Macrophage Lxrα reduces atherosclerosis in Ldlr^-/- mice independent of Arl7 transactivation.

BACKGROUND:Liver X receptor alpha (Lxrα) is a sterol-regulated transcription factor that limits atherogenesis by regulating cholesterol homeostasis and inflammation in macrophages. Transcriptional profiling identified the reverse cholesterol transport protein Arf-like 7 (Arl7, Arl4c) as a Lxrα target gene. We hypothesized that the LXR response element (LXRE) sequence on the murine macrophage Arl7 promoter may play a critical role in Lxrα's atherosuppressive effects. METHODS:Employing low density lipoprotein receptor-deficient mice with macrophage-specific Lxrα overexpression (Ldlr^-/- MΦ-Lxrα), we constructed a novel in vivo Ldlr^-/- MΦ-Lxrα Arl7^MutLXRE model possessing macrophage-specific mutations within the Arl7 promoter LXRE sequences (Arl7^MutLXRE) using the CRISPR/spCas9 genome editing technique. In vitro and in vivo transplantation studies were conducted using bone marrow-derived macrophages (BMDMs) and peritoneal macrophages (PMs). RESULTS:Ldlr^-/-, Ldlr^-/- MΦ-Lxrα, and Ldlr^-/- MΦ-Lxrα Arl7^MutLXRE mice on a 60% high-fat diet displayed no significant differences in body weight, fat mass, glucose homeostasis, or lipid metabolism. Macrophage Lxrα promoted Arl7 expression, enhanced cholesterol efflux, and reduced foam cell formation in an Arl7 LXRE-dependent manner. In contrast, Lxrα reduced macrophage activation, inflammatory cytokine expression, and efferocytosis independent of Arl7 LXRE. Western diet-fed Ldlr^-/- mice reconstituted with transgenic BMDMs revealed that macrophage Lxrα reduced atherosclerotic plaque formation independent of Arl7 LXRE. CONCLUSION:Lxrα's anti-atherosclerotic effects in Ldlr^-/- mice are not primarily attributable to Lxrα's influence on Arl7 expression. This evidence suggests that Lxrα's effects on plaque inflammation may be more critical to in vivo atherogenesis than its effects on macrophage cholesterol efflux and foam cell development. Copyright © 2020 Elsevier Inc. All rights reserved.

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