title: Transgenic CGI-58 expression in macrophages alleviates the atherosclerotic lesion development in ApoE knockout mice.
abstract: Comparative Gene Identification-58 (CGI-58), as an adipose triglyceride lipase (ATGL) activator, strongly in- creases 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 upregulated 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Xu
authors.initials: X
authors.lastname: Zeng
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D001692:Biological Transport; D001854:Bone Marrow Cells / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D015203:Reproducibility of Results; D019076:Transgenes
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D003094:Collagen; D002784:Cholesterol; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C492986:Abhd5 protein, mouse