ATP-binding membrane cassette transporter A1 (ABCA1): a possible link between inflammation and reverse cholesterol transport

Abstract

Atherosclerosis is characterized by a chronic inflammatory condition that involves numerous cellular and molecular inflammatory components. A wide array of inflammatory mediators, such as cytokines and proteins produced by macrophages and other cells, play a critical role in the development and progression of the disease. ATP-binding membrane cassette transporter A1 (ABCA1) is crucial for cellular cholesterol efflux and reverse cholesterol transport (RCT) and is also identified as an important target in antiatherosclerosis treatment. Evidence from several recent studies indicates that inflammation, along with other atherogenic-related mediators, plays distinct regulating roles in ABCA1 expression. Proatherogenic cytokines such as interferon (IFN)-γ and interleukin (IL)-1β have been shown to inhibit the expression of ABCA1, while antiatherogenic cytokines, including IL-10 and transforming growth factor (TGF)-β1, have been shown to promote the expression of ABCA1. Moreover, some cytokines such as tumor necrosis factor (TNF)-α seem to regulate ABCA1 expression in species-specific and dose-dependent manners. Inflammatory proteins such as C-reactive protein (CRP) and cyclooxygenase (COX)-2 are likely to inhibit ABCA1 expression during inflammation, and inflammation induced by lipopolysaccharide (LPS) was also found to block the expression of ABCA1. Interestingly, recent experiments revealed ABCA1 can function as an antiinflammatory receptor to suppress the expression of inflammatory factors, suggesting that ABCA1 may be the molecular basis for the interaction between inflammation and RCT. This review aims to summarize recent findings on the role of inflammatory cytokines, inflammatory proteins, inflammatory lipids, and the endotoxin-mediated inflammatory process in expression of ABCA1. Also covered is the current understanding of the function of ABCA1 in modulating the immune response and inflammation through its direct and indirect antiinflammatory mechanisms including lipid transport, high-density lipoprotein (HDL) formation and apoptosis.

Figure 1

The primary mechanisms through which ABCA1 has protective effects on macrophage inflammatory response induced by LPS and cytokines. In one way, the cholesterol export activity of ABCA1 could account for its potent antiinflammatory properties. ABCA1-mediated cholesterol efflux disrupts lipid raft membrane microdomains and results in a significant redistribution of cholesterol from rafts to nonrafts via its ATPase-related functions, which in turn activates the ADAM17-dependent cleaving of several transmembrane proteins, including TNF and TNF receptors (TNFR). Furthermore, ABCA1-mediated cholesterol efflux decreased cell membrane LPS-mediated inflammatory signal, such as Toll-like receptor 4 (TLR4), which inhibits the MyD88-mediated activation of MAPK, which then enhanced the expression of proinflammatory cytokines, revealing the suppression role of ABCA1 for LPS-mediated inflammatory signal pathways in macrophages. In another way, ABCA1 can function as a direct antiinflammatory receptor. The interaction of apoA-I with ABCA1-expressing macrophage dramatically increased phosphorylation of JAK2 and thus activates JAK2. The activated JAK2 further activates STAT3, which is independent of the lipid transport function of ABCA1. Two candidate STAT3 docking sites contained in ABCA1 are required for the apoA-I/ABCA1/JAK2 phosphorylation of STAT3. The activated STAT3 further suppressed the ability of LPS to induce the inflammatory cytokines in macrophages.