Lipopolysaccharide Augments Foam Cell Formation through the Downregulation of ABCG1 in Murine Macrophages: Role of ERK1/2 Signaling

Abstract

Bacterial lipopolysaccharide (LPS) has been reported to suppress the expression of ATP-binding cassette transporter G1 (ABCG1), a molecule facilitating cholesterol efflux, in macrophages and augmented the formation of foam cells, a critical step in the pathogenesis of atherosclerosis. The essential role of MAP kinases in ABCG1 expression in macrophage and foam cell formation is also reported. However, the role of MAP kinases in LPS-induced downregulation of ABCG1 is still unknown. Therefore, this study aimed to examine whether the overexpression of ABCG1 could attenuate the foam cell formation augmented by LPS and to explore the role of MAP kinase pathways in LPS-induced downregulation of ABCG1. In RAW 264.7 macrophages, LPS stimulation time- and dose-dependently reduced the expression of ABCG1 without affecting ABCA1. Moreover, the overexpression of ABCG1 significantly reduced the foam cell formation augmented by LPS. Although LPS induced the activation of MAP kinases (p38, JNK1/2, ERK1/2), AP1 (c-FOS/JUN), and NF-kB signaling molecules, a specific ERK1/2 inhibitor (U0128) effectively inhibited the downregulation of ABCG1 mediated by LPS. In addition, transient knockdown of ERK1/2 by small interference RNA similarly prevented the downregulation of ABCG1 mediated by LPS. Furthermore, we confirmed that T0901317, a specific agonist of the Liver X receptor, reduced LPS-induced downregulation of ABCG1 and partly inhibited the activation of ERK1/2 mediated by LPS. Overall, our study suggests that ERK1/2 signaling plays a crucial role in LPS-induced downregulation of ABCG1, which may be further implicated in atherogenic foam cell formation. Additional in vivo and in vitro studies are certainly warranted to gain a deeper understanding of these effects.