Regulation of ABCA1 functions by signaling pathways

Abstract

ATP-binding cassette transporter A1 (ABCA1) is an integral cell membrane protein that protects cardiovascular disease by at least two mechanisms: by export of excess cholesterol from cells and by suppression of inflammation. ABCA1 exports cholesterol and phospholipids from cells by multiple steps that involve forming cell surface lipid domains, binding of apolipoproteins to ABCA1, activating signaling pathways, and solubilizing these lipids by apolipoproteins. ABCA1 executes its anti-inflammatory effect by modifying cell membrane lipid rafts and directly activating signaling pathways. The interaction of apolipoproteins with ABCA1 activates multiple signaling pathways, including Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3), protein kinase A, Rho family G protein CDC42 and protein kinase C. Activating protein kinase A and Rho family G protein CDC42 regulates ABCA1-mediated lipid efflux, activating PKC stabilizes ABCA1 protein, and activating JAK2/STAT3 regulates both ABCA1-mediated lipid efflux and anti-inflammation. Thus, ABCA1 behaves both as a lipid exporter and a signaling receptor. Targeting ABCA1 receptor-like property using agonists for ABCA1 protein could become a promising new therapeutic target for increasing ABCA1 function and treating cardiovascular disease. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

Figure 1. Scheme for the apoA-I/ABCA1/JAK2/STAT3 pathway

Lipid-poor apoA-I or its mimetic peptides bind directly to ABCA1 or a closely associated protein (step 1) that rapidly stimulates JAK2 autophosphorylation (step 2). The activated JAK2 then has two distinct effects on the cells. First, it recruit and/or dissociate ABCA1 partner proteins and causes confirmation change of ABCA1, thus enhancing apoA-I binding to ABCA1 (step 3) and lipid removal from the cells (step 4). Second, it generates STAT3 docking sites and activates STAT3 (step 5), which promotes translocation of STAT3 to the nucleus (step 6) where it regulates transcription of proteins that repress inflammatory processes (step 7). P: Phosphorylated.