ABC transporters, atherosclerosis and inflammation

Abstract

Atherosclerosis, driven by inflamed lipid-laden lesions, can occlude the coronary arteries and lead to myocardial infarction. This chronic disease is a major and expensive health burden. However, the body is able to mobilize and excrete cholesterol and other lipids, thus preventing atherosclerosis by a process termed reverse cholesterol transport (RCT). Insight into the mechanism of RCT has been gained by the study of two rare syndromes caused by the mutation of ABC transporter loci. In Tangier disease, loss of ABCA1 prevents cells from exporting cholesterol and phospholipid, thus resulting in the build-up of cholesterol in the peripheral tissues and a loss of circulating HDL. Consistent with HDL being an athero-protective particle, Tangier patients are more prone to develop atherosclerosis. Likewise, sitosterolemia is another inherited syndrome associated with premature atherosclerosis. Here mutations in either the ABCG5 or G8 loci, prevents hepatocytes and enterocytes from excreting cholesterol and plant sterols, including sitosterol, into the bile and intestinal lumen. Thus, ABCG5 and G8, which from a heterodimer, constitute a transporter that excretes cholesterol and dietary sterols back into the gut, while ABCA1 functions to export excess cell cholesterol and phospholipid during the biogenesis of HDL. Interestingly, a third protein, ABCG1, that has been shown to have anti-atherosclerotic activity in mice, may also act to transfer cholesterol to mature HDL particles. Here we review the relationship between the lipid transport activities of these proteins and their anti-atherosclerotic effect, particularly how they may reduce inflammatory signaling pathways. Of particular interest are recent reports that indicate both ABCA1 and ABCG1 modulate cell surface cholesterol levels and inhibit its partitioning into lipid rafts. Given lipid rafts may provide platforms for innate immune receptors to respond to inflammatory signals, it follows that loss of ABCA1 and ABCG1 by increasing raft content will increase signaling through these receptors, as has been experimentally demonstrated. Moreover, additional reports indicate ABCA1, and possibly SR-BI, another HDL receptor, may directly act as anti-inflammatory receptors independent of their lipid transport activities. Finally, we give an update on the progress and pitfalls of therapeutic approaches that seek to stimulate the flux of lipids through the RCT pathway.

Figure 1. ABC transporters and lipoprotein metabolism

Cells and organisms use lipoproteins to move hydrophobic lipid molecules, which are not water soluble, through the aqueous environment of the blood and tissue lymph. Lipoprotein particles are defined by their complement of associated apolipoproteins and their content of cholesterol (CHOL), triglyceride (TG) and phospholipid that each particle carries. This protein and lipid content defines the particles buoyant density and subdivides them into 4 major classes: High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Very Low Density Lipoprotein (VLDL), and chylomicrons. HDL is form by the transfer of cholesterol and phospholipids onto apolipoproteinA-I (apoA-I) to generate preβ-HDL. This process is catalyzed by the ABCA1 transporter, which is expressed in the peripheral tissues, intestine and liver. Lysolecithin Cholesterol Acyltransferase (LCAT) then esterifies the cholesterol in nascent preβ-HDL as part of the process that generates mature spherical HDL. ABCG1 is another ABC transporter that is able to load more cholesterol onto mature HDL from peripheral tissues and along with ABCA1 is important in allowing macrophages to efflux artery wall cholesterol, which prevents atherosclerotic vascular disease. HDL cholesteryl-esters are taken up by scavenger receptor BI (SRBI) in liver and after hydrolysis the resulting free cholesterol is metabolized to bile acids (BA). The bile acids, along with more free cholesterol, are excreted into the digestive tract via biliary secretion in a process that again utilizes ABC transporters (ABCG5/8, ABCB11, ABCB4, ABCC2). Conversely, in the small intestine, absorbed dietary fatty acids are converted into triglycerides (TG) and are packaged and secreted into the bloodstream as chylomicrons, a lipoprotein particle rich in TG and apoB-48. TG in this lipoprotein is rapidly hydrolyzed into free fatty acids by lipoprotein lipase (LPL), leading to the formation of chylomicron remnants (Chylo Remn), which are taken up by the liver via the apoE receptor (ApoER). Dietary cholesterol is also packaged into HDL particles by the action of ABCA1 and ABCG1, and as HDL circulates there is an increase in its apoC2 and apoE ratio due to apolipoprotein exchange between HDL and VLDL. Cholesteryl ester from HDL is also transferred to VLDL remnant particles (IDL) by the action of cholesteryl ester transfer protein (CETP). IDL looses most of apolipoprotein except apoB and is converted to LDL by the action of hepatic lipase (LIPC). Finally, liver and other tissues take up LDL by an endocytotic process that involves the LDL receptor (LDLR). In humans, mutation of the LDL receptor leads to elevated plasma LDL levels (hypercholesterolemia), whereas mutation of ABCA1 ablates circulating HDL (Tangier disease). Mutations of ABCG5 or ABCG8 leads to the sitosterolemia, which is characterized by elevated levels of circulating cholesterol and dietary plant sterols.

Figure 2. Anti-inflammatory properties of HDL and ABC transporters

Bacterial sepsis can lead to the systemic circulation of microbial cell wall constituents such as lipopolysaccaride (LPS). This leads to an acute inflammatory response and a remodeling of HDL particles with serum amyloid A (SAA) displacing apoA-I. It has long been appreciated that HDL can play an anti-inflammatory role by binding circulating LPS and blocking its ability to trigger innate immune signaling cascades mediated by the CD14/MD2/Toll like Receptor 4 complex. However, more recent data indicates ABCA1 and ABCG1 mediate additional mechanisms by which these transporters can inhibit TLR4 signaling. Through their lipid transport activity ABCA1 and ABCG1 can reduce cell surface lipid rafts, and as a consequence inhibit TLR4 signal transduction, presumably because the formation and clustering of the CD14/MD2/TLR4 complex depends upon these lipid microdomains. Moreover, triggered by the binding of lipid poor apoA-I released by remodeled HDL particles, ABCA1 may directly act as a receptor by binding Janus kinase 2 (JAK2) and the transcriptional factor STAT3, which inhibits downstream signaling steps that macrophages use to express and secrete inflammatory cytokines. However, not all anti-inflammatory properties of the RCT process can be ascribed to the activity of ABCA1 and ABCG1 since scavenger receptor BI (SR-BI) expressed in macrophages and in adrenal tissues has also been reported to protect against endotoxemia by respectively inhibiting TLR4 signaling and stimulating glucocorticoid production (GC).