Transgenic CGI-58 expression in macrophages alleviates the atherosclerotic lesion development in ApoE knockout mice

• Transgenic overexpression of CGI-58 in macrophages is atheroprotective in Apo E−/− mice.
• CGI-58 transgene in macrophages enhances in vitro cellular cholesterol efflux.
• CGI-58 transgene inhibits macrophage inflammatory responsiveness.

Comparative Gene Identification-58 (CGI-58), as an adipose triglyceride lipase (ATGL) activator, strongly increases ATGL-mediated triglyceride (TG) catabolism. Previous studies have shown that CGI-58 affects intestinal cholesterol homeostasis independently of ATGL activity. Therefore, we hypothesized that CGI-58 was involved in macrophage cholesterol metabolism and consequently atherosclerotic lesion formation. Here, we generated macrophage-specific CGI-58 transgenic mice (Mac-CGI-58 Tg) using an SRA promoter, which was further mated with ApoE−/− mice to create litters of CGI-58 Tg/ApoE−/− mice. These CGI-58 Tg/ApoE−/− mice exhibited an anti-atherosclerosis phenotype compared with wild type (WT) controls (CGI-58 WT/ApoE−/−), illustrated by less plaque area in aortic roots. Moreover, macrophage-specific CGI-58 overexpression in mice resulted in up-regulated levels of plasma total cholesterol and HDL-cholesterol. Consequently, higher expression levels of PPARa, PPARγ, LXRα, ABCA1, and ABCG1 were detected in macrophages from CGI-58 Tg/ApoE−/− mice compared to CGI-58 WT/ApoE−/− counterparts, which were accompanied by elevated macrophage cholesterol efflux toward HDL and Apo A1. Nevertheless, serum levels of TNF-α and IL-6 were reduced by macrophage-specific CGI-58 overexpression. Finally, bone marrow (BM) transplantation experiments further revealed that ApoE−/− mice reconstituted with Mac-CGI-58 Tg BM cells (ApoE−/−/Tg-BM chimera) displayed a significant reduction of atherosclerosis lesions compared with control mice reconstituted with Mac-CGI-58 WT BM cells (ApoE−/−/WT-BM chimera). Collectively, these data strongly suggest that CGI-58 overexpression in macrophages may protect against atherosclerosis development in mice.