Background: Liver X receptor alpha (Lxr alpha) 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 Lxr alpha target gene. We hypothesized that the LXR response element (LXRE) sequence on the murine macrophage Arl7 promoter may play a critical role in Lxr alpha's atherosuppressive effects. Methods: Employing low density lipoprotein receptor-deficient mice with macrophage-specific Lxr alpha overexpression (Ldlr(-)(/-) M Phi-Lxr alpha), we constructed a novel in vivo Ldlr(-)(/-) M Phi-Lxr alpha Arl7(MutLXRE) model possessing macrophage-specific mutations within the Arl7 promoter LXRE sequences (Arl7(Mut)(LXRE)) 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(-/-) M Phi-Lxr alpha, and Ldlr(-)(/-) M Phi-Lxr alpha Arl7(MutLXRE) mice on a 60% high-fat diet displayed no significant differences in body weight, fat mass, glucose homeostasis, or lipid metabolism. Macrophage Lxr alpha promoted Arl7 expression, enhanced cholesterol efflux, and reduced foam cell formation in an Arl7 ME-dependent manner. In contrast, Lxr alpha reduced macrophage activation, inflammatory cytokine expression, and efferocytosis independent of Arl7 LXRE. Western diet-fed Ldlr(-)(/-) mice reconstituted with transgenic BMDMs revealed that macrophage Lxr alpha reduced atherosclerotic plaque formation independent of Arl7 LXRE. Conclusion: Lxr alpha's anti-atherosclerotic effects in Ldlr(-)(/-) mice are not primarily attributable to Lxr alpha's influence on Arl7 expression. This evidence suggests that Lxr alpha's effects on plaque inflammation may be more critical to in vivo atherogenesis than its effects on macrophage cholesterol efflux and foam cell development. (C) 2020 Elsevier Inc. All rights reserved.