . Inhibition of ERK1/2 significantly increases www.nature.com/aps Qin L et al Acta Pharmacologica Sinica npg cellular cholesterol efflux, which suggests that ERK1/2 activity is closely linked to cholesterol trafficking [43] . Once phosphorylated, ERK becomes an active kinase that translocates to the nucleus, where it has been shown to regulate the transcription of target genes.…”