Abstract 10658: Activation of the Liver X Receptor Decreases Atherosclerosis in LDLr-/- Mice in the Absence of ATP-Binding Cassette Transporters A1 and G1 in Myeloid Cells
Objective- Liver X Receptor (LXR) activation consistently decreases atherosclerosis in mice, however it also causes induction of lipogenic genes and hepatic steatosis. Properties of LXR activation that may contribute to its anti-atherogenic effects are (1) direct upregulation of genes involved in reverse cholesterol transport (RCT) and (2) anti-inflammatory effects mediated by transrepression of NFkB target genes. While (1) is known to be anti-atherogenic, it is unknown whether (2) is anti-atherogenic. We investigated whether myeloid cell deficiency of ATP-binding cassette transporters A1 and G1 (ABCA1/G1), principal targets of LXR that promote cholesterol efflux and initiate RCT, would abolish the beneficial effects of LXR activation on atherosclerosis.
Methods & Results- Ldlr-/- mice were transplanted with Abca1-/-Abcg1-/- or wild-type bone marrow (BM) and fed Western diet for 6 weeks with or without LXR activator TO901317 (10mg/kg). The Abca1-/-Abcg1-/- group showed increased atherosclerotic lesion area (64012 ± 10043 vs 42238 ± 8410 μm2, Abca1-/-Abcg1-/- vs wild-type), as well as infiltration of inflammatory cells into the adventitia compared to wild-type. TO901317 decreased this phenotype. In addition, LXR activation decreased atherosclerotic lesion size in wild-type (42238 ± 8410 vs 34783 ± 4830 μm2, wild-type ctrl vs LXR) and Abca1-/-Abcg1-/- BM transplanted mice (64012 ± 10043 vs 25281 ± 8814 μm2, Abca1-/-Abcg1-/- ctrl vs LXR; P<0.01) without decreasing plasma cholesterol or blood monocyte and neutrophil counts in Abca1-/-Abcg1-/- BM transplanted mice. Unlike in controls, TO901317 failed to increase cholesterol efflux in macrophages lacking ABCA1/G1 (Mac-Abca1/g1KO) in vitro. In addition, TO901317 decreased inflammatory gene expression (TNF-α, 36%, MIP-1α, 67%, and IL-6, 55% (all P<0.01)) in Mac-Abca1/g1KO cells.
Conclusions- The results suggest that anti-inflammatory effects of LXR are of key importance to its anti-atherosclerotic effects in vivo independent of ABCA1/G1 in macrophages. Thus selective LXR activators that mediate inflammatory transrepression without direct targeting of cholesterol efflux and lipogenic genes would retain anti-atherogenic properties but lack the adverse effect of hepatic steatosis.
- © 2011 by American Heart Association, Inc.