| First Author | Yin Y | Year | 2020 |
| Journal | Biochem Biophys Res Commun | Volume | 529 |
| Issue | 3 | Pages | 540-547 |
| PubMed ID | 32736671 | Mgi Jnum | J:304169 |
| Mgi Id | MGI:6694377 | Doi | 10.1016/j.bbrc.2020.06.071 |
| Citation | Yin Y, et al. (2020) Macrophage Lxralpha reduces atherosclerosis in Ldlr(-/-) mice independent of Arl7 transactivation. Biochem Biophys Res Commun 529(3):540-547 |
| abstractText | BACKGROUND: Liver X receptor alpha (Lxralpha) 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 Lxralpha target gene. We hypothesized that the LXR response element (LXRE) sequence on the murine macrophage Arl7 promoter may play a critical role in Lxralpha's atherosuppressive effects. METHODS: Employing low density lipoprotein receptor-deficient mice with macrophage-specific Lxralpha overexpression (Ldlr(-/-) MPhi-Lxralpha), we constructed a novel in vivo Ldlr(-/-) MPhi-Lxralpha 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(-/-) MPhi-Lxralpha, and Ldlr(-/-) MPhi-Lxralpha Arl7(MutLXRE) mice on a 60% high-fat diet displayed no significant differences in body weight, fat mass, glucose homeostasis, or lipid metabolism. Macrophage Lxralpha promoted Arl7 expression, enhanced cholesterol efflux, and reduced foam cell formation in an Arl7 LXRE-dependent manner. In contrast, Lxralpha reduced macrophage activation, inflammatory cytokine expression, and efferocytosis independent of Arl7 LXRE. Western diet-fed Ldlr(-/-) mice reconstituted with transgenic BMDMs revealed that macrophage Lxralpha reduced atherosclerotic plaque formation independent of Arl7 LXRE. CONCLUSION: Lxralpha's anti-atherosclerotic effects in Ldlr(-/-) mice are not primarily attributable to Lxralpha's influence on Arl7 expression. This evidence suggests that Lxralpha's effects on plaque inflammation may be more critical to in vivo atherogenesis than its effects on macrophage cholesterol efflux and foam cell development. |
