Abstract 619: A Role for Macrophage Lipopolysaccharide Binding Protein in Atherosclerosis Development

Abstract

Introduction: The liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate sterol metabolism and inflammation. Knockout of LXRs in macrophages greatly accelerates the development of atherosclerosis whereas pharmacological LXR activation has potent athero-protective effects. Previous studies have shown that deletion of LXR target genes in hematopoietic cells can have opposing effects on atherosclerosis development. For example, deletion of ABCA1 using bone marrow transfer in atherogenic mouse models showed increases atherosclerotic plaque burden where as knockout studies of ABCG1 and Aim1 decreased lesion formation in bone marrow transplantation experiments owing to an increase in macrophage apoptosis. Rationale: We sought to identify previously unknown genes regulated by LXRs in macrophages and to determine their contribution to atherogenesis. Methods & Results: We demonstrate that the lipopolysaccharide binding protein (LBP), a secreted glycoprotein, is an LXR target gene in macrophages. Treatment of mouse peritoneal macrophages with modified LDL or oxysterols induces LBP expression, an effect that was lost in LXRαβ-/- macrophages, consistent with a role for LBP in the cellular response to cholesterol overload. To investigate this further, we performed bone marrow transplant studies using WT or LBP-/- donors and LDLR-/- recipients. After 18 weeks of western diet feeding atherosclerotic lesion burden was assessed by en face and aortic root section analysis. LDLR-/- mice receiving LBP-/- bone marrow had markedly smaller lesions compared to those receiving WT (P<0.0001 in en face analysis; P<.01 in root section analysis). Furthermore, loss of bone marrow LBP expression led to a strong increase in apoptosis in atherosclerotic lesions as determined by TUNEL staining. In vitro studies with isolated macrophages and stable cell lines showed that LBP expression does not affect cholesterol efflux but promotes the survival of macrophages in the setting of cholesterol loading. Conclusions: The LBP gene is a macrophage LXR target that promotes foam cell survival and atherogenesis. Our study identifies LBP as a potential diagnostic and therapeutic target in human cardiovascular disease.