Effect of Macrophage Overexpression of Murine Liver X Receptor -α ( LXR -α) on Atherosclerosis in LDL-Receptor Deficient Mice

Abstract

Background-The nuclear liver X receptor-␣ (LXR-␣) has been implicated in the regulation of intracellular cholesterol homeostasis, inflammatory response, and atherosclerosis susceptibility. The aim of the present study was to test whether transgenic expression of LXR-␣ might affect these mechanisms and result in a reduction of atherosclerosis. Methods and Results-We generated mice with macrophage overexpression of mouse LXR-␣, evidenced by significantly elevated expression levels of LXR-target genes (ABCA1, ABCG1) in these cells. For atherosclerosis studies, mice were crossed onto the LDL-receptor deficient background. Plasma lipids and lipoproteins as well as liver triglycerides were not significantly different between transgenic animals and nontransgenic controls. However, lesion area at the brachiocephalic artery (BCA) was significantly reduced (Ϫ83%, Pϭ0.02) in male LXR-␣ transgenic mice. This was associated with a significantly increased cholesterol efflux to acceptor-free media (ϩ24%, Pϭ0.002) and ApoA1 containing media (ϩ20%, PϽ0.0001) as well as reduced lipopolysaccharide (LPS)-induced NO-release from macrophages of transgenic animals, providing a potential mechanism for the reduction of atherosclerosis. Conclusion-Our data show for the first time that transgenic overexpression of LXR-␣ in macrophages has significant antiatherogenic properties. We conclude that overexpression of LXR-␣ in macrophages might be useful as a therapeutic principle for the prevention of atherosclerosis. (Arterioscler

Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice

“…It is unclear as to what caused these anatomical and gender differences in their study. Furthermore, unlike our study, these investigators did not observe a significant difference in plasma triglycerides between transgenic animals and non-transgenic controls, 25 presumably due to residual liver expression of the LXRa transgene in their experiments.…”

“…25 The authors generated transgenic mice with macrophage overexpression of LXRa driven by chicken lysozyme promoter and crossed them onto the LDLR À/À background. Atherosclerotic lesion area at the brachiocephalic artery was significantly reduced (83%) in these male LXRa transgenic mice, but not at aortic root and in female mice.…”

Macrophage Fatty-acid Synthase Deficiency Decreases Diet-induced Atherosclerosis

“…Thus, depletion of this pool through FAS deficiency disinhibits LXR␣ leading to its increased expression. LXR␣ activation with synthetic agonists in mice decreases atherosclerosis (47); transplanting mice with LXR-deficient marrow increases atherosclerosis (48), and macrophage overexpression of LXR␣ in transgenic mice decreases atherosclerosis (49). These effects are mediated in part through ABCA1.…”

The macrophage LBP gene is an LXR target that promotes macrophage survival and atherosclerosis

“…At least in part, the atheroprotective properties of LXR agonists are derived from effects on hematopoietic cells (21)(22)(23). LXRs prevent foam cell formation in macrophages by enhancing cholesterol effl ux and reverse cholesterol transport in addition to their potent anti-infl ammatory effects.…”