Increased ABCA1 activity protects against atherosclerosis

Abstract

is the chair of the scientific advisory board of Xenon Genetics Inc. Nonstandard abbreviations used: HDL cholesterol (HDL-C); adenosine triphosphate-binding cassette transporter A1 (ABCA1); bacterial artificial chromosome (BAC); oil red O (ORO); acyl-CoA:cholesterol O-acyltransferase (ACAT); coronary artery disease (CAD). Online first publication increased deposition of cholesteryl esters in several tissues and cells, most notably in macrophages (13). A 50% reduction in ABCA1 activity is associated with a significant decrease in plasma HDL-C levels (14-16). To study the role of ABCA1 in HDL metabolism and atherosclerosis, we have developed human ABCA1 overexpressing bacterial artificial chromosome (BAC) transgenic mice that show increased total plasma cholesterol and HDL-C levels and increased ApoA-I and ApoA-II levels (17), associated with increased cholesterol efflux from macrophages. We hypothesized that increasing ABCA1 activity would be associated with reduced atherosclerotic lesion formation. ApoE-/mice have been used extensively to study atherogenesis. These mice spontaneously develop severe atherosclerosis, with complex lesions that include a fibrous cap in mice as young as 15 weeks of age. Because of its validation and acceptance as a model to study factors influencing atherogenesis, we chose to test the effect of ABCA1 overexpression on atherosclerosis development, macrophage cholesterol efflux, and HDL composition in this model.

Identification of an Apolipoprotein A-I Structural Element That Mediates Cellular Cholesterol Efflux and Stabilizes ATP Binding Cassette Transporter A1

“…Mutations in ABCA1 abolish the ability of apoA-I to mediate phospholipid and cholesterol efflux from cells producing HDL deficiency and premature atherosclerosis (8 -13). Targeted disruption of ABCA1 in mice produces a phenotype similar to human Tangier disease (14,15), whereas overexpression of ABCA1 protects against atherosclerosis in mice (16,17). These findings underscore the importance of apoA-I/ABCA1 interactions in heart disease protection.…”

Diabetic dyslipidaemia: from basic research to clinical practice*

“…The discovery of PPAR-α as the target of fibrate action has opened a renaissance for fibrates to correct the key lipoprotein abnormalities of diabetic dyslipidaemia [169]. The activation of both PPARs α and γ seems to promote the expression of ABCA1 gene via LXR activation and consequently enhance the reverse cholesterol transport [170,171]. This action explains the consistent increase of HDL cholesterol induced by thiazolidinediones (TZDs) [172].…”

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

“…In humans, mutations in ABCA1 expression cause Tangier disease, which is characterized by very low levels of serum HDL cholesterol, rapid catabolism of apoAI, severe cholesteryl ester accumulation in peripheral tissues, and a high risk of development of coronary heart disease (14 -16). In animal models, overexpression of human ABCA1 reduces total cholesterol levels and atherosclerosis, whereas selective suppression of macrophage ABCA1 increases atherosclerosis without affecting total cholesterol levels (1,6,17,18). …”

“…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).…”